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Background Gastric cancer is worldwide the fourth more common cancer type by incidence, and the third by mortality. We analyzed three missense variants of TAS2R38 gene: rs713598 (A49P), rs1726866 (V262A), and rs10246939 (I296V). These variants and their combination in haplotypes (proline, alanine and valine/tasters or alanine, valine and isoleucine/nontasters) and diplotypes are responsible for individual differences in bitter perception. The single-nucleotide polymorphisms and the related phenotypes are known to be associated with susceptibility to Gram-negative bacterial infections, such as Helicobacter pylori, and with risk of various cancer types. An association between intermediate tasters (as defined by TAS2R38 diplotypes) and increased risk of gastric cancer was reported in a Korean population. Methods We analyzed 2616 individuals of Latin American origin, representing the whole spectrum of lesions from gastritis to gastric cancer. Results Comparing cancer cases vs. noncancers we observed a decrease in risk associated with heterozygous carriers of rs10246939 (P = 0.006) and rs1726866 (P = 0.003) when compared with homozygotes of the more common allele. Also, the analysis of diplotypes/phenotypes reflected the same association, with super-tasters showing a borderline increased risk of developing gastric cancer compared to medium-tasters [odds ratio (OR) = 1.63; 95% confidence interval (CI), 1.04-2.56; P = 0.033]. Also, nontasters showed an increased risk when compared to medium-tasters although not reaching statistical significance (OR = 1.58; 95% CI, 0.80-2.87; P = 0.203). We also tested the interactions between the TAS2R38 genotypes and H. pylori cagA status in a subset of samples and found no interaction. Conclusion In conclusion, our results suggest only a modest contribution of TAS2R38 gene genetic variability in gastric cancer etiology.

Anesthesia with propofol is frequently associated with hypotension. The TRPA1 gene contributes to the vasodilator effect of propofol. Hypotension is crucial for anesthesiologists because it is deleterious in the perioperative period. We tested whether the TRPA1 gene polymorphisms or haplotypes interfere with the hypotensive responses to propofol. PCR-determined genotypes and haplotype frequencies were estimated. Nitrite, nitrates, and NOx levels were measured. Propofol induced a more expressive lowering of the blood pressure (BP) without changing nitrite or nitrate levels in patients carrying CG+GG genotypes for the rs16937976 TRPA1 polymorphism and AG+AA genotypes for the rs13218757 TRPA1 polymorphism. The CGA haplotype presented the most remarkable drop in BP. Heart rate values were not impacted. The present exploratory analysis suggests that TRPA1 genotypes and haplotypes influence the hypotensive responses to propofol. The mechanisms involved are probably other than those related to NO bioavailability. With better genetic knowledge, planning anesthesia with fewer side effects may be possible.

Background: Severe spermatogenic failure (SPGF) represents one of the most relevant causes of male infertility. This pathological condition can lead to extreme abnormalities in the seminal sperm count, such as severe oligozoospermia (SO) or non-obstructive azoospermia (NOA). Most cases of SPGF have an unknown aetiology, and it is known that this idiopathic form of male infertility represents a complex condition. In this study, we aimed to evaluate whether common genetic variation in TEX15, which encodes a key player in spermatogenesis, is involved in the susceptibility to idiopathic SPGF. Materials and Methods: We designed a genetic association study comprising a total of 727 SPGF cases (including 527 NOA and 200 SO) and 1,058 unaffected men from the Iberian Peninsula. Following a tagging strategy, three tag singlenucleotide polymorphisms (SNPs) of TEX15 (rs1362912, rs323342, and rs323346) were selected for genotyping using TaqMan probes. Case-control association tests were then performed by logistic regression models. In silico analyses were also carried out to shed light into the putative functional implications of the studied variants. Results: A significant increase in TEX15-rs1362912 minor allele frequency (MAF) was observed in the group of SO patients (MAF = 0.0842) compared to either the control cohort (MAF = 0.0468, OR = 1.90, p = 7.47E-03) or the NOA group (MAF = 0.0472, OR = 1.83, p = 1.23E-02). The genotype distribution of the SO population was also different from those of both control (p = 1.14E-02) and NOA groups (p = 4.33–02). The analysis of functional annotations of the human genome suggested that the effect of the SO-associated TEX15 variants is likely exerted by alteration of the binding affinity of crucial transcription factors for spermatogenesis. Conclusion: Our results suggest that common variation in TEX15 is involved in the genetic predisposition to SO, thus supporting the notion of idiopathic SPGF as a complex trait., Spanish Ministry of Science and Innovation through the Spanish National Plan for Scientific and Technical Research and Innovation, Andalusian Government PID 2020-120157RB-I 00, Ministry of Science and Innovation, Spain (MICINN) Spanish Government PY20_00212 B-CTS-584-UGR20 MCIN/AEI IJC 2018-03802 6-I, European Commission FPU20/02926, Portuguese Foundation for Science and Technology, European Social Fund (ESF), National Funds, Portuguese Foundation for Science and Technology European Commission PEstC/SAU/LA0003/2013 POCI-01-0145-FEDER-007274 Portuguese State Budget of the Ministry for Science, Technology and High Education SFRH/BPD/120777/201 6 UID/BIM/00 009/2016 UIDB/00009/20 20, ToxOmics-Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, Nova Medical School, Lisbon, Instituto de Salud Carlos III European Commission FEDER funds/European Regional Development Fund (ERDF) DTS18/001 01, SNS-Dpt, Generalitat de Catalunya, SNS-Dpt. Salut Generalitat de Catalunya 2017SGR191 Exp. CES09/020

The study of genetic polymorphisms has significantly advanced the field of personalized medicine. Polymorphism of genes influence the efficacy of drugs used for treating medical conditions such as depression, cardiac diseases, thromboembolic disorders, oncological diseases, etc. The study of genetic polymorphism is beneficial for drug safety as well as for assessing therapeutic outcomes. Understanding and detecting genetic polymorphisms early on in patients can be useful in selecting the correct chemotherapeutic agent and appropriate dosage for a patient. Knowing the genetic profile of a patient and the interindividual response to various drugs significantly influences the proper selection of medication - a key step towards personalized medicine. Polymorphisms also make patients susceptible to certain cancers and identification of these polymorphisms early can be useful for a personalized treatment plan. The Genome-Wide Association Studies (GWAS) project where millions of genetic variants in the genomes of many individuals are studied to identify connections between what is present on the gene and the phenotype of the patient has enhanced the prospect of personalized medicine. GWAS has been used to identify hundreds of diseases associated to genetic polymorphisms. Individual pharmacokinetic profiles of patients to drugs enable the development of early surveillance protocols to prophylactically prevent patients from having adverse reactions. Furthermore, patient-derived cellular organoids are another advancement that allows researchers to screen for polymorphisms of the patient for adverse reactions from chemotherapy and will allow for the development of new medications that are specific to the profile of the patient's tumor. These advances have led to significant progress towards personalized medicine. The functional consequences of genetic polymorphism on cancer drugs and treatment are studied here.

The multifactorial nature of type 2 diabetes mellitus (T2D) was confirmed by numerous researches. The first investigations devoted to molecular-genetic mechanisms of T2D were carried out on the basis of linkage disequilibrium (LD) studying and later the candidate genes of T2D have begun investigated. We have analyzed the literature data including the case-control studies in populations of Russia. There were revealed 33 genes and 65 polymorphic markers in the analyzed works. The analysis of association of T2D in the ethnic groups of Russian Federation was carried out on following genes: ABCC8, ADIPOQ, ADIPOR1, ADIPOR2, C2CD4A/C2CD4A, CDKAL1, ­CDKN2A/2B, CCL11, CCL20, CCL5, CYBA, FABP2, FTO, GCLC, GPX2, GSTP1, GSTT1, HHEX/IDE, IGF2BP2, IRS1, KCNJ11, KCNQ1, LPL, LRP5, MC4R, PPARG, SLC2A2, SLC30A8, SLC30A8, TCF7L2, TMEM18, WFS1, ZFAND6. The major of studies are replicative, i.e. repeating previous investigations of foreign authors, and were performed on Russian, Tatar and Yakut populations. At the same time not all the loci of genetic susceptibility have demonstrated the association with T2D in the population of Russia. In this work the systematic review of studies of molecular-genetic markers of T2D in the ethnic groups of Russian Federation was made for the first time.

Trigonella foenum-graecum L. is a widely used herb in traditional medicine. The aim of this study was to evaluate the genetic polymorphisms in fenugreek plants following the treatment of fenugreek seeds with different combinations of biotic and abiotic agents using the random amplified polymorphic DNA (RAPD)-PCR technique. We assessed the effects of two strains of the fungus Trichoderma harzianum (Th-1 and Th-2), methyl jasmonate (MeJA), and Aloe vera gel (AVG) on growth parameters of fenugreek plants. Combinations of Th-1, MeJA, AVG significantly increased fenugreek root length, shoot length, shoot fresh weight, number of true leaves, and chlorophyll content. The Th-2 isolate, on the other hand, markedly slowed plant development (except for root length which was not affected significantly). In contrast, the combination with MeJA had no considerable effect on all growth measures, whereas the combination with VAG resulted in a substantial drop in shoot height and chlorophyll content when compared to other growth parameters that were unaffected. The present study has shown that the PCR amplification of DNA, using five primers for RAPD analysis, produced 62 DNA fragments that could be scored in all genotypes. The total number of polymorphic bands was 26, and the average percentage of polymorphism was 54.21%. The RAPD-PCR results showed that the treatment of fenugreek seeds with Th-1 alone or in combination with MeJA and AVG induced polymorphisms in fenugreek leaves.

Background: We conducted a comprehensive meta-analysis to explore the association of polymorphisms at XRCC1, XRCC2 and XRCC3 genes with susceptibility to thyroid cancer (TC). Methods: We searched PubMed, EMBASE, Web of Science, and CNKI for relevant available studies. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of the associations. Results: A total of 67 studies including 17 studies with 6,806 cases and 5,229 controls on XRCC1 Arg399Gln, 13 studies with 3,234 cases and 4,807 controls on XRCC1 Arg280His, 13 studies with 2,956 cases and 3,860 controls on XRCC1 Arg194Trp, five studies with 1,287 cases and 1,422 controls on XRCC2 Arg188His, 13 studies with 2,488 cases and 3,586 controls on XRCC3 Thr241Met, and six studies with 1,828 cases and 2,060 controls on XRCC3 IVS5-14 polymorphism were selected. Polled data revealed that the XRCC1 Arg399Gln, Arg280His, Arg194Trp, XRCC2 Arg188His and XRCC3 Thr241Met and IVS5-14 polymorphisms were not significantly associated with an increased risk of TC. Stratified analyses by ethnicity showed that the XRCC1 Arg399Gln polymorphism was associated with TC risk in Caucasians, but not in Asians. Conclusions: Our meta-analysis indicated that the XRCC1 Arg399Gln, Arg280His, Arg194Trp, XRCC2 Arg188His, XRCC3 Thr241Met and IVS5-14 polymorphisms were not associated with risk of TC in the global population. Further well-designed investigations with large sample sizes are required to confirm our results.

Background: Vitamin D deficiency has been associated with the severity of COVID-19. The role of vitamin D in pregnant women with COVID-19 has been poorly investigated to date. The aim of this study was to evaluate the influence of vitamin D in affecting some clinical features in pregnancy between SARS-CoV-2 positive and negative patients. Methods: Vitamin D pathway related polymorphisms and 25-hydroxyvitamin D levels were quantified in pregnant women followed from the first to the third trimester of pregnancy. Vitamin D deficiency was considered with values ≤ 30 ng/mL. Results: In total, 160 women were enrolled: 23 resulted positive for at least one SARS-CoV-2 related test (molecular swab or antibody tests). Vitamin D-associated polymorphisms were able to affect vitamin D levels in SARS-CoV-2 negative and positive subjects: remarkably, all the VDR TaqICC genotype patients were negative for SARS-CoV-2. In a sub-population (118 patients), vitamin D levels correlated with pregnancy-related factors, such as alpha-fetoprotein levels. Third-trimester vitamin D levels were lower in preterm births compared to full-term pregnancy: this trend was highlighted for SARS-CoV-2 positive patients. Conclusions: This is the first study demonstrating a role of vitamin D in affecting the clinical characteristics of pregnant women during the COVID-19 era. Further studies in larger and different cohorts of patients are required to confirm these findings.

X chromosomal short tandem repeats (X-STRs) have the characteristics of both autosomal and uniparental genetic markers and have been shown to be particularly useful in forensic casework. However, relevant research or reports have not focused on X-STRs in the Hani population. To investigate the genetic variation and forensic efficiency of 16 X-STR loci in the Hani ethnic minority, we calculated the allele frequencies and forensic parameters of 451 (116 males and 335 females) unrelated healthy Hani individuals from Yunnan Province, Southwest China. All these loci are highly polymorphic in Hani individuals in Yunnan Province except DXS6800. The combined power of discrimination in males (PDM) and power of discrimination in females (PDF) were found to be 0.999 999 998 433 993 and 0.999 999 999 999 998, respectively. Furthermore, a population genetic structure investigation between the Yunnan Hani population and another 18 populations was performed using a principal component analysis, multidimensional scaling plot and neighbouring-joining phylogenetic tree and the findings illustrated that neighbouring populations and different nationalities in the same area appeared to have a closer evolutionary relationship. This study provides the first batch of X chromosome genetic polymorphism data of the Hani population in Yunnan Province, Southwest China and enriches the reference database of the Chinese minority population. Key points This is the first study of X-STR in the Hani population. We calculated the allele frequencies and forensic parameters of 451 unrelated healthy Hani individuals from Yunnan Province, Southwest China. All these loci are highly polymorphic in Hani individuals in Yunnan Province except DXS6800. The genetic relationship between the Hani and the other 18 nationalities was analyzed. This study provides the first batch of X chromosome genetic polymorphism data of the Hani population in Yunnan Province, Southwest China and enriches the reference database of the Chinese minority population.

Objective Different genetic polymorphisms of human leukocyte antigen (HLA) have been associated with the risk and prognosis of autoimmune and infectious diseases. The objectives of this study were to determine whether there is an association between HLA genetic polymorphisms and the susceptibility to and mortality of coronavirus disease 2019 (COVID-19) patients. Design Observational and prospective study. Setting Eight Intensive Care Units (ICU) from 6 hospitals of Canary Islands (Spain). Patients COVID-19 patients admitted in ICU and healthy subjects. Interventions Determination of HLA genetic polymorphisms. Main variable of interest Mortality at 30 days. Results A total of 3886 healthy controls and 72 COVID-19 patients (10 non-survivors and 62 survivor patients at 30 days) were included. We found a trend to a higher rate of the alleles HLA-A*32 (p = 0.004) in healthy controls than in COVID-19 patients, and of the alleles HLA-B*39 (p = 0.02) and HLA-C*16 (p = 0.02) in COVID-19 patients than in healthy controls; however, all these p-values were not significant after correction for multiple comparisons. Logistic regression analysis showed that the presence of certain alleles was associated with higher mortality, such as the allele HLA-A*11 after controlling for SOFA (OR = 7.693; 95% CI = 1.063–55.650; p = 0.04) or APACHE-II (OR = 11.858; 95% CI = 1.524–92.273; p = 0.02), the allele HLA-C*01 after controlling for SOFA (OR = 11.182; 95% CI = 1.053–118.700; p = 0.04) or APACHE-II (OR = 17.604; 95% CI = 1.629–190.211; p = 0.02), and the allele HLA-DQB1*04 after controlling for SOFA (OR = 9.963; 95% CI = 1.235–80.358; p = 0.03). Conclusions The new finding from our preliminary study of small sample size was that HLA genetic polymorphisms could be associated with COVID-19 mortality; however, studies with a larger sample size before definitive conclusions can be drawn.

This study aimed to investigate the influence of genetic variants in neuroplasticity-related genes on antidepressant treatment phenotypes. The BDNF-TrkB signaling pathway, as well as the downstream kinases Akt and ERK and the mTOR pathway, have been implicated in depression and neuroplasticity. However, clinicians still struggle with the unpredictability of antidepressant responses in depressed patients. We genotyped 26 polymorphisms in BDNF, NTRK2, NGFR, CREB1, GSK3B, AKT, MAPK1, MTOR, PTEN, ARC, and SYN1 in 80 patients with major depressive disorder treated according to the Texas Medical Algorithm for 27 months at Hospital Magalhães Lemos, Porto, Portugal. Our results showed that BDNF rs6265, PTEN rs12569998, and SYN1 rs1142636 SNP were associated with treatment-resistant depression (TRD). Additionally, MAPK1 rs6928 and GSK3B rs6438552 gene polymorphisms were associated with relapse. Moreover, we found a link between the rs6928 MAPK1 polymorphism and time to relapse. These findings suggest that the BDNF, PTEN, and SYN1 genes may play a role in the development of TRD, while MAPK1 and GSK3B may be associated with relapse. GO analysis revealed enrichment in synaptic and trans-synaptic transmission pathways and glutamate receptor activity with TRD-associated genes. Genetic variants in these genes could potentially be incorporated into predictive models of antidepressant response.

Harmful alcohol consumption has been considered a major public health issue globally, with the amounts of alcohol drunk being highest in the WHO European Region including Hungary. Alcohol consumption behaviors are complex human traits influenced by environmental factors and numerous genes. Beyond alcohol metabolization and neurotransmitter gene polymorphisms, taste preference-related genetic variants may also mediate alcohol consumption behaviors. Applying the Alcohol Use Disorders Identification Test (AUDIT) we aimed to elucidate the underlying genetic determinants of alcohol consumption patterns considering taste preference gene polymorphisms (TAS1R3 rs307355, TAS2R38 rs713598, TAS2R19 rs10772420 and CA6 rs2274333) in the Hungarian general (HG) and Roma (HR) populations. Alcohol consumption assessment was available for 410 HG and 387 HR individuals with 405 HG and 364 HR DNA samples being obtained for genotyping. No significant associations were found between TAS1R3 rs307355, TAS2R19 rs10772420, and CA6 rs2274333 polymorphisms and alcohol consumption phenotypes. Significant associations were identified between TAS2R38 rs713598 and the number of standard drinks consumed in the HG sample (genotype GG negatively correlated with the number of standard drinks; coef: −0.136, p = 0.028) and the prevalence of having six or more drinks among Roma (a negative correlation was identified in the recessive model; genotype GG, coef: −0.170, p = 0.049), although, none of these findings passed the Bonferroni-corrected probability criterion (p > 0.05). Nevertheless, our findings may suggest that alcohol consumption is partially driven by genetically determined taste preferences in our study populations. Further studies are required to strengthen the findings and to understand the drivers of alcohol consumption behavior in more depth.

Nermeen Abuelsoud,1,2 Hala Fayed,3 Engy Elkateeb4 1Department of Clinical Pharmacy Practice, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; 2Department of Pharmacy Practice/Clinical Pharmacy, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt; 3Department of Rheumatology and Rehabilitation, Kasr Alaini University Hospital, Faculty of Medicine, Cairo University, Cairo, Egypt; 4Department of Chemical and Clinical Pathology, Kasr Alaini University Hospital, Faculty of Medicine, Cairo University, Cairo, EgyptCorrespondence: Nermeen Abuelsoud Misr-Ismailia Road, PO Box 43, El Sherouk City, 11837, EgyptTel +00201226117118Email nersoud09@gmail.comPurpose: The study aimed to detect the frequencies of allelic variants (TPMT*3A, TPMT*3C, and TPMT*3G) in the TPMT genes in the Egyptian population and assess the association between TPMT polymorphisms and azathioprine (AZA)—clinical efficacy and adverse drug reactions among Egyptian patients with autoimmune diseases.Patients and Methods:: Design: A prospective, observational single-center clinical trial.Setting: Rheumatology and Rehabilitation Department, Kasr Alainy University Hospital, Faculty of Medicine, Cairo University.Patients: Patients attending Kasr Alainy Rheumatology Outpatient Clinic between December 1, 2017 and June 30, 2019 were included in the study after signing a consent form. TPMT genetic polymorphisms were detected for all patients, and the association between polymorphisms presence and azathioprine’s clinical efficacy and adverse drug reactions were determined.Results: A total of 150 patients with a mean age of 35.85 years were enrolled in this study. About 72% of patients were heterozygous in the TPMT*3 G460A and TPMT*3 A719G mutant alleles and 81% were wild type in the TPMT*2 G238C mutant allele. Abnormal liver function tests were detected in 42% of patients. Myelosuppression was presented as anemia which was detected in 63% of patients, leucopenia in 51%, and thrombocytopenia in 25% of patients. AZA clinical failure has occurred in 50% of patients where AZA was discontinued or shifted to another drug which occurred in 45% of patients. Myelosuppression rates were higher in homozygous patients in the three mutant alleles, but statistically significant in TPMT*2 G238C while not statistically significant in TPMT*3 G460A and TPMT*3 A719G. Females had a higher risk of immunosuppression than males (p-value 0.031).Conclusion: The study provided an overview of the genomic variations in the Egyptian population. Routine TPMT genotyping prior to the initiation of AZA therapy should be considered.Keywords: azathioprine, genetic polymorphisms, autoimmune diseases, Egyptian patients

Li-Ming Tian,1 Dan Ke2 1Department of Dermatology, Wuhan No.1 Hospital, Hospital of Traditional Chinese and Western Medicine Affiliated to Hubei University of Chinese Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine Affiliated to Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Department of Dermatology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400000, People’s Republic of ChinaCorrespondence: Li-Ming TianDepartment of Dermatology, Wuhan No.1 Hospital, Hospital of Traditional Chinese and Western Medicine Affiliated to Hubei University of Chinese Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine Affiliated to Huazhong University of Science and Technology, No. 215 of Zhongshan Avenue, Qiaokou District, Wuhan, 430022, People’s Republic of ChinaTel +86 27 8533 2606Fax +86 27 8583 2563Email tianlm632587@tom.comDan KeDepartment of Dermatology, Chongqing Traditional Chinese Medicine Hospital, No. 40 of Daomenkou, Yuzhong District, Chongqing, 400000, People’s Republic of ChinaTel +86 23 6390 1120Fax +86 23 6373 1325Email ked98527@163.comObjective: To study the relationship between the single nucleotide polymorphisms (SNPs) of the human β-defensin 1-gene (DEFB1) and the genetic susceptibility of acne vulgaris in the Han Chinese ethnic group.Methods: A total of 104 patients with acne vulgaris and 126 healthy participants were included in our study. We analyzed the association between acne vulgaris and the polymorphisms in the DEFB1 G-52A, C-44G, and G-20A gene. We then analyzed the relationship between the different genotypes and the susceptibility to acne vulgaris.Results: The frequency of DEFB1 C-44G genetic polymorphisms between the acne vulgaris group and the control group was significantly different (P < 0.05). The frequency of DEFB1 G-20A genetic polymorphisms between the acne vulgaris group and the control group was also significantly different (P < 0.05).Conclusion: The − 44G or − 20A allele showed a low expression in acne vulgaris, which has already been shown to correlate with the low risk of acne vulgaris among Chinese Han patients. This further supports the contribution of the DEFB1 gene to the pathogenesis of acne.Keywords: human β-defensin 1, genetic polymorphisms, acne vulgaris, Cutibacterium acnes, Han Chinese

Vitamin D receptor (VDR) gene polymorphisms could play a significant role in the susceptibility and pathogenesis of osteoarthritis (OA), the most common degenerative joint disorder in humans. The current study involved 94 OA patients and 100 healthy, asymptomatic controls. VDR variants FokI (rs2228570), TaqI (rs731236), ApaI (rs7975232) and EcoRV (rs4516035) were genotyped using TaqMan-based real-time PCR. Adjusted odds ratio (OR) analysis showed that VDR TaqI and FokI polymorphisms are significantly associated with susceptibility to OA (OR=1.986, P=0.001 and OR=1.561, P=0.017, respectively). Joint-specific analysis showed that the VDR TaqI polymorphism was associated with risk of hip OA (OR=1.930, P=0.005) and knee OA (OR=1.916, P=0.028), while the VDR FokI polymorphism was associated with higher risk of knee OA (OR=2.117, P=0.012). VDR TaqI and FokI polymorphisms are associated with the occurrence of persistent pain (P=0.005 and P=0.027, respectively), while ApaI was associated with a family history of OA (p=0.004). The VDR FokI and TaqI genetic variants significantly contribute to osteoarthritis susceptibility, the occurrence of persistent pain, and potentially to joint-specific OA risk.

NAFLD is currently considered the most common liver disease worldwide and mounting data support its strong link with atherosclerotic cardiovascular disease (ASCVD). This association is important as cardiovascular disease (CVD) is generally recognized as the leading cause of death in individuals with NAFLD. However, NAFLD represents a heterogeneous condition showing a wide spectrum of clinical and pathophysiological sub-phenotypes with different adverse outcomes ranging from ASCVD to liver damage progression. The contribution to NAFLD pathogenesis of different environmental, metabolic, and genetic factors underlies this heterogeneity. The more frequent phenotype of NAFLD patients is associated with metabolic dysfunctions such as obesity and insulin-resistant syndrome and this has been recently named as Metabolic Associated Fatty Liver disease (MAFLD). However, NAFLD is encountered also in subjects without insulin resistance and metabolic alterations and in whom genetic factors play a major role. It has been suggested that these individuals are at risk of liver disease progression but not of cardiovascular complications. Separating metabolic from genetic factors could be useful in disentangling the intricate relationship between NAFLD and atherosclerosis. In the present review, we aim to address the epidemic of NAFLD, its epidemiologically association with ASCVD complications and the overall mechanisms involved in the pathophysiology of atherosclerotic vascular damage in NAFLD patients. Finally, we will revise the potential role of genetics in identifying disease subtyping and predicting individualised CVD risk.

Anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED) are the three most common eating disorders (EDs). Their etiopathogenesis is multifactorial where both the environmental and genetic factors contribute to the disease outcome and severity. Several polymorphisms in genes involved in the dopaminergic pathways seem to be relevant in the susceptibility to EDs, but their role has not been fully elucidated yet. In this study, we have analyzed the association between selected common polymorphisms in the DRD2 and DRD4 genes in a large cohort of Italian patients affected by AN (n = 332), BN (n = 122), and BED (n = 132) compared to healthy controls (CTRs) (n = 172). Allelic and genotypic frequencies have been also correlated with the main psychopathological and clinical comorbidities often observed in patients. Our results showed significant associations of the DRD2-rs6277 single nucleotide polymorphism (SNP) with AN and BN, of the DRD4-rs936461 SNP with BN and BED and of DRD4 120-bp tandem repeat (TR) polymorphism (SS plus LS genotypes) with BED susceptibility. Moreover, genotyping of DRD4 48-bp variable number TR (VNTR) identified the presence of ≥7R alleles as risk factors to develop each type of EDs. The study also showed that ED subjects with a history of drugs abuse were characterized by a significantly higher frequency of the DRD4 rs1800955 TT genotype and DRD4 120-bp TR short-allele. Our findings suggest that specific combinations of variants in the DRD2 and DRD4 genes are predisposing factors not only for EDs but also for some psychopathological features often coupled specifically to AN, BN, and BED. Further functional research studies are needed to better clarify the complex role of these proteins and to develop novel therapeutic compounds based on dopamine modulation.

It is a common fact that children are less susceptible to COVID-19 than adults, and they usually have milder forms often without symptoms, due to the age-related characteristics of their immune response and the features of the renin-angiotensin system (RAS). The recent studies have shown that the RAS elements are widely represented in the lungs, and they actively participate in the inflammation process in addition to their main vasoregulatory function. The cascade of RAS reactions is one of the key links in the pathogenesis of COVID-19, and it is analyzed from two positions: expression of ACE2 receptors and polymorphisms of certain genes of this system. The studies have demonstrated that the ACE2 transmembrane protein is both the “entry gate” for the virus, and it also plays a regulatory role, turning the pro-inflammatory vasoconstrictor angiotensin II into anti-inflammatory angiotensin (1—7) with vasodilating properties. A higher content of ACE2 in children as compared to that in adults maintains the RAS system balance and prevents the development of complications. It has been also found that certain genetic polymorphisms (AGTR1, AGTR2, ACE2, ACE) can cause the imbalance of RAS components, leading to more pronounced reactions of alveolocytes, vascular endothelium and smooth muscle fibers in response to SARS-CoV-2 infection due to a shift of the vasoconstrictor, proliferative and profibrotic mechanisms. The patients with certain genetic polymorphisms of NOS genes regulating vascular tone, cell growth and proliferation may have a genetic predisposition to the development of severe forms of COVID-19.

Pregnancy short- or long-term complications may involve the mother’s health, the fetus’s health, or both. A systematic literature review was performed, including studies up to October 2018 from Medline (PubMed), Science Direct, Web of Science and Google Scholar. The following inclusion criteria were applied: studies published until 2018 concerning the genetic background of pregnancy complications such as high blood pressure, gestational diabetes, preeclampsia, pregnancy loss, endometrial death, placental abruption, premature labor, and intrauterine growth retardation which may render pregnancy a high risk condition. We identified 164 articles that met the inclusion criteria and reviewed and analyzed them. The results so far are contradictory and the pathogenicity of these pregnancy complications remains unclear. For most of the polymorphisms studied so far, data refer to small studies size but research is on-going. The identification of genetic polymorphisms with strong correlations with certain pregnancy complications could provide us with useful tools which could be incorporated in diagnostic algorithms that could facilitate early detection and treatment of major pregnancy complications.

The purpose of the present study was to investigate the impact of genetic polymorphism on fluvastatin pharmacokinetics. In addition, we compared the fluvastatin pharmacokinetics differences between extended-release (ER) 80 mg tablet and immediate-release (IR) 40 mg capsule in terms of drug metabolism enzyme and transporter genetic polymorphisms. In this open-label, randomized, two-period, two-treatment, crossover study (n = 24), effects of ABCG2, SLCO1B1, ABCB1, CYP2C9 and CYP3A5 polymorphisms on the pharmacokinetics of fluvastatin were analyzed. The administration dosage for IR 40 mg and ER 80 mg were twice and once daily, respectively, for total 7 d. Blood samples for pharmacokinetic evaluation were taken on the 1st and 7th d. The lower exposure following ER was observed. For ER tablets, SLCO1B1 T521C genotype correlated with AUC0-24 of repeat doses (P = 0.010). SLCO1B1 T521C genotype had no statistically significant effect on AUC0-24 of IR capsule of fluvastatin after single or repeated doses. In vitro study demonstrated that when the concentration of fluvastatin was low (< 1 µmol/l), the uptake of fluvastatin in the HEK293-OATP1B1 with SLCO1B1 521TT (Km=0.18 µmol/l) was faster than that with SLCO1B1 521CC (Km=0.49 µmol/l), On the other hand, when concentration reached to higher level (> 1 µmol/l), transport velocity of fluvastatin by HEK293-OATP1B1 with SLCO1B1 521TT (Km = 11.4 µmol/l) and with SLCO1B1 521TCC (Km=15.1 µmol/l) tend to be the same. It suggests that the increased effect of SLCO1B1 T521C genotype on ER formulation of fluvastatin was mainly caused by lower blood concentrations. We recommend that formulation should be incorporated into future pharmacogenomics studies., Graphical abstract Image, graphical abstract

BackgroundObservational studies have reported multiple risk factors for pancreatic ductal adenocarcinoma (PDAC). Some are well established, like tobacco smoking, alcohol drinking, obesity and type 2 diabetes, whereas some others are putative, such as allergy and dietary factors. Identifying causal risk factors can help establishing those that can be targeted to contribute to prevent PDAC.ObjectiveWe sought to investigate the possible causal effects of established and putative factors on PDAC risk.MethodsWe conducted a two-sample Mendelian randomisation (MR) study using publicly available data for genetic variants associated with the factors of interest, and summary genetic data from genome-wide association studies of the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including in total 8769 cases and 7055 controls. Causality was assessed using inverse-variance weighted, MR-Egger regression and weighted median methods, complemented with sensitivity and radial MR analyses.ResultsWe found evidence for a causal effect of body mass index (BMI) on PDAC risk (OR 1.43, 95% CI 1.20 to 1.71, p=8.43×10−5). Fasting insulin (OR 2.84, 95% CI 1.23 to 6.56, p=0.01), low-density lipoprotein cholesterol (OR 1.16, 95% CI 1.02 to 1.32, p=0.03) and type 2 diabetes (OR 1.09, 95% CI 1.01 to 1.17, p=0.02) were also causally associated with PDAC risk. BMI showed both direct and fasting insulin-mediated causal effects.ConclusionWe found strong evidence that BMI is causally associated with PDAC risk, providing support that obesity management may be a potential prevention strategy for reducing pancreatic cancer risk while fasting insulin and type 2 diabetes showed a suggestive association that should be further investigated.

Aim The primary objective of this review is to develop a practice-based expert group opinion on the role of precision medicine with a specific focus on sulfonylureas (SUs) in diabetes management. Background The clinical etiology, presentation and complications of diabetes vary from one patient to another, making the management of the disease challenging. The pre-eminent feature of diabetes mellitus (DM) are chronically elevated blood glucose concentrations; however, in clinical practice, the exclusion of autoimmunity, pregnancy, pancreatic disease or injury and rare genetic forms of diabetes is crucial. Within this framework, precision medicine provides unique insights into the risk factors and natural history of DM. Precision medicine goes beyond genomics and encompasses patient-centered care, molecular technologies and data sharing. Precision medicine has evolved in the field of diabetology. It has helped improve the efficacy of SUs, a class of drugs, which have been effectively used in the management of diabetes mellitus for decades, and it has enabled the expansion of SUs use in diabetes patients with genetic mutations. Review Results After due discussions, the expert group analyzed studies that focused on the use of SUs in diabetes patients with genomic variations and rare mutations. The expert group opined that SUs are important glucose-lowering drugs and that precision medicine helps in improving the efficacy of SUs by matching them to those patients who will benefit most. Conclusion Precision medicine opens new vistas for the effective use of SUs in unexpected patient populations, such as those with genetic mutations.

Background: CYP1A1 is an enzyme in phase I of the cytochrome P450 (CYP) superfamily, and plays a key role in detoxification of carcinogens. Host genetic predisposition in the CYP1A1 may be associated with an increased susceptibility to cervical cancer.The study aimed to evaluate four common polymorphisms of the CYP1A1 and cervical cancer susceptibility among Northeast Thai women. Methods: A case-control study was conducted involving 204 patients with squamous cell cervical cancer (SCCA) and 204 age-matched healthy controls. DNA was extracted from peripheral blood leucocytes. CYP1A1 m1, m3, and m4 genotypes were detected using PCR-RFLP, whereas the CYP1A1 m2 genotype was investigated using real-time PCR. Haplotype analysis was performed using PHASE algorithm version 2.1.1. Results: CYP1A1 m3 was monomorphic. Association between the common CYP1A1 polymorphisms, m1 and m2, and cervical cancer risk was not observed (p>0.05), nor was any association found between the m1–m2–m4 haplotype and cervical cancer risk (p>0.05). Interestingly, the CA genotype of CYP1A1 m4 was observed in 30.88% of the cervical cancer patients but was absent in healthy controls. Conclusion: Our results demonstrated a possible involvement of the CYP1A1 m4 polymorphism but no other common polymorphisms (viz., m1, m2, and m3) in the risk for cervical cancer.This finding may be useful when screening for risk of cervical cancer among Northeast Thai women.

Over the past four decades, patients with advanced ovarian cancer (OC) has enjoyed greatly improved survival rate considering advances in combined chemotherapy with platinum and paclitaxel. We investigated the association between polymorphisms within glutathione S-transferase genes (GSTM1, GSTT1 and GSTP1) and short- and long-term efficacy of concurrent chemoradiotherapy (CCRT) in advanced OC. Patients with advanced OC and healthy females were selected in our study. Multiplex polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) were applied to detect homozygous deletions in GSTM1 and GSTT1, as well as codon 105 genetic polymorphisms in GSTP1 exon 5. All the patients with advanced OC were treated with CCRT. Toxicity of chemotherapy, short-term efficacy, recurrence and metastasis, respectively. Long-term survival outcomes were checked with a further examination and all patients were followed up for three years after CCRT.Compared with healthy females, patients with advanced OC showed higher frequencies of GSTT1 non-null genotype and homozygous mutation type GG of GSTP. GSTP1genetic polymorphisms were relevant to neutropenia resulted from CCRT in patients with advanced OC. Compared with patients with GSTT1non-null genotype, those with GSTT1 null genotype appeared to enjoy a better short-term efficacy, lower recurrence and metastasis rate, higher survival rate and longer mean survival time. Compared with patients with GG genotype, those with GSTP1 AA + AG genotype also enjoyed more positive results. Our results reveal that GSTT1 null genotype and GSTP1AA + AG genotype are associated with short- and long-term efficacy of CCRT in advanced OC.

Omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) are critical for cell membrane structure and function. Human beings have a limited ability to synthesise docosahexaenoic acid (DHA), the main n-3 LCPUFA required for neurological development. Inadequate levels of n-3 LCPUFA can affect the dopaminergic system in the brain and, when combined with genetic and other factors, increase the risk of developing aggression, inattention and impulse-control disorders. In this study, male prisoners were administered questionnaires assessing aggressive behaviour and executive functions. Participants also produced blood sampling for the measurement of the Omega-3 Index and the genotyping of dopaminergic genetic variants. Significant associations were found between functional genetic polymorphism in DBH rs1611115 and verbal aggression and between DRD2 rs4274224 and executive functions. However, the Omega-3 Index was not significantly associated with the tested dopaminergic polymorphisms. Although previous interactions between specific genotypes and n-3 LCPUFA were previously reported, they remain limited and poorly understood. We did not find any association between n-3 LCPUFA and dopaminergic polymorphisms in adult male prisoners; however, we confirmed the importance of genetic predisposition for dopaminergic genes (DBH and DRD2) in aggressive behaviour, memory dysfunction and attention-deficit disorder.

Moderate to severe cancer pain treatment in children is based on the use of weak and strong opioids. Pharmacogenetics play a central role in developing personalized pain therapies, as well as avoiding treatment failure and/or intolerable adverse drug reactions. This observational study aimed to investigate the association between IL-6, IL-8, and TNFα genetic single nucleotide polymorphisms (SNPs) and response to opioid therapy in a cohort of pediatric cancer patients. Pain intensity before treatment (PIt0) significantly differed according to IL-6 rs1800797 SNP, with a higher PI for A/G and G/G individuals (p = 0.017), who required a higher dose of opioids (p = 0.047). Moreover, compared to G/G subjects, heterozygous or homozygous individuals for the A allele of IL-6 rs1800797 SNP had a lower risk of having a PIt0 > 4. Dose24h and Dosetot were both higher in G/G individuals for TNFα rs1800629 (p = 0.010 and p = 0.031, respectively), while risk of having a PIt0 > 4 and a ∆VAS > 2 was higher for G/G subjects for IL-6 rs1800795 SNP compared to carriers of the C allele. No statistically significant association between genotypes and safety outcomes was found. Thus, IL-6 and TNFα SNPs could be potential markers of baseline pain intensity and opioid dose requirements in pediatric cancer patients.

Riparian ecosystems, in long-time developed regions, are among the most heavily impacted by human activities; therefore, the distribution of tree riparian species, such as Ulmus laevis, is highly affected. This phenomenon is particularly relevant at the margins of the natural habitat of the species, where populations are small and rare. In these cases, it is difficult to distinguish between relics or introductions, but it is relevant for the restoration of natural habitats and conservation strategies. The aim of this study was to study the phylogeography of the southern distribution of the species. We sequenced the entire chloroplast (cp) genomes of 54 individuals from five sampled populations across different European regions to highlight polymorphisms and analyze their distribution. Thirty-two haplotypes were identified. All the sampled populations showed private haplotypes that can be considered an indicator of long-term residency, given the low mutation rate of organellar DNA. The network of all haplotypes showed a star-like topology, and Serbian haplotypes were present in all branches. The Balkan population showed the highest level of nucleotide and genetic diversity. Low genetic differentiation between populations was observed but we found a significant differentiation among Serbia vs. other provenances. Our estimates of divergent time of U. laevis samples highlight the early split of above all Serbian individuals from other populations, emphasizing the reservoir role of white elm genetic diversity of Serbian population.

Study of polymorphisms in genes related to the generation and removal of oxidative stress and repair of oxidative DNA damage will lead to new insights into the genetic basis of prostate cancer. In the Prostate Cancer Prevention Trial (PCPT), a double-blind, randomized controlled trial testing finasteride versus placebo for prostate cancer prevention, we intend to investigate the role of oxidative stress/DNA repair mechanisms in prostate cancer etiology and whether these polymorphisms modify prostate cancer risk by interacting with antioxidant status in both placebo and finasteride arms. We evaluated associations of selected candidate polymorphisms in genes in these pathways, and interactions with pre-diagnostic serum antioxidants, and the risk of prostate cancer among 1,598 cases and 1,706 frequency-matched controls enrolled in the PCPT. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable-adjusted logistic regression models. While there were no statistically significant associations observed in the placebo arm, several SNPs were associated with prostate cancer in the finasteride arm. Specifically, APEX1-rs1760944 was associated with increased risk of total prostate cancer (per minor allele: p-trend=0.04). OGG1-rs1052133 was positively (CG/GG vs. CC: OR=1.32, 95% CI: 1.01-1.73) and NOS3-rs1799983 was inversely (per minor allele: p-trend=0.04) associated with risk of low-grade prostate cancer. LIG3-rs1052536 and XRCC1-rs25489 were suggestively associated with reduced risk of high-grade prostate cancer (per minor allele: both p-trend=0.04). In the placebo arm, significant associations were observed among men with higher serum lycopene for APEX1-rs1760944 and NQO1-rs1800566, or higher serum β-cryptoxanthin for ERCC4-rs1800067. In the finasteride arm, stronger associations were observed among men with lower serum lycopene for NOS3-rs1799983, higher serum α-carotene, β-carotene, and β-cryptoxanthin for LIG3-rs1052536, or lower serum retinol for SOD2-rs1799725. These results suggest that germline variations in oxidative stress and DNA repair pathways may contribute to prostate carcinogenesis and that these associations may differ by intraprostatic sex steroid hormone status and be further modified by antioxidant status. Findings provide insights into the complex role of gene, gene-antioxidant and -finasteride interactions in prostate cancer etiology, and thus may lead to the development of preventative strategies.

Background: Clinical-related risk factors to freezing of gait (FOG) in Parkinson’s disease (PD) have been iden- tified. Still, the influence of genetic variations on the FOG occurrence has been poorly studied thus far. Aim: We aimed to evaluate the association of six selected polymorphisms of DRD2, ANKK1, and COMT genes with the FOG occurrence and explore the influence of ANNK1/DRD2 haplotypes on the onset of FOG in the group of PD patients. Method: PD patients (n = 234), treated with levodopa for at least two years, were genotyped for the rs4680 in COMT, rs6277, rs1076560, and rs2283265 in DRD2, and rs1800497 and rs2734849 polymorphisms in ANKK1 genes. FOG was evaluated by posing a direct question. In addition, a comprehensive set of clinical scales was applied to all patients. Results: FOG occurred in 132 (56.4%) PD patients in our cohort. Freezers were younger at PD onset, had longer disease duration, used higher levodopa daily doses and dopaminergic agents, and had higher motor and non- motor scales scores than non-freezers. FOG was more frequent among AA rs4680 COMT carriers than AG and GG rs4680 COMT carriers. Independent predictors of FOG were: disease duration of more than ten years, levodopa daily dose higher than 500 mg/day, motor status, and COMT AA genotype. AGGAA and GGAAA haplotypes were revealed as protective and vulnerability factors for FOG occurrence. Conclusion: In addition to previously identified disease- and therapy-related risk factors, our results suggested a possible contribution of dopamine-related genes to the FOG occurrence.

The immune system plays a key role in the host defense against viral pathogens. A signaling cascade is activated upon infection involving a variety of molecules such as pattern-recognition receptors (PRRs), interleukins or antiviral interferons. Long-term immunosuppression after solid organ transplantation (SOT) mainly abrogates adaptive T-cell-mediated responses, thus highlighting the relative contribution of innate immunity. Single-nucleotide polymorphisms (SNPs) within genes coding for PRRs or soluble mediators have been associated with differential susceptibility to viral infections among SOT recipients. A protective effect against cytomega-lovirus (CMV) infection or disease has been attributed to certain SNPs in TLR9 or IFNL3 genes, whereas the opposite effect has been attributed to genetic polymorphisms in TLR2, MBL2, DC-SIGN, IL10 or IFNG. The presence of SNPs in other molecules not directly involved in innate or adaptive immune responses such as aquaporins or pregnane X appear to modulate the risk of CMV or BK polyomavirus infection, respectively. Little information is available on the genetic determinants of the post-transplant susceptibility to herpesviruses causing clinical infection (herpes simplex virus or varicella zoster virus) or the replication kinetics of components of the human blood virome used as immune surrogates (Torque teno virus). The present review critically summarizes the current knowledge on how SNP genotyping would be useful to stratify SOT recipients according to the in-dividual risk of viral infection and proposes next research steps. Genetic susceptibility testing may improve personalized medicine and contribute to minimize the risk of viral infection after SOT.

Adolescence is marked by changes and vulnerability to the emergence of psychological problems. This study aimed to investigate associations between anxiety/depression/chronic pain and oral health-related quality of life (OHRQoL)/happiness/polymorphisms in the COMT, HTR2A and FKBP5 genes in Brazilian adolescents. A cross-sectional study was conducted with ninety adolescents 13 to 18 years. Anxiety, depression and chronic pain were evaluated using the RDC/TMD. The Oral Health Impact Profile was used to assess oral OHRQoL. The Subjective Happiness Scale was used to assess happiness. Single-nucleotide polymorphisms in COMT (rs165656, rs174675), HTR2A (rs6313, rs4941573) and FKBP5 (rs1360780, rs3800373) were genotyped using the Taqman® method. Bivariate and multivariate logistic regression analyses were performed (p < 0.05). Chronic pain and depression were associated with feelings of happiness (p < 0.05). A significant inverse association was found between anxiety and OHRQoL (p = 0.004). The presence of minor allele C of COMT rs174675 was significantly associated with depression (p = 0.040). Brazilian adolescents with depression and chronic pain considers themselves to be less happy than others and those with anxiety are more likely to have a negative impact on OHRQoL. Moreover, the rs174675 variant allele in the COMT gene was associated with depressive symptoms in Brazilian adolescents.

This protocol aims to characterize patients with dual disorders (DD; comorbid major depression and schizophrenia) compared with patients with only a diagnosis of substance use disorder (SUD) and those with only a diagnosis of severe mental illness (SMI; major depression and schizophrenia), evaluating clinical and personality characteristics, circadian rhythmic functioning, genetic polymorphism and neuropsychological performance in order to obtain a clinical endophenotype of differential vulnerability for these diagnostic entities. Patients will be divided into three groups: DD (45 men with comorbid schizophrenia, 45 men and 30 women with major depression), SUD (n = 90, with a minimum of 30 women) and SMI males (45 with schizophrenia, 45 with major depression). All patients will be under treatment, with at least three months of SUD abstinence and/or with SMI in remission or with stabilized symptoms. Outpatients of both sexes with insufficient restoration of circadian rhythmicity with SUD (n = 30) and dual depression (n = 30) will be asked to participate in a second two-month study, being alternately assigned to the condition of the chronobiological adjuvant approach to the treatment of regular hour habits and exposure to light or to the usual treatment (control). The effect of the intervention and patient compliance will be monitored with a Kronowise KW6® ambulatory device during the first two weeks of treatment and again at weeks 4 and 8 weeks. After completing the evaluation, follow-up of the clinical evolution will be carried out at 3, 6 and 12 months. This project will allow us to analyze the functional impact of DD comorbidity and to develop the first study of chronobiological therapy in the treatment of SUD and dual depression, with results transferable to the clinical setting with cost-effective recommendations for a personalized approach.

Responses to drugs are influenced by multiple factors, including health status, environmental influences, and genetic characteristics. The bioavailability of a drug can vary widely among individuals with a similar weight under the same drug dosage, which might result in toxicity and adverse drug reactions (ADRs). Genetic polymorphisms are known causes of interindividual differences in disease risk and treatment response in humans. In fact, a relevant number of associations between human genetic variants and predisposition to adverse events were described for diverse kinds of drug interactions, involving hundreds of proteins like receptors, transporters, and metabolizing enzymes. In this way, Pharmacogenetics and Pharmacogenomics emerged aiming to determine the genetic component responsible for drug response. A particular attention is showed if a treatment benefits (or harms) a particular subgroup, considering the interaction between treatment and genetic background. In this scenario, researchers have focused on better understanding personalized medicine, which holds the potential to maximize drug efficiency and minimize toxic effects. This review aims to introduce some principles, perspectives, and clinical applications of pharmacogenetics, emphasizing important findings and clinical applications that may contribute to therapeutical improvement. Las respuestas a las drogas están influenciadas por múltiples factores, incluido el estado de salud, las influencias ambientales y las características genéticas. La biodisponibilidad de un fármaco puede variar ampliamente entre individuos de peso similar bajo la misma cantidad de fármaco, lo que puede provocar toxicidad y reacciones adversas a drogas (RADs). Los polimorfismos genéticos son causas conocidas de las diferencias interindividuales en el riesgo de desarrollar enfermedades y la respuesta al tratamiento farmacológico. Se ha descrito un número relevante de asociaciones entre variantes genéticas humanas y predisposición a los eventos adversos para diferentes tipos de interacciones medicamentosas, involucrando a las proteinas como receptores, transportadores y enzimas metabolizadoras. Así, la Farmacogenética y la Farmacogenómica surgieron con el objetivo de determinar el componente genético responsable de la respuesta a las drogas. Se presta la debida atención a si un tratamiento beneficia (o perjudica) a un subgrupo de personas, considerando una interacción entre el tratamiento y los antecedentes genéticos de la población. En este escenario, los investigadores se han centrado en comprender mejor la medicina personalizada que tiene el potencial de maximizar la eficacia de las drogas y minimizar los efectos tóxicos. Esta revisión tiene como objetivo presentar algunos principios, perspectivas y aplicaciones clínicas de la farmacogenética, enfatizando hallazgos importantes y aplicaciones clínicas que pueden contribuir a la mejora terapéutica. As respostas aos fármacos são influenciadas por múltiplos fatores, incluindo estado de saúde, influências ambientais e características genéticas. A biodisponibilidade de um fármaco pode variar amplamente entre indivíduos com peso semelhante sob a mesma quantidade de fármaco, o que pode resultar em toxicidade e reações adversas aos fármacos (RAFs). Polimorfismos genéticos são causas conhecidas para as diferenças interindividuais no risco para desenvolvimento de doenças e na resposta ao tratamento farmacológico. Um número relevante de associações entre variantes genéticas humanas e predisposição aos eventos adversos tem sido descrito para diferentes tipos de interações medicamentosas, envolvendo centenas de proteínas tais como receptores, transportadores e enzimas metabolizadoras. Dessa forma, a Farmacogenética e a Farmacogenômica surgiram com o objetivo de determinar o componente genético responsável pela resposta aos fármacos. Uma atenção é dada para se um tratamento beneficia (ou prejudica) um determinado subgrupo de pessoas, considerando uma interação entre o tratamento e o histórico genético da população. Nesse cenário, os pesquisadores têm se concentrado em entender melhor a medicina personalizada que tem o potencial de maximizar uma eficiência dos fármacos e minimizar os efeitos tóxicos. Esta revisão visa apresentar alguns princípios, perspectivas e aplicações clínicas da farmacogenética, enfatizando achados importantes e aplicações clínicas que podem contribuir para o aprimoramento terapêutico.

SummaryNeuronal oscillations, their inter-areal synchronization, and scale-free dynamics constitute fundamental mechanisms for cognition by regulating communication in neuronal networks. These oscillatory dynamics have large inter-individual variability that is partly heritable. However, the genetic underpinnings of oscillatory dynamics have remained poorly understood. We recorded resting-state magnetoencephalography (MEG) from 82 healthy participants and investigated whether oscillation dynamics were influenced by genetic polymorphisms in Catechol-O-methyltransferase (COMT) Val158Met and brain-derived neurotrophic factor (BDNF) Val66Met. Both COMT and BDNF polymorphisms influenced local oscillation amplitudes and their long-range temporal correlations (LRTCs), while only BDNF polymorphism affected the strength of large-scale synchronization. Our findings demonstrate that COMT and BDNF genetic polymorphisms contribute to inter-individual variability in local and large-scale synchronization dynamics of neuronal oscillations. Comparison of these results to computational modelling of near-critical synchronization dynamics further suggested that COMT and BDNF polymorphisms influenced local oscillations by modulating the excitation-inhibition balance according to the brain criticality framework.

This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort (n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = −8.4, 95% CI −11.4–−5.4, p = 3.9 × 10−8) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3–6.7, p = 7.4 × 10−7) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = −1.5, 95% CI −5.3–2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8–3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.

Parkinson’s disease (PD) is the second most common neurodegenerative disease characterised by both motor- and non-motor symptoms, including cognitive impairment. The aetiopathogenesis of PD, as well as its protective and susceptibility factors, are still elusive. Neuroprotective effects of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors—statins—via both cholesterol-dependent and independent mechanisms have been shown in animal and cell culture models. However, the available data provide conflicting results on the role of statin treatment in PD patients. Moreover, cholesterol is a vital component for brain functions and may be considered as protective against PD. We present possible statin effects on PD under the hypothesis that they may depend on the HMG-CoA reductase gene (HMGCR) variability, such as haplotype 7, which was shown to affect cholesterol synthesis and statin treatment outcome, diminishing possible neuroprotection associated with HMG-CoA reductase inhibitors administration. Statins are among the most prescribed groups of drugs. Thus, it seems important to review the available data in the context of their possible neuroprotective effects in PD, and the HMG-CoA reductase gene’s genetic variability.

Objective To more precisely estimate the association between the tumor necrosis factor ligand superfamily member 4 (TNFSF4) gene polymorphisms and systemic lupus erythematosus (SLE) susceptibility, we performed a meta-analysis on the association of the following single nucleotide polymorphisms (SNPs) of TNFSF4 with SLE: rs1234315, rs844648, rs2205960, rs704840, rs844644, rs10489265. Methods A literature-based search was conducted using PubMed, MEDLINE, Embase, Web of Science databases, and Cochrane Library databases to identify all relevant studies. And the association of TNFSF4 gene polymorphisms and SLE susceptibility was evaluated by pooled odds ratio (OR) with 95% confidence interval (CI). Results The meta-analysis produced overall OR of 1.42 (95% CI 1.36–1.49, P P P P = 0.54) for the rs844644 polymorphism, suggesting no significant association. And no association was also found between either rs844648 1.11 (OR 1.11, 95% CI 0.86–1.43, P = 0.41) or rs10489265 (OR 1.17, 95% CI 0.94–1.47, P = 0.17) polymorphism with SLE susceptibility, respectively. Conclusions Our meta-analysis demonstrated that the TNFSF4 rs2205960, rs1234315 and rs844840 SNPs was significantly associated with an increased risk of SLE.

The human organic cation transporter 1 (OCT1) is expressed in the liver and mediates hepatocellular uptake of organic cations. However, some studies have indicated that OCT1 could transport neutral or even anionic substrates. This capability is interesting concerning protein-substrate interactions and the clinical relevance of OCT1. To better understand the transport of neutral, anionic, or zwitterionic substrates, we used HEK293 cells overexpressing wild-type OCT1 and a variant in which we changed the putative substrate binding site (aspartate474) to a neutral amino acid. The uncharged drugs trimethoprim, lamivudine, and emtricitabine were good substrates of hOCT1. However, the uncharged drugs zalcitabine and lamotrigine, and the anionic levofloxacin, and prostaglandins E2 and F2α, were transported with lower activity. Finally, we could detect only extremely weak transport rates of acyclovir, ganciclovir, and stachydrine. Deleting aspartate474 had a similar transport-lowering effect on anionic substrates as on cationic substrates, indicating that aspartate474 might be relevant for intra-protein, rather than substrate-protein, interactions. Cellular uptake of the atypical substrates by the naturally occurring frequent variants OCT1*2 (methionine420del) and OCT1*3 (arginine61cysteine) was similarly reduced, as it is known for typical organic cations. Thus, to comprehensively understand the substrate spectrum and transport mechanisms of OCT1, one should also look at organic anions.

Alcohol use disorder (AUD) is a multifactorial disease caused by environmental and genetic factors. Genetic polymorphisms of the enzymes involved in alcohol metabolism influence the susceptibility to alcohol dependence. The distribution of the genetic variants varies depending on ethnicity. The aim of this study was to evaluate the effects of the polymorphisms of the three genes responsible for the degradation of ethanol, ADH1B, ADH1C, and CYP2E1 to examine the influence of these mutations on the risk for alcohol use disorder in a population from northeastern Brazil. In addition, the allelic distribution of the northeastern population will be compared with that obtained for other populations. The allelic and genotypic frequencies were determined in 163 alcoholic patients and 182 control subjects. Genotyping was performed by PCR-RFLP. The allele frequencies in the northeastern population were similar to those reported in studies in Mexico but differed significantly from those reported in studies of a Chinese population. The polymorphic variants of CYP2E1 were associated with a higher risk for alcohol use disorder [odds ratio (OR) = 2.80; 95% confidence interval (CI) = 1.35-5.83, p = 0.0072]. No significant result was obtained from the analyses of the ADH1C gene. A significant protective effect against alcohol dependence was observed in individuals carrying allelic and genotypic variations of the ADH1B gene, as determined through the combined analysis of homozygous and heterozygous variant forms of the gene in controls and alcoholics (P = 0.03). Furthermore, the combination of ADH1B*2 with ADH1C*1 and CYP2E1 (c1/c1) may confer protection against alcohol use disorder. El trastorno por consumo de alcohol es una enfermedad multifactorial causada por factores ambientales y genéticos. Los polimorfismos genéticos de las enzimas involucradas en el metabolismo del alcohol influyen en la susceptibilidad a la dependencia del alcohol. La distribución de las variantes genéticas varía según la etnia. El objetivo de este estudio fue evaluar los efectos de los polimorfismos de los tres genes responsables de la degradación del etanol, ADH1B, ADH1C y CYP2E1 para examinar la influencia de estas mutaciones en el riesgo de alcoholismo en una población del noreste de Brasil. Además, se comparará la distribución alélica de la población nororiental con la obtenida para otras poblaciones. Las frecuencias alélicas y genotípicas se determinaron en 163 pacientes alcohólicos y 182 sujetos control. El genotipado se realizó por PCR-RFLP. Las frecuencias alélicas en la población del noreste fueron similares a las reportadas en estudios en México pero difirieron significativamente de las reportadas en estudios de una población china. Las variantes polimórficas de CYP2E1 se asociaron con un mayor riesgo de trastorno por consumo de alcohol [odds ratio (OR) = 2,80; Intervalo de confianza (IC) del 95% = 1,35-5,83, P = 0,0072]. No se obtuvo ningún resultado significativo de los análisis del gen ADH1C. Se observó un efecto protector significativo contra la dependencia del alcohol en individuos portadores de variaciones alélicas y genotípicas del gen ADH1B, según se determinó a través del análisis combinado de formas variantes homocigóticas y heterocigóticas del gen en controles y alcohólicos (P = 0,03). Además, la combinación de ADH1B*2 con ADH1C*1 y CYP2E1 (c1/c1) puede conferir protección contra el trastorno por consumo de alcohol. O transtorno por uso de álcool (TUA) é uma doença multifatorial causada por fatores ambientais e genéticos. Polimorfismos genéticos das enzimas envolvidas no metabolismo do álcool influenciam a suscetibilidade à dependência do álcool. A distribuição das variantes genéticas varia dependendo da etnia. O objetivo deste estudo foi avaliar os efeitos dos polimorfismos dos três genes responsáveis pela degradação do etanol, ADH1B, ADH1C e CYP2E1 para examinar a influência dessas mutações no risco de alcoolismo em uma população do nordeste do Brasil. Além disso, a distribuição alélica da população nordestina será comparada com a obtida para outras populações. As frequências alélicas e genotípicas foram determinadas em 163 pacientes alcoolistas e 182 controles. A genotipagem foi realizada por PCR-RFLP. As frequências alélicas na população do nordeste foram semelhantes às relatadas em estudos no México, mas diferiram significativamente daquelas relatadas em estudos de uma população chinesa. As variantes polimórficas de CYP2E1 foram associadas a um maior risco de alcoolismo [odds ratio (OR) = 2,80; intervalo de confiança de 95% (CI) = 1,35-5,83, P = 0,0072]. Nenhum resultado significativo foi obtido das análises do gene ADH1C. Um efeito protetor significativo contra a dependência de álcool foi observado em indivíduos portadores de variações alélicas e genotípicas do gene ADH1B, determinado através da análise combinada de formas variantes homozigóticas e heterozigotas do gene em controles e alcoolistas (P = 0,03). Além disso, a combinação de ADH1B*2 com ADH1C*1 e CYP2E1 (c1/c1) pode conferir proteção contra o transtorno por uso de álcool.

Orientador: Marta Helena Krieger Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia Resumo: O Óxido Nítrico (NO) é um radical livre gasoso sintetizado nos vasos sanguíneos principalmente pela enzima óxido nítrico sintase endotelial (eNOS). No sistema cardiovascular ele está diretamente envolvido no controle do fluxo sanguíneo regional, especialmente na musculatura esquelética. O polimorfismo G894T do gene da eNOS vem sendo amplamente investigado e o alelo 894T, que resulta na troca do aminoácido glutamato por aspartato na posição 298 da enzima, parece estar associado ao desenvolvimento de doenças cardiovasculares. No entanto, não se conhece o efeito dessa variante genética na vasodilatação muscular. Neste estudo testou-se a hipótese de que a resposta reflexa de vasodilatação muscular durante o exercício isométrico de handgrip estaria atenuada em indivíduos portadores do alelo 894T. Em adição, que a resposta atenuada estaria ocorrendo em conseqüência de uma biodisponibilidade reduzida do NO e/ou aumento da atividade nervosa simpática vasoconstritora para a musculatura esquelética. Para testar tais hipóteses, 287 voluntários foram previamente genotipados e, deste total, 33 indivíduos saudáveis foram selecionados para representar 3 genótipos: GG (n=15, Idade=43±3 anos, IMC=22,9±0,3 kg/m2), GT (n=9, Idade=39±3 anos, IMC=24,6±1,2 kg/m2) e TT (n=9, Idade=40±4 anos, IMC=23,5±0,9 kg/m2). A freqüência cardíaca (FC; ECG), pressão arterial média (PAM; oscilométrico) e fluxo sangüíneo no antebraço (FSA; pletismografia de oclusão venosa) foram avaliados por 3 minutos no basal e 3 minutos durante o exercício isométrico de handgrip, realizado a 30% da máxima contração voluntária. Não houve diferença nos valores basais de FC, PAM, FSA e condutância vascular no antebraço (CVA) entre GG (69±2 bpm; 91±3 mmHg; 1,81±0,09 ml.min-1.100 ml-1; 2,03±0,12 unidades, respectivamente), GT (69±4 bpm; 94±2 mmHg; 1,80±0,23 ml.min-1.100 ml-1; 1,90±0,24 unidades) e TT (63±3 bpm; 95±3 mmHg; 1,79±0,17 ml.min-1.100 ml-1; 1,89±0,17 unidades). Em resposta ao exercício, a CVA foi significativamente menor no genótipo TT ('delta'=0,07±0,14 unidades, P=.002) quando comparado aos genótipos GG ('delta'=0,57±0,09 unidades) e GT ('delta'=0,64±0,20 unidades). Para investigar os mecanismos responsáveis pela vasodilatação reduzida no genótipo TT, o FSA foi estudado durante a infusão intra-arterial de L-NMMA (4 mg.min-1) e L-NMMA + fentolamina (4 mg.min-1 e 100µg.min-1), num subgrupo de 8 indivíduos com genótipo GG e 7 indivíduos com genótipo TT. Em adição, avaliou-se a xvi atividade nervosa simpática muscular (ANSM; microneurografia). Em resposta ao exercício, L-NMMA não alterou a CVA no genótipo TT ('delta'-0,05±0,20 vs. -0,09±0,18 unidades). Ao contrário, L-NMMA reduziu significativamente a CVA no genótipo GG ('delta'=0,79±0,14 vs. 0,14±0,09 unidades). Desta forma, a diferença entre os genótipos não foi mais observada (P=.62). L-NMMA + fentolamina aumentou similarmente a CVA em resposta ao exercício nos genótipos GG e TT ('delta'=1,16±0,26 vs. 0,56±0,24 unidades, P=.43). A PAM e a ANSM aumentaram significativamente e de forma similar em ambos os genótipos. Estes resultados permitem concluir que o polimorfismo G894T do gene da eNOS está associado à vasodilatação muscular reflexa diminuída em resposta ao exercício. Em adição, esta atenuação na vasodilatação nos indivíduos homozigotos para o alelo 894T parece ser primariamente mediada por uma biodisponibilidade reduzida do óxido nítrico, mas não por um aumento da atividade nervosa simpática muscular Abstract: Nitric oxide (NO) is a free radical synthesized in vessels mainly by endothelial nitric oxide synthase (eNOS) enzyme. In the cardiovascular system NO is involved in the modulation of regional blood flow, mainly in the skeletal muscle. The G894T polymorphism of the eNOS gene has been extensively investigated, and the 894T allele that results in glutamate to aspartate exchange at the position 298 of the eNOS enzyme, has been associated with cardiovascular diseases. However, the effects of 894T allele on muscle vasodilatation are unknown. We hypothesized that the reflex forearm blood flow responses during handgrip isometric exercise would be attenuated in individuals carrying the 894T allele. In addition, these responses would be mediated by impairment in nitric oxide availability and/or an increase in vasoconstrictor sympathetic nerve activity to skeletal muscle. To test the previous hypothesis, 287 volunteers were previously genotyped, and 33 healthy individuals selected to represent three genotypes: GG (n=15, age=43±3 years, BMI=22.9±0.3 kg/m2), GT (n=9, age=39±3 years, BMI=24.6±1.2 kg/m2) and TT (n=9, age=40±4 years, BMI=23.5±0.9 kg/m2). Heart rate (HR; ECG), mean blood pressure (MBP; oscillometric cuff) and forearm blood flow (FBF; venous occlusion plethysmography) were recorded for 3 minutes at baseline and 3 minutes during isometric handgrip exercise performed at 30% of maximal voluntary contraction. Baseline HR, MBP, FBF and forearm vascular conductance (FVC) were similar among GG (69±2 bpm; 91±3 mmHg; 1.81±0.09 ml.min-1.100 ml-1; 2.03±0.12 units, respectively), GT (69±4 bpm; 94±2 mmHg; 1.80±0.23 ml.min-1.100 ml-1; 1.90±0.24 units) and TT (63±3 bpm; 95±3 mmHg; 1.79±0.17 ml.min-1.100 ml-1; 1.89±0.17 units). FVC responses to exercise were significantly lower in TT ('delta'=0.07±0.14 units, P=.002) when compared with GG ('delta'=0.57±0.09 units) and GT ('delta'=0.64±0.20 units). To investigate the mechanisms underlying the lowered vasodilatation in TT genotype, we studied FBF during brachial intra-arterial infusion of L-NMMA (4 mg.min-1) and L- NMMA + phentolamine (4 mg.min-1 and 100µg.min-1, respectively) in a subset of 8 GG and 7 TT individuals. In addition, we directly measured muscle sympathetic nerve activity (MSNA) by means of microneurography. L-NMMA did not significantly change FVC responses to exercise in TT when compared with saline control infusion ('delta'=- 0.05±0.20 vs. -0.09±0.18 units). In contrast, L-NMMA significantly reduced FVC in GG xviii genotype ('delta'=0.79±0.14 vs. 0.14±0.09 units), and the difference between genotypes were no longer observed (P=.62). L-NMMA + phentolamine increased similarly FVC responses to exercise in GG and TT individuals ('delta'=1.16±0.26 vs. 0.56±0.24 units, respectively, P=.43). MBP and MSNA increased significant and similarly throughout experimental protocols in GG and TT genotypes. We concluded that G894T gene eNOS polymorphism is functionally associated with impaired reflex muscle vasodilatation to exercise. In addition, the attenuated vasodilatation responsiveness to exercise in individuals who are homozygous for the 894T allele of the eNOS gene seems to be primarily mediated by a reduced nitric oxide bioavailability, but not increase in MSNA Doutorado Fisiologia Doutor em Biologia Funcional e Molecular

Orientador: Carmen Silvia Passos Lima Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas Resumo: A angiogênese é um importante processo para o desenvolvimento e progressão do câncer de mama esporádico (CME). Há evidências de que as células tumorais podem produzirproteínas antiangiogènicas como a endostatina (ES). A ES é codificada pelo gene COL18A1. Recentemente, um polimorfismo do gene COL18A1, o D104N, foi associado ao aumento do risco de ocorrência do adenocarcinoma de próstata. Considerando que não há descrições sobre a influência do polimorfismo D104N na susceptibilidade ao CME, este foi definido como o objetivo do estudo. Assim, o DNA genômico de 181 mulheres com CME e 448 controles foi analisado por meio da reação em cadeia da polimerase e digestão enzimática com a enzima Msél. O método ELISA foi utilizado para a quantificação da ES sérica de 118 pacientes com CME e 158 controles. As amostras dos controles estiveram no Equilíbrio de Hardy-Weinberg (X = 2,15; P= 0,14). Em contraste, as amostras das pacientes não confirmaram a expectativa de Hardy-Weinberg no lócus D104N do gene COL18A1 (X2= 22,87; P< 0,0001). Observamos que a freqüência do polimorfismo 104NN foi maior em pacientes do que em controles (2,8% vs 0,0%; respectivamente). Os indivíduos com o genótipo NN apresentaram um risco infinitamente maior de ocorrência da doença do que aqueles com os outros genótipos (P= 0,003). As freqüências do polimorfismo 104NN foram similares em pacientes estratificados por variáveis clínicas (idade, raça, idades da menarca, menopausa, da primeira gestação a termo, lactação, terapia de reposição hormonal e hábito de fumar) e laboratoriais (histologia, graus histológico e nuclear, padrão dos receptores de estrogênio e progesterona e estágio TNM do tumor). A mediana das concentrações da ES foi maior em pacientes do que em controles (P< 0,001). Valores similares foram encontrados em pacientes (P> 0,759) e controles (P= 0,535) estratificados por genótipos. Os nossos resultados sugerem que o polimorfismo 104NN do gene COL18A1 está associado à susceptibilidade do CME, possivelmente devido à anormalidade funcional da proteína. Abstract: Angiogenesis is an important step in sporadic breast cancer (SBC) development and progression There is evidence that neoplastic cells play a role in the generation of endogenous antiangiogenic proteins, such as endostatin (ES). ES is codified by the COL18A1 gene. Recently, a COL18A1 polymorphism (D104N) was associated with increased risk for the prostatic adenocarcinoma. Considering that it is unknown whether the D104N polymorphism of the COL18A1 gene alters the risk for SBC, this was the aim of this study. Thus, genomic DNA from peripheral blood of 181 SBC women and 448 controls were analysed using the polymerase chain reaction followed by restriction endonuclease digestion with Msel. ELISA for quantification of ES was performed in serum from 118 SBC woman and 158 controls. Controls' samples were in Hardy-Weinberg equilibrium (X2= 2.15, P= 0.14). In contrast, patients' samples did not confirm the Hardy-Weinberg expectations at the D104N locus (X2= 22.87, P< 0.0001). We observed a higher frequency of 104NN polymorphism in SBC patients than in controls (2.8% vs 0.0%, respectively). Individuals with the 104NN polymorphism had an infinite risk for disease (P= 0.003) when compared with those with other genotypes. The frequencies of the 104NN polymorphism were similar in patients stratified by clinical (age, ethnical origin, ages of menarche, menopause, first full-term pregnancy, lactation, hormone replacement therapy, and smoke habit) and laboratory variables (tumour histology, histological and nuclear grades, status of estrogen and progesterone receptors, and stage TNM of the tumour). The median values of ES was higher in patients than in controls (P< 0.001). Similar median values of ES were seen among patients (P> 0 759) and controls (P= 0.535) stratified by genotypes However, differences in clinical and laboratory manifestation and levels of ES may not have reached statistical significance due to the small number of individuals with the 104N allele, enrolled in study. Our results suggest that the 104NN genotype of the COLI8AI gene is associated with SBC susceptibility, possibly due to an abnormal ES function. Mestrado Clínica Médica Mestre em Clínica Médica

Orientador: Zanoni Dias Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Computação Resumo: A pesquisa genomica é de grande interesse para area medica. Por isso o entendimento de como os genes influenciam na aparição de doencas é de grande relevancia para a criação de metodos de diagnostico e criação de drogas apropriadas. A maioria dos genes apresenta uma grande frequencia de variações alelicas, conhecida como polimorfismo. Estas variações podem ser a chave para a predisposição de certos indiv?duos a certas doenças. Dentre os polimorfismos, os SNPs tem uma grande importancia, por representarem cerca de 90% dos polimorfismos encontrados no genoma humano [21]. Neste trabalho iremos estudar tres etapas no processo de detecção e analise de SNPs. A primeira etapa consiste no processo de alinhamento de sequencias de EST e cDNA com DNA genomico. A identificaçãode genes em sequencias de DNA não-caracterizadas é um dos grandes problemas na pesquisa genomica. Os algoritmos tradicionais [45, 55, 83, 84, 106] descrevem metodos para alinhar duas sequencias arbitrarias. Iremos descrever as estrategias de alinhamento de duas sequencias, discutir os metodos existentes para alinhamento de cDNA com DNA genomico e propor um conjunto de coeficientes apropriados a serem usados com os algoritmos classicos para resolver este tipo de alinhamento. A segunda etapa consiste na detecção de SNPs, seja atraves de alinhamentos multiplos ou da analise de cromatogramas. Iremos descrever o funcionamento dos dois metodos citados acima e discutir uma nova metodologia para detectar SNPs em sequencias de v?rus HIV. A terceira etapa consiste em correlacionar SNPs. Sabe-se que a predisposição genetica para muitas doenças não é devido a apenas uma mutação, ou presença ou não de um certo alelo. Em muitos casos, varios SNPs agem em conjunto e aumentam ou não a chance de uma doença se manifestar em um indiv?duo. Assim, é muito importante desenvolver metodos de correlação entre diversos SNPs para se entender como eles interagem entre si. Iremos descrever medidas de correlação e estudar a presença de LDs e LDs multiplos em genes da cana-de-açucar, mapeados pelo projeto SUCEST, e em genes humanos Abstract: Genomic research is of great interest in the medical field. Therefore, understanding how genes impact the ocurrence of diseases is of significant relevance, so that proper diagnosis can be made and appropriate drugs can be developed. Most genes present great variantion and allele frequency, known as polymorphism. These variantions may be key to understanding the predisposition in individuals to certain diseases. Among polymorhisms, SNPs are of great importance, representing circa 90% of all polymorphism found in the human genome. [21]. For this work, we will study three phases in the process of detecting and analysis of SNPs. The first phase consists in the process of aligning EST sequences and cDNA to genomic DNA. Identiying genes in non-caracterized DNA sequences is one of the challenging problems in genomic research. Traditional algorithms [45, 55, 83, 84, 106] describe methods to align two arbitrary sequences. We shall describe alignment strategies of two sequences, discuss over existing existing methods for aligning cDNA with genomic DNA and propose a set of apropriate coefficients to be used in the classical algorithms to perform this kind of alignment. The seconde phase consists in detecting SNPs, whether through multiple alignments or cromatogram analysis. We shall describe how the two above mentioned methods work and discuss a new methodology to detect SNPs and HIV sequences. The third phase consists of correlating SNPs. It is known that the genetic predisposition for many diseases is not only due to a single mutation, or to the presence or absence of a single allele. In many cases, several SNPs act together and may increase or decrease the chance for a disease to manifest in a individual. Thus, it is very important to develop methods of correlation between SNPs to better understand how they interact. We shall describe correlation measures and study the presence of LD or multiple LDs in sugarcane genes,which were mapped by the SUCEST project, and in human genes Mestrado Biologia Computaçional Mestre em Ciência da Computação

Orientador: Maria Salete Costa Gurgel Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas Resumo: Introdução: As deleções dos genes GSTM1 e GSTT1 têm sido associadas ao aumento do risco de várias neoplasias, porém não há consenso sobre suas influências no câncer de mama. Objetivo: Avaliar a ocorrência das deleções homozigóticas dos GSTM1 e GSTT1 em mulheres com câncer de mama esporádico (CME) ¿ casos - e em mulheres sem câncer ¿ controles - e comparar as características clínicas e biológicas dos CME entre mulheres portadoras e não-portadoras das referidas deleções. Casuística e Método: Foram avaliados 177 casos e 169 controles, com determinação das freqüências das referidas deleções pelo PCR. Estas foram correlacionadas às características clínicas e biológicas através do cálculo de odds ratio com seus respectivos intervalos de confiança de 95%. Resultados: Dos casos e controles, respectivamente, 46% e 45% não apresentaram qualquer deleção, 37% e 35% apenas do GSTM1, 11% e 10% apenas do GSTT1, 6% e 9% apresentaram ambos os genes deletados. Observou-se freqüência menor da deleção do GSTM1 em mulheres pardas (p=0,1128), OR=0,48 (0,24 ¿ 0,98). O risco foi menor de ocorrência de tumores grau nuclear 3 em pacientes com deleção do GSTT1 (p=0,04), OR=0,37 (0,15 - 0,90). A deleção homozigótica de pelo menos um dos genes associou-se com mulheres que não amamentaram (p=0,0202), OR=0,41 (0,19 ¿ 0,88), e com a ausência de expressão dos receptores hormonais (p=0,0300), ORadj=2,25 (1,03 ¿ 4,90). Já a deleção de ambos os genes associou-se ao aumento de risco da ocorrência de tipos histológicos diferentes do carcinoma ductal invasivo clássico (p=0,0571), ORadj=12,09 (1,03 ¿ 142,03). Conclusões: mulheres com CME e antecedente de miscigenação com etnia negra tiveram menor freqüência da deleção do GSTM1, enquanto os tumores com grau de diferenciação nuclear mais favorável relacionaram-se à deleção do GSTT1. Já as pacientes com pelo menos um dos genes deletados apresentaram maior risco de tumores que não expressam receptores hormonais, e a deleção combinada de ambos os genes associou-se ao aumento de risco para tipo histológico não ductal clássico Abstract: Introduction: The GSTM1 and GSTT1 gene deletions have been associated with an increased risk of various neoplasms, although there is a lack of consensus about their influence on breast cancer. Objective: To evaluate the occurrence of homozygous deletions of the GSTM1 and GSTT1 genes in women with sporadic breast cancer (SBC) ¿ cases ¿ and in women without cancer ¿ controls ¿ and compare the clinical and biological characteristics of SBC among women with and without the referred deletions. Case Study and Method: The study evaluated 177 cases and 169 controls, determining the frequency of the abovementioned deletions by PCR. These were correlated with the clinical and biological characteristics by calculating the odds ratios and their 95% confidence intervals. Results: Of the cases and controls, 46% and 45% did not present any deletion, 37% and 35% had only GSTM1 deletion, 11% and 10% had only GSTT1 deletion, 6% and 9% had both genes deleted, respectively. A lower frequency of GSTM1 deletion was observed in mulatto women (p=0.1128), OR=0.48 (0.24 ¿ 0.98). The risk of occurring nuclear grade 3 tumors was lower in patients with GSTT1 deletion (p=0.04), OR=0.37 (0.15 ¿ 0.90). Homozygous deletion of at least one gene was associated with women who had not breastfed (p=0.0202), OR=0.41 (0.19 ¿ 0.88), and with absence of hormone receptor expression (p=0.0300), ORadj=2.25 (1.03 ¿ 4.90). The deletion of both genes was associated with an increased risk of occurring histologic types different from classic invasive ductal carcinoma (p=0.0571), ORadj=12.09 (1.03 ¿ 142.03). Conclusions: women with SBC and a history of miscegination with the black race had a lower frequency of GSTM1 deletion, while tumors with a more favorable degree of nuclear differentiation were related to GSTT1 deletion. Patients with at least one gene deleted had a higher risk for tumors that did not express hormone receptors, and the combined deletion of both genes was associtated with a greater risk for the non-classic ductal histologic type Mestrado Tocoginecologia Mestre em Tocoginecologia

Background: Breast cancer has recently become one of the most common causes of cancer-related deaths, and several studies have suggested that genetic polymorphisms in the folate metabolism pathway may be associated with susceptibility to breast cancer, although their results have been inconsistent or inconclusive. Therefore, the aim of this meta-analysis was to obtain accurate, consistent conclusions regarding the potential associations of genetic polymorphisms in the folate metabolism pathway with the risk of breast cancer, based on case-controlled studies. Methods: From the beginning of database establishment through May 2021, we indexed and searched domestic and foreign databases, including the Chinese National Knowledge Infrastructure, Web of Science, VIP and BioMedical Database of China, PubMed, EMBASE, Wanfang database, and the Cochrane Library. To determine the effects of folate metabolism-related genetic polymorphisms on breast cancer risk, we used Stata version 16.0 to analyze all data and calculated variable odds ratios and 95% confidence intervals. Results: The findings of the current meta-analysis are going to be presented to peer-reviewed journals for publication when the analysis is completed. Conclusion: The meta-analysis will summarize the association of genetic polymorphisms in the folate metabolism pathway with breast cancer. Registration number: May 26, 2021.osf.io/25r48. (https://osf.io/25r48/).

Abstract Background Obesity has been recognized as a worldwide growing problem, producing many pathologies including the promotion of “proinflammatory state.” The etiology of human obesity is still only partially understood; however, the genetic background has been proved. Its nature is complex, and currently, it appears that the combined effects of the interactions among multiple genes should receive more attention. Due to the fact that obesity promotes proinflammatory conditions, in this study, we investigated the genetic polymorphism of IL-1 family genes in healthy people with normal and elevated body mass index (BMI) and fat %. Results The single-nucleotide polymorphisms (SNPs) within the IL1A -889C > T (rs1800587), IL1B + 3954 T > C (rs1143634), and IL1RN -87G > A (rs2234677) genes alone were associated neither with BMI nor fat % values in tested group. The associations between SNP–SNP interaction and BMI for the IL1B × IL1RN interactions were significant for dominant model (p = 0.02) and codominant model (p = 0.03). The same SNP-SNP interaction (IL1B × IL1RN) was associated also with fat % for codominant (p = 0.01) and recessive (p = 0.002) models. Conclusions This study further confirmed that IL-1 family genes are involved in genetic background of obesity. It has been shown that interaction IL1B × IL1RN was associated with both BMI and fat % with rare T allele protecting form higher values. Thus, even if certain polymorphisms in single genes of IL-1 family cannot be defined as related to obesity in examined population, the genetic interrelationships should be analyzed.

Orientador: Marcus Aloizio Martinez de Aguiar Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Física Gleb Wataghin Resumo: O processo evolutivo é guiado por pressões seletivas que agem nos indivíduos e modificam os caracteres da população ao longo das gerações. Em certas populações as pressões seletivas são geradas pelo comportamento dos próprios indivíduos da população e não por predadores ou competição por recursos. Neste caso, o ambiente gerado pela própria população altera a superfície de fitness. Nesse contexto, deve-se lançar mão da chamada teoria de jogos, onde o valor adaptativo de um indivíduo deve ser calculado em relação àqueles com quem ele interage. Um exemplo biológico desse tipo de dinâmica ocorre com os lagartos da espécie Uta stansburiana onde a cor de sua garganta está correlacionada com seu comportamento reprodutivo. Estudos mostram que os ciclos populacionais e a distribuição espacial desses lagartos e seus diferentes morfos é bastante complexa, revelando configurações populacionais não triviais ainda não explicadas pelos modelos anteriores. Portanto, neste trabalho nós propomos três modelos que tentam dar um passo adiante no entendimento da dinâmica populacional dos lagartos uta. O primeiro modelo proposto, RPS genotípico, usa equações discretas incluindo explicitamente os genótipos e mostrou que a estabilidade da dinâmica RPS aumenta ao incluirmos a reprodução sexuada. O segundo modelo proposto, o modelo RPS espacial genotípico é um modelo que leva em consideração explicitamente os genótipos e suas interações no espaço obtendo resultados semelhantes ao primeiro modelo. O terceiro modelo, é um modelo espacial que leva em consideração explicitamente os genótipos e a dinâmica Kr das fêmeas dos lagartos uta. O modelo RPS-Kr conseguiu reproduzir os ciclos populacionais de forma sistemática e configurações não triviais encontradas na natureza Abstract: The evolutionary process is guided by selective pressures that act on individuals and modify the characters of the population throughout the generations. In certain populations selective pressures are generated by the behavior of the individuals themselves, not by predators or competition for resources. In this case, the environment generated by the population itself alters the fitness surface. In this context, one should describe the dynamics game theory, where the adaptive value of an individual must be calculated in relation to those with whom it interacts. A biological example of this type of dynamics occurs with the lizards from the specie Uta stansburiana where the color of their throat is correlated with their reproductive behavior. Studies show that the spatial cycles and the spatial distribution of these lizards and their different morphs is quite complex revealing nontrivial population configurations not yet explained by previous models. In this work we propose three models that try to take a step forward in understanding the population dynamics of uta lizards. The first one, the genotypic RPS model, uses discrete equations explicitly including the genotypes and shows that the stability of the RPS dynamics increases by including sexual reproduction. The second, genotype spatial RPS, is a model that explicitly takes into account genotypes and their interactions in space, obtaining similar results to the first model. The third one, is a spatial model that explicitly takes into account the genotypes and Kr dynamics of the females lizards. The RPS-Kr model was able to reproduce population cycles systematically and non-trivial configurations found in nature Doutorado Física Doutor em Ciências CNPQ 153006/2013-7

Purpose This study aimed to evaluate the associations between immune-related gene (FCRL3, NLRP3 and IL2) polymorphisms and the risk of head and neck cancer (HNC). Methods Six polymorphisms of FCRL3, NLRP3 and IL2 were genotyped in 400 HNC cases and 400 controls using a MassARRAY platform. Results rs11264799-T was a protective variant against HNC risk, while rs7528684-G, rs35829419-A and rs6822844-T were all risk alleles for HNC (p < 0.05). rs11264799-TT was correlated with reduced HNC risk, while rs7528684-GG and rs6822844-TG were associated with an elevated risk of disease (p < 0.05). Moreover, rs11264799 was correlated with a declining risk of HNC in three genetic models (p < 0.05). In contrast, rs7528684 exhibited an elevated risk of HNC in recessive and additive models; rs35829419 and rs6822844 were associated with an increased risk of disease in dominant and additive models (p < 0.05). Finally, an interaction was observed between the above SNPs and drinking (p < 0.05). Conclusion The results expand our knowledge on immune-related gene polymorphisms in HNC and provide clues for further functional study on the pathogenesis of HNC.

Tooth agenesis is a common congenital anomaly in humans and is more common in oral cleft patients than in the general population. Many previous studies suggested that oral cleft and tooth agenesis share a similar genetic background. Therefore, this study explored the association between isolated tooth agenesis and genetic polymorphisms in genes that are crucial for craniofacial and tooth development. Panoramic radiographs, anamnesis, and genomic DNA from 273 patients were included. Patients were classified as tooth agenesis present, when at least one permanent tooth was congenitally missing. Patients with syndromes and oral cleft were excluded. Only unrelated patients were included. The genetic polymorphisms in BMP2 (rs235768 and rs1005464), BMP4 (rs17563), RUNX2 (rs59983488 and rs1200425), and SMAD6 (rs3934908 and rs2119261) were genotyped by real-time polymerase chain reaction. Genotype and allele distributions were compared between the tooth agenesis phenotypes and controls by Chi-square test. Haplotype and diplotype analysis were also performed, in addition to multivariate analysis (alpha of 0.05). A total of 86 tooth agenesis cases and 187 controls were evaluated. For the rs235768 in BMP2, patients carrying TT genotype have higher chance to present tooth agenesis [p < 0.001; prevalence ratio (PR) = 8.29; 95% confidence interval (CI) = 4.26–16.10]. The TT genotype in rs3934908 (SMAD6) was associated with higher chance to present third molar agenesis (p = 0.023; PR = 3.25; 95% CI = 1.17–8.99). BMP2 was also associated in haplotype and diplotype analysis with tooth agenesis. In conclusion, genetic polymorphisms in BMP2 and SMAD6 were associated with isolated tooth agenesis.

Venous thromboembolism (VTE) is one of the major complications in most cancer patients leading to poor prognosis and short survival. Several common clinical risk factors coexist in cancer patients are used as risk predictive biomarkers to help in the management and prevention of VTE. These include cancer site and stage, chemotherapy regimen and elevated biological markers. However, Genetic polymorphisms in genes controlling coagulation and fibrinolysis are significantly associated with VTE if detected, then they might be more sensitive individual predictive biomarkers for VTE risk assessment. This study was conducted to evaluate the association between ITGB3 rs3809865 and rs5918 with VTE risk as well as monitor the effect of VTE on overall survival of these cancer patients. In this retrospective case-control study, 195 cancer patients’ formalin-fixed paraffin embedded tissue (FFPE) samples were collected (controls n = 157, case n = 38) using the stored data through Jan 2010 to Sep 2018 from King Fahad Specialist Hospital in Dammam. Samples were genotyped using TaqMan genotyping assay, then logistic regression analysis and Chi-square were used to predict the association between risk factors and VTE. Survival Comparison was tested by the log-rank test. Genetic polymorphisms in ITGB3 (rs3809865 and rs5918) found not to be associated with VTE increasing risk in cancer patients (p>0.05). While the advanced stage was potentially increasing the risk of VTE events (OR 5.1 CI 2.01–12.9p = 0.001). Patients with VTE showed a poor overall survival reflected by the median survival rate of only three years compared to seven years for cancer patients without VTE. This study highlighted the potential influence of VTE on prognosis and survival of cancer patients and raised the importance of exploring risk predictive biomarkers in our population. This will improve the risk prediction biomarkers leading to implementing safe and effective thrombosis prophylaxis strategies.

Modern genetic studies have allowed the development of new disciplines that have high hopes for the treatment of severe conditions such as cancer and HIV/AIDS. The application of the notions of pharmacogenetics and pharmacoepigenetics, largely still under the sign of research, opens new horizons for medical and pharmaceutical practice.