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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.

Genome-wide association studies (GWASs) have been used to discover genetic polymorphisms that affect cardiovascular diseases (CVDs). Structural equation modelling (SEM) has been identified as a robust multivariate analysis tool. However, there is a paucity of research that has conducted SEM in African populations. The purpose of this study was to create a model that may be used to examine the relationships between genetic polymorphisms and their respective cardiovascular risk (CVR) factors. The procedure involved three steps. Firstly, the creation of latent variables and the hypothesis model. Next, confirmatory factor analysis (CFA) to examine the relationships between the latent variables, SNPs, dyslipidemia and metabolic syndrome, with their respective indicators. Then finally, model fitting using JASP statistical software v.0.16.4.0. The indicators for the SNPs and dyslipidemia all indicated significant factor loadings, −0.96 to 0.91 (p =

This study looked at genetic polymorphisms and transcript levels of immune, antioxidant, and erythritol-related markers for postparturient endometritis prediction and tracking in Holstein dairy cows. One hundred and thirty female dairy cows (65 endometritis affected and 65 apparently healthy) were used. Nucleotide sequence variations between healthy and endometritis-affected cows were revealed using PCR-DNA sequencing for immune (TLR4, TLR7, TNF-α, IL10, NCF4, and LITAF), antioxidant (ATOX1, GST, and OXSR1), and erythritol-related (TKT, RPIA, and AMPD1) genes. Chi-square investigation exposed a noteworthy variance amongst cow groups with and without endometritis in likelihood of dispersal of all distinguished nucleotide variants (p < 0.05). The IL10, ATOX1, and GST genes were expressed at substantially lower levels in endometritis-affected cows. Gene expression levels were considerably higher in endometritis-affected cows than in resistant ones for the genes TLR4, TLR7, TNF-α, NCF4, LITAF, OXSR1, TKT, RPIA, and AMPD1. The sort of marker and vulnerability or resistance to endometritis had a significant impact on the transcript levels of the studied indicators. The outcomes might confirm the importance of nucleotide variants along with gene expression patterns as markers of postparturient endometritis susceptibility/resistance and provide a workable control plan for Holstein dairy cows.

Individual taste sensitivity influences food preferences, nutritional control, and health, and differs greatly between individuals. The purpose of this study was to establish a method of measuring and quantifying an individual’s taste sensitivity and to evaluate the relationship between taste variation and genetic polymorphisms in humans using agonist specificities of the bitter taste receptor gene, TAS2R38, with the bitter compound 6-n-propylthiouracil (PROP). We precisely detected the threshold of PROP bitter perception by conducting the modified two-alternative forced-choice (2AFC) procedure with the Bayesian staircase procedure of the QUEST method and examined genetic variation in TAS2R38 in a Japanese population. There were significant differences in PROP threshold between the three TAS2R38 genotype pairs for 79 subjects: PAV/PAV vs AVI/AVI, p < 0.001; PAV/AVI vs AVI/AVI, p < 0.001; and PAV/PAV vs PAV/AVI, p < 0.01. Our results quantified individual bitter perception as QUEST threshold values: the PROP bitter perception of individuals with the PAV/PAV or PAV/AVI genotypes was tens to fifty times more sensitive than that of an individual with the AVI/AVI genotype. Our analyses provide a basic model for the accurate estimation of taste thresholds using the modified 2AFC with the QUEST approach.

Immune dysfunction in patients with multiple myeloma (MM) affects both the innate and adaptive immune system. Molecules involved in the immune checkpoint pathways are essential to determine the ability of cancer cells to escape from the immune system surveillance. However, few data are available concerning the role of these molecules in predicting the kinetics of progression of MM. We retrospectively analysed polymorphisms of CTLA4 (rs231775 and rs733618), BTLA (rs9288953), CD28 (rs3116496), PD-1 (rs36084323 and rs11568821) and LAG-3 (rs870849) genes in 239 patients with newly diagnosed MM. Patients with a CTLA4 rs231775 AA/AG genotype showed a median progression-free survival (PFS) significantly lower than those with GG genotype (32.3 months versus 96.8 months respectively; p: 0.008). The 5-year PFS rate was 25% for patients with grouped AA and AG genotype vs 55.4% for patients with GG genotype. Multivariate analysis confirmed the CTLA4 rs231775 genotype as an independent risk factor for PFS (Hazard Ratio (HR): 2.05; 95% CI: 1.0-6.2; p: 0.047). Our results suggest that the CTLA4 genotype may identify patients with earlier progression of MM. This polymorphism could potentially be used as a prognostic biomarker.

Purpose - to determine the presence of genetic determinism on the part of thrombophilia and angiogenesis candidate genes, their prognostic value in the development of preeclampsia (РЕ) in women with retrochorial hematoma (RCH). Materials and methods. The course of pregnancy was analyzed in 137 women with the threat of miscarriage aged 20 to 47 years (the Group 1 - 60 patients with RCH, the Group 2 - 77 patients without hematoma). Additionally, polymorphisms of the thrombophilia genes, the vascular endothelial growth factor gene - A (VEGF-A-634C>G) and the nitric oxide synthase 3 gene (NOS3 -786 C>T) were studied. To assess the correlation dependencies, the water-soluble tyrosine kinase-1 (sFlt-1) / placental growth factor (PlGF) (sFlt-1/PlGF) ratio was determined using TRACE-technologe (BRAHSMS Kryptor). Results. The average age of women in the Group 1 was 31.2±0.6 (95% CI: 30.0-32.4) years, in the Group 2 was 32.2±0.6 (95% CI: 31.0-33.3) years (p=0.243 by t-criterion). The calculation of the risk of developing PE in women of both groups established a high risk of its development in 28 (46.7%) and 23 (29.9%), respectively (p=0.044 by c2). Significant correlations in pairs were revealed: F13A1 gene polymorphism (9 G>T) - a decrease in the level of PlGF (rs=-0.296; p=0.023) and an increase in the value of sFlt-1/PlGF at 32-33+6 weeks (rs=0.248; p=0.050); FGB-fibrinogen gene (455 G>A) - the presence of chronic arterial hypertension (CAH) in a pregnant woman (rs=0.260, p=0.002), an increased risk of developing PE in the trimester I (rs=0.180; p=0.038); PAI-1 gene - reduced level of sFlt-1 (rs=-0.331; p=0.010) and sFlt-1/PlGF at 32-33+6 weeks (rs=-0.310; p=0.015); ITGB3-β gene - the presence of CAH in a pregnant woman (rs=0.176; p=0.040), an increase in sFlt-1/PlGF (rs=0.221; p=0.087). There was a trend towards an increased risk of developing PE in the first trimester in carriers of the VEGF-A gene polymorphism (-634 C>G) (rs=0.226; p=0.083). NOS3 gene polymorphism was associated with increased sFlt-1 (rs=0.252; p=0.063) and sFlt-1/PlGF ratio at 32-33+6 weeks (rs=0.239; p=0.079). Conclusions. Calculation of the risk of developing PE in women with RCH found a high risk of its development. The presence of VEGF-A polymorphism (-634 C>G) leads to an increased risk of developing PE and other placenta-associated complications. The presence of the NOS3 gene polymorphism (-786 C>T) affects the level of sFlt-1, leading to its increase and a change in the level of the sFlt-1/PlGF ratio at 32-33+6 weeks, which indicates an increased risk of developing late PE. The best predictor value has a combination of studying not only clinical data and biochemical parameters, but also genetic determinism. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors., Цель - определить наличие генетической детерминированности со стороны генов-кандидатов тромбофилии и ангиогенеза, их прогностическую ценность в развитии преэклампсии (ПЭ) у женщин с ретрохориальной гематомой (РХГ). Материалы и методы. Проанализировано течение беременности у 137 женщин с угрозой невынашивания в возрасте от 20 до 47 лет (I группа - 60 пациенток с РХГ, II группа - 77 пациенток без гематомы). Дополнительно проведены исследования полиморфизмов генов тромбофилии, гена фактора роста эндотелия сосудов - А (VEGF-A-634 С>G) и гена синтазы окиси азота 3 (NOS3 -786 C>T). Для оценки корреляционных зависимостей определен показатель соотношения водорастворимая тирозинкиназа-1 (sFlt-1) / плацентарный фактор роста (PlGF) (sFlt-1/PlGF) с помощью TRACE-technologe (BRAHSMS Kryptor). Результаты. Средний возраст женщин I группы составлял 31,2±0,6 (95% ДИ: 30,0-32,4) лет, ІІ группы - 32,2±0,6 (95% ДИ: 31,0-33,3) лет (р=0,243 по t-критерию). Расчет риска развития ПЭ у женщин обеих групп показал высокий риск её развития у 28 (46,7%) и 23 (29,9%) случаях соответственно (р=0,044 по c2). Выявлены значимые корреляционные зависимости в парах: полиморфизм гена F13A1 (9 G>T) - снижение уровня PlGF (rs=-0,296; p=0,023) и повышение значения sFlt-1/PlGF в 32-33+6 недели (rs=0,248; p=0,050); гена FGB-фибриногена (455 G>A) - наличие у беременной хронической артериальной гипертензии (ХАГ) (rs=0,260; p=0,002), повышенный риск развития ПЭ в I триместре (rs=0,180; p=0,038); гена PAI-1 - сниженный уровень sFlt-1 (rs=-0,331; p=0,010) и sFlt-1/PlGF в 32-33+6 недели (rs=-0,310; p=0,015); гена ITGB3-β - наличие у беременной ХАГ (rs=0,176; p=0,040), увеличение sFlt-1/PlGF (rs=0,221; p=0,087). Отмечена тенденция к повышению риска развития ПЭ в I триместре у носителей полиморфизма гена VEGF-A (-634 С>G) (rs=0,226; p=0,083). Полиморфизм гена NOS3 ассоциировался с повышением sFlt-1 (rs=0,252; p=0,063) и соотношения sFlt-1/PlGF в 32-33+6 недели (rs=0,239; p=0,079). Выводы. Расчёт риска развития ПЭ у женщин с РХГ установил высокий риск её развития. Наличие полиморфизма VEGF-A (-634 C>G) приводит к формированию повышенного риска развития ПЭ и других плацента-ассоциированных осложнений. Наличие полиморфизма гена NOS3 (-786 C>T) влияет на уровень sFlt-1, приводя к его повышению и изменению уровня соотношения sFlt-1/PlGF в 32-33+6 недели, что свидетельствует о повышенном риске развития поздней ПЭ. Лучшую предикторную ценность имеет сочетание изучения не только клинических данных и биохимических параметров, но и генетической детерминированности. Исследование выполнено в соответствии с принципами Хельсинкской декларации. Протокол исследования одобрен Локальным этическим комитетом участвующего учреждения. На проведение исследований получено информированное согласие родителей детей. Авторы заявляют об отсутствии конфликта интересов., Мета - визначити наявність генетичної детермінованості з боку генів-кандидатів тромбофілії та ангіогенезу, їхню прогностичну цінність у розвитку прееклампсії (ПЕ) у жінок із ретрохоріальною гематомою (РХГ). Матеріали та методи. Проаналізовано перебіг вагітності у 137 жінок із загрозою її невиношування віком від 20 до 47 років (І група - 60 пацієнток із РХГ, ІІ група - 77 пацієнток без гематоми). Додатково проведено дослідження поліморфізму генів тромбофілії, гена фактора росту ендотелію судин А (VEGF-A -634 С>G) та гена синтази окису азоту 3 (NOS3 -786 C>T). Для оцінювання кореляційних залежностей визначено показник співвідношення водорозчинна тирозинкіназа-1 (sFlt-1) / плацентарний фактор росту (PlGF) (sFlt-1/PlGF) за допомогою TRACE-technologe (BRAHSMS Kryptor). Результати. Середній вік жінок І групи становив 31,2±0,6 (95% ДІ: 30,0-32,4) року, ІІ групи - 32,2±0,6 (95% ДІ: 31,0-33,3) року (р=0,243 за t-критерієм). Розрахунок ризику розвитку ПЕ в жінок обох груп показав високий ризик її розвитку у 28 (46,7%) і 23 (29,9%) випадках, відповідно (р=0,044 за c2). Виявлено значущі кореляційні залежності в парах: поліморфізми гена F13A1 (9 G>T) - зниження рівня PlGF (rs=-0,296; p=0,023) і підвищення значення sFlt-1/PlGF в 32-33+6 тижні (rs=0,248; p=0,050); гена FGB-фібриногену (455 G>A) - наявність у вагітної хронічної артеріальної гіпертензії (ХАГ) (rs=0,260; p=0,002), підвищений ризик розвитку ПЕ в І триместрі (rs=0,180; p=0,038); гена PAI-1 - знижений рівень sFlt-1 (rs=-0,331; p=0,010) і sFlt-1/PlGF у 32-33+6 тижні (rs=-0,310; p=0,015); гена ITGB3-β - наявність у вагітної ХАГ (rs=0,176; p=0,040), збільшення sFlt-1/PlGF (rs=0,221; p=0,087). Відзначено тенденцію до підвищення ризику розвитку ПЕ в І триместрі в носіїв поліморфізму гена VEGF-A (-634 С>G) (rs=0,226; p=0,083). Поліморфізм гена NOS3 асоціювався з підвищенням sFlt-1 (rs=0,252; p=0,063) і співвідношення sFlt-1/PlGF в 32-33+6 тижні (rs=0,239; p=0,079). Висновки. Розрахунок ризику розвитку ПЕ в жінок з РХГ свідчить про високий ризик її розвитку. Наявність поліморфізмів VEGF-A (-634 C>G) призводить до формування підвищеного ризику розвитку ПЕ та інших плацента-асоційованих ускладнень. Наявність поліморфізму гена NOS3 (-786 C>T) впливає на рівень sFlt-1, призводячи до його підвищення та зміни рівня співвідношення sFlt-1/PlGF в 32-33+6 тижні, яке свідчить про підвищений ризик розвитку пізньої ПЕ. Найкращу передбачувану цінність має поєднання вивчення не тільки клінічних даних і біохімічних параметрів, але й генетичної детермінованості. Дослідження виконано відповідно до принципів Гельсінської декларації. Протокол дослідження ухвалено Локальним етичним комітетом зазначеної в роботі установи. На проведення досліджень отримано інформовану згоду жінок. Автори заявляють про відсутність конфлікту інтересів.

High blood pressure (HBP) is the leading risk factor for cardiovascular disease (CVD) and all-cause mortality worldwide. The progression of the disease leads to structural and/or functional alterations in various organs and increases cardiovascular risk. Currently, there are significant deficiencies in its diagnosis, treatment, and control. Vitamin D is characterized by its functional versatility and its involvement in countless physiological processes. This has led to the association of vitamin D with many chronic diseases, including HBP and CVD, due to its involvement in the regulation of the renin–angiotensin–aldosterone system. The aim of this study was to evaluate the effect of 13 single nucleotide polymorphisms (SNPs) related to the vitamin D metabolic pathway on the risk of developing HBP. An observational case-control study was performed, including 250 patients diagnosed with HBP and 500 controls from the south of Spain (Caucasians). Genetic polymorphisms in CYP27B1 (rs4646536, rs3782130, rs703842, and rs10877012), CYP2R1 rs10741657, GC rs7041, CYP24A1 (rs6068816, and rs4809957), and VDR (BsmI, Cdx2, FokI, ApaI, and TaqI) were analyzed by real-time PCR using TaqMan probes. Logistic regression analysis, adjusted for body mass index (BMI), dyslipidemia, and diabetes, showed that in the genotypic model, carriers of the GC rs7041 TT genotype were associated with a lower risk of developing HBP than the GG genotype (odds ratio (OR) = 0.44, 95% confidence interval (CI): 0.41–0.77, p = 0.005, TT vs. GG). In the dominant model, this association was maintained; carriers of the T allele showed a lower risk of developing HBP than carriers of the GG genotype (OR = 0.69, 95% CI: 0.47–1.03; TT + TG vs. GG, p = 0.010). Finally, in the additive model, consistent with previous models, the T allele was associated with a lower risk of developing HBP than the G allele (OR = 0.65, 95% CI: 0.40–0.87, p = 0.003, T vs. G). Haplotype analysis revealed that GACATG haplotypes for SNPs rs1544410, rs7975232, rs731236, rs4646536, rs703842, and rs10877012 were associated with a marginally significant lower risk of developing HBP (OR = 0.35, 95% CI: 0.12–1.02, p = 0.054). Several studies suggest that GC 7041 is associated with a lower active isoform of the vitamin D binding protein. In conclusion, the rs7041 polymorphism located in the GC gene was significantly associated with a lower risk of developing HBP. This polymorphism could therefore act as a substantial predictive biomarker of the disease., ERDF funds (EU) from the Instituto de Salud Carlos III (PT13/0010/0039) supported by co-funding grants from the Biobank of the Hospital Universitario Virgen de las Nieves.

The effectiveness of breeding for inherent disease resistance in animals could be considerably increased by identifying the genes and mutations that cause diversity in disease resistance. One hundred and twenty adult female Baladi goats (sixty pneumonic and sixty apparently healthy) were used in this study. DNA and RNA were extracted from blood samples collected from the jugular vein of each goat. SLC11A1, CD-14, CCL2, TLR1, TLR7, TLR8, TLR9, β defensin, SP110, SPP1, BP1, A2M, ADORA3, CARD15, IRF3, and SCART1 SNPs that have been previously found to be associated with pneumonia resistance/susceptibility were identified via PCR-DNA sequencing. The pneumonic and healthy goats differed significantly, according to a Chi-square analysis of the discovered SNPs. The mRNA levels of the studied immune markers were noticeably greater in the pneumonic goats than in the healthy ones. The findings could support the significance of the use of immune gene expression profiles and nucleotide variations as biomarkers for the susceptibility/resistance to pneumonia and provide a practical management technique for Baladi goats. These results also suggest a potential strategy for lowering pneumonia in goats by employing genetic markers linked to an animal’s ability to fend off infection in selective breeding.

Shaowei Jiang,1 Jing Ma,2 Shan Ye,3 Connor Meaney,4 Timothy Evan Moore,4 Shuming Pan,1 Chengjin Gao1 1Department of Emergency, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People’s Republic of China; 2Department of Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People’s Republic of China; 3Department of Internal Medicine, Shanghai Songnan Community Health Service Center, Shanghai, 200092, People’s Republic of China; 4Division of Rheumatology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, 84132, USACorrespondence: Chengjin Gao; Shuming Pan Email gaochengjin@xinhuamed.com.cn; panshuming@xinhuamed.com.cnObjectives(s): Toll-like receptors (TLRs) on platelets have been extensively studied. Both TLR2 and TLR4 have been shown to augment platelet activation and alter its function from a hemostatic regulator to an immune sentinel. However, few studies have investigated the relationship between genetic polymorphisms in TLR2, TLR4 and platelets. We investigated whether genetic polymorphisms of TLR2 and TLR4 were related to thrombocytopenia and coagulation failure in Chinese patients with sepsis.Basic Methods: Adult Chinese patients with sepsis in the intensive care unit of a university medical center were monitored for up to 28 days. Thrombocytopenia and disseminated intravascular coagulation (DIC), diagnosed using Japanese Association for Acute Medicine (JAAM) criteria, were observed as the primary outcomes. Single-nucleotide polymorphisms (SNPs) in TLR2 (rs111200466, rs5743708) and TLR4 (rs11536889, rs145801336, rs11536896, rs7869402) in patients with sepsis were detected by polymerase chain reaction. The data were analyzed using chi-square and rank sum tests.Results: The genotype of TLR2 (rs111200466) (Del/Del) was associated with the initial DIC. The genotype of TLR4 (rs11536889) (C/C&C/G) was associated with initial DIC, DIC onset during hospitalization and platelet counts. Furthermore, both DIC and platelet counts were associated with cytokines and chemokines, especially the IL10.Conclusion: Our results demonstrate that in Chinese sepsis patients, the rs111200466 SNP in TLR2 and rs11536889 SNP in TLR4 are associated with thrombocytopenia and DIC, with potential effects on the TLR4 pathways of platelets.Keywords: sepsis, disseminated intravascular coagulation, TLR2/4, genetic polymorphisms

The impact of amino acid mutations within the peptide structure of bovine milk protein is important to understand as it can effect processability and subsequently effect its physiological properties. Genetic polymorphisms of bovine caseins can influence the chemical, structural, and technological properties, including casein micelle morphology, calcium distribution, network creation upon gelation, and surface activity. The A1 and A2 genetic variants of β-casein have recently acquired growing attention from both academia and industry, prompting new developments in the area. The difference between these two genetic variants is the inclusion of either proline in β-casein A2 or histidine in β-casein A1 at position 67 in the peptide chain. The aim of this review was to examine the extent to which milk and ingredient functionality is influenced by β-casein phenotype. One of the main findings of this review was although β-casein A1 was found to be the dominant variant in milks with superior acid gelation and rennet coagulation properties, milks comprised of β-casein A2 possessed greater emulsion and foam formation capabilities. The difference in the casein micelle assembly, hydrophobicity, and chaperone activity of caseins may explain the contrast in the functionality of milks containing β-casein from either A1 or A2 families. This review provides new insights into the subtle variations in the physicochemical properties of bovine milks, which could potentially support dairy producers in the development of new dairy products with different functional properties.

Background/purpose: Genetics plays a role in the susceptibility to periodontitis and tooth loss. Several studies examined the involvement of polymorphisms in candidate genes. We hypothesize that bone metabolism-related polymorphisms could be associated with the number of remaining teeth. Materials and methods: Participants in the Pro.V.A. longitudinal Study: 3099 Italians (aged 65+ at baseline), 2196 at follow-up 1 (5yrs), 1641 at follow-up 2 (7yrs) underwent detailed interview and clinical-instrumental examination. Subjects, grouped by remaining teeth number (0, 1–7, 8–19, 20+), were genotyped for six different bone-related polymorphisms: collagen type Iα1 (COL1A1, Sp1, Ss alleles, n = 1068), vitamin D receptor (VDR, Fok I, Ff alleles, n = 300), calcitonin receptor (CALCR, Alu I, CT alleles, n = 1430), estrogen receptor alpha (ESR1, Pvu II and Xba I, Pp and Xx alleles, n = 1335 and n = 1324). Results: COL1A1 associated with dental status: ss carriers had reduced incident tooth loss (p

Background and Objectives: In the development of type 2 diabetes mellitus (T2DM) and its complications, genetic and environmental factors play important roles. Diabetic nephropathy (DN), one of the major microangiopathic chronic diabetic complications, is associated with an increased risk of major cardiovascular events and all-cause mortality. The present study was designed to investigate the possible modifying effect of glutathione transferase polymorphisms (GSTM1, GSTT1, GSTP1 rs1138272/rs1695, GSTO1 rs4925 and GSTO2 rs156697) in the susceptibility to T2DM and diabetic nephropathy. Materials and Methods: GSTM1 and GSTT1 deletion polymorphisms were determined by multiplex PCR, whereas GSTO1, GSTO2, and GSTP1 polymorphisms were determined by the real-time PCR in 160 T2DM patients and 248 age- and gender-matched controls. Advanced glycation end products (AGEs) were measured by ELISA. Results: Among six investigated GST polymorphisms, a significant association between the GST genotypes and susceptibility for development of diabetes mellitus was found for the GSTM1, GSTT1, GSTP1 (rs1138272) and GSTO1 polymorphisms. When the GST genotypes’ distribution in diabetes patients was assessed in the subgroups with and without diabetic nephropathy, a significant association was found only for the GSTO2 rs156697 polymorphism. Diabetic patients, carriers of the GSTM1 null, GSTT1 null and variant GSTO1*AA genotypes, had significantly increased levels of AGEs in comparison with carriers of the GSTM1 active, GSTT1 active and referent GSTO1*CC genotypes (p < 0.001, p < 0.001, p = 0.004, respectively). Conclusions: The present study supports the hypothesis that GST polymorphisms modulate the risk of diabetes and diabetic nephropathy and influence the AGEs concentration, suggesting the potential regulatory role of these enzymes in redox homeostasis disturbances.

Background and Objectives: Oxidative stress induced by increased reactive oxygen species (ROS) production plays an important role in carcinogenesis. The entire urinary tract is continuously exposed to numerous potentially mutagenic environmental agents which generate ROS during their biotransformation. In first line defense against free radicals, antioxidant enzymes superoxide dismutase (SOD2) and glutathione peroxidase (GPX1) both have essential roles. Altered enzyme activity and decreased ability of neutralizing free oxygen radicals as a consequence of genetic polymorphisms in genes encoding these two enzymes are well described so far. This study aimed to investigate the association of GPX1 (rs1050450) and SOD2 (rs4880) genetic variants with the urothelial bladder cancer (UBC) risk independently and in combination with smoking. Furthermore, we aimed to determine whether the UBC stage and pathological grade were influenced by GPX1 and SOD2 polymorphisms. Material and Methods: The study population included 330 patients with UBC (mean age 65 ± 10.3 years) and 227 respective controls (mean age 63.4 ± 7.9 years). Single nucleotide polymorphism (SNP) of GPX1 (rs1050450) was analyzed using the PCR-RFLP, while SOD2 (rs4880) SNP was analyzed using the q-PCR method. Results: Our results showed that UBC risk was significantly increased among carriers of at least one variant SOD2 Val allele compared to the SOD2 Ala16Ala homozygotes (OR = 1.55, p = 0.03). Moreover, this risk was even more pronounced in smokers with at least one variant SOD2 Val allele, since they have even 7.5 fold higher UBC risk (OR = 7.5, p < 0.001). Considering GPX1 polymorphism, we have not found an association with UBC risk. However, GPX1 genotypes distribution differed significantly according to the tumor stage (p ˂ 0.049) and pathohistological grade (p ˂ 0.018). Conclusion: We found that SOD2 genetic polymorphism is associated with the risk of UBC development independently and in combination with cigarette smoking. Furthermore, we showed that GPX1 genetic polymorphism is associated with the aggressiveness of the disease.

Several papers have been published suggesting a probable role of inflammatory factors in the etiopathogenesis of migraine. In this study, we investigated the possible association between common variants in the LAG3/CD4 genes (both genes, which are closely related, encode proteins involved in inflammatory and autoimmune responses) in the risk of migraine in a cohort of Caucasian Spanish participants. For this purpose, the frequencies of CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 genotypes and allelic variants, using a specific TaqMan-based qPCR assay, were assessed in 290 patients diagnosed with migraine and in 300 healthy controls. The relationship of these variables with several clinical features of migraine was also analyzed. The frequencies of the analyzed LAG3/CD4 genotypes did not differ significantly between the two study groups and were not related to the sex, age at onset of migraine, family history of migraine, presence or absence of aura, or the triggering effect of ethanol on migraine episodes. These results suggest a lack of association between common variants in the LAG3/CD4 genes and the risk of developing migraine in the Caucasian Spanish population.

© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)., Host regulatory immune response is involved in the hepatic inflammatory process caused by the hepatitis C virus (HCV). We aimed to determine if HCV clearance with direct-acting antivirals (DAAs) changes the hepatic fibrosis stage, biochemical parameters of liver injury, and inflammatory/immune responses. Sample: 329 chronic hepatitis C (CHC) patients, 134 of them treated with DAAs. Liver fibrosis was evaluated by transient elastography (FibroScan), biochemical and cellular parameters were determined by standard methods, cytokine concentration by enzyme-linked immunoabsorbent assay (ELISA), and genetic polymorphisms by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or endpoint genotyping. Before DAA treatment, severe fibrosis or cirrhosis (F3/4) was associated with higher values of tumor necrosis factor-alpha (TNF-α) and genotypes transforming growth factor-beta-509 C/T_CC (TGF-β-509 C/T_CC), interleukine-10-1082 T/C_CC (IL-10-1082 T/C_CC), and IL-10-592 G/T_GT. After DAA treatment, fewer F3/4 patients and lower values of TNF-α were found. Patients with TNF-α-308 G/A_GG and IL-10-592 G/T_GT were at risk for F3/4. Lack of improvement of liver fibrosis was associated with lower baseline values of platelet count for genotypes TNF-α-308 G/A_GG and haplotype TT/GG of IL-10-1082 T/C and IL-10-592 G/T. Our study showed decreased liver fibrosis/inflammation and normalization of liver injury biomarkers after DAA treatment. It also points to the importance of suppressing the pro-inflammatory response by DAAs in the resolution of hepatitis C, contributing to the improvement of liver damage evaluated by transient elastography., Ph.D. scholarship from Technology and Science Foundation (FCT); PDE/BDE/114585/2016. The writing of the manuscript was also supported by funds from the Foundation for Science and Technology to ISAMB (ref. UIDB/04295/2020 and UIDP/04295/2020).

Background: Single-nucleotide polymorphisms (SNPs) in collagen genes are predisposing factors for anterior cruciate ligament (ACL) rupture. Although these events are more frequent in females, the sex-specific risk of reported SNPs has not been evaluated. Purpose: We aimed to assess the sex-specific risk of historic non-contact ACL rupture considering candidate SNPs in genes previously associated with muscle, tendon, ligament and ACL injury in elite footballers. Study Design: This was a cohort genetic association study. Methods: Forty-six (twenty-four females) footballers playing for the first team of FC Barcelona (Spain) during the 2020–21 season were included in the study. We evaluated the association between a history of non-contact ACL rupture before July 2022 and 108 selected SNPs, stratified by sex. SNPs with nominally significant associations in one sex were then tested for their interactions with sex on ACL. Results: Seven female (29%) and one male (4%) participants had experienced non-contact ACL rupture during their professional football career before the last date of observation. We found a significant association between the rs13946 C/C genotype and ACL injury in women footballers (p = 0.017). No significant associations were found in male footballers. The interaction between rs13946 and sex was significant (p = 0.027). We found that the C-allele of rs13946 was exclusive to one haplotype of five SNPs spanning COL5A1. Conclusions: The present study suggests the role of SNPs in genes encoding for collagens as female risk factors for ACL injury in football players. Clinical Relevance: The genetic profiling of athletes at high risk of ACL rupture can contribute to sex-specific strategies for injury prevention in footballers.

Park, MacLean, et al. conduct an exome-wide association study of liver fat content in the Penn Medicine BioBank. By leveraging machine learning-assisted analysis of clinical CT scans to quantify steatosis, they uncover previously undescribed liver fat-associated genetic variants. Non

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

Ishemijski moždani udar (IMU) u djece je relativno rijedak poremećaj miješane etiologije koja je nerazjašnjena u približno 30 % slučajeva. Protrombotički poremećaji prepoznati su kao rizični čimbenik za nastanak IMU-a u djece, ali su potencijalne pozadinske genske varijacije analizirane u oskudnom broju studija u specifičnim populacijama ili u odraslih, dok u djece rijetko ili uopće nisu analizirane. Kako se povezanost protrombotičkih polimorfizama s IMU-om može razlikovati ovisno o geografskoj i etničkoj pripadnosti ispitivane populacije, a poznato je dodatno povećanje rizika u prisutnosti više od jednoga protrombotičkog rizičnog čimbenika, cilj ovoga istraživanja jest ispitati povezanost pojedinačnih polimorfizama u genima za čimbenike zgrušavanja, glikoproteinima trombocitne membrane i intermedijarne rizične čimbenike te potencijal zajedničke povezanosti s pojavom IMU-a u djece u Hrvatskoj ovisno o tipu, dobi nastanka i lokalizaciji IMU-a. Genotipizacija 21 polimorfizma u 13 gena kandidata provedena je iz uzorka DNA leukocita dobivenih nakon prikupljanja uzoraka ostatne periferne krvi od 185 djece starosne dobi do 18 godina s potvrđenom dijagnozom arterijskog IMU-a ili tromboze venskih sinusa mozga (CSVT) i 185 zdrave djece podudarne po dobi i spolu djeci s IMU-om. Dobiveni rezultati potvrdili su veću zastupljenost dječaka u svim podtipovima bolesti, osim perinatalnog arterijskog IMU-a i CSVT-a te različite genetičke čimbenike za karakterizaciju različitih podtipova IMU-a u djece. Na temelju dobivenih rezultata predložen je i algoritam ispitanih genetičkih čimbenika za IMU u djece za razlikovanje rizika nastanka podtipova bolesti te je uspostavljena baza podataka djece s IMU-om u Hrvatskoj. Rezultati predloženog istraživanja proširili su dosadašnja saznanja o potencijalnoj ulozi ispitanih genskih varijacija u etiologiji IMU-a u djece u Hrvatskoj, ali i u općoj populaciji. Ischemic paediattric stroke (IPS) is a relatively rare disorder of mixed aetiology that is unexplained in approximately 30% of cases. Prothrombotic disorders are recognized as a risk factor for the development of IPS, but potential genetic variations in prothrombotic risk factors have been analysed in a limited number of studies in specific populations or in adults, while in children they have been scarcely analysed or they have not been analysed at all. As the association of prothrombotic polymorphisms with IPS can differ depending on the geographic and ethnic categorisation of the population studied, and an additional increased risk is known in the presence of more than one prothrombotic risk factor, the aim of this study is to examine the association of individual polymorphisms in the genes coding clotting factors, platelet membrane glycoproteins and intermediate risk factors, and the potential of their joint association with the occurrence of IPS in children in Croatia depending on the type of IPS, age of onset and localization of the lesion. Genotyping of 21 polymorphisms in 13 candidate genes was performed in a DNA samples obtained from leukocytes after collecting residual peripheral blood samples from 185 children aged up to 18 years with confirmed diagnosis of arterial IPS (AIS) or cerebral venous sinus thrombosis (CSVT) and 185 healthy children matched by age and gender to children with IPS. Obtained results confirmed a higher frequency of AIS in boys and other subtypes, but not in perinatal AIS and CSVT. Also, it has been proven that different subtypes of IPS are caracterised by different genetic factors. Based on the obtained results, an algorithm of tested genetic risk factors for IPS was proposed to distinguish the risk of subtypes of the disease, which established a database of children with IPS in Croatia. The results of the proposed research expanded the previous knowledge about the potential role of the examined genetic variations in the aetiology of IPS in Croatia, with translational potential to the adult population.

Several recent works have raised the possibility of the contribution of the lymphocyte activation gene 3 (LAG3) protein in the inflammatory processes of multiple sclerosis (MS). Results of studies on the possible association between LAG3 gene variants and the risk of MS have been inconclusive. In this study, we tried to show the possible association between the most common single nucleotide variants (SNVs) in the CD4 and LAG3 genes (these two genes are closely related) and the risk of MS in the Caucasian Spanish population. We studied the genotypes and allelic variants CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 in 300 patients diagnosed with MS and 400 healthy patients using specific TaqMan-based qPCR assays. We analyzed the possible influence of the genotype frequency on age at the onset of MS, the severity of MS, clinical evolutive subtypes of MS, and the HLADRB1*1501 genotype. The frequencies of the CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 genotypes and allelic variants were not associated with the risk of MS and were unrelated to gender, age at onset and severity of MS, the clinical subtype of MS, and HLADRB1*1501 genotype. The results of the current study showed a lack of association between the CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 SNVs and the risk of developing MS in the Caucasian Spanish population.

Several population studies showed an association between variation in pain sensitivity and genetic polymorphisms located in Prodynorphin (PDYN) and Kappa Opioid Receptor (OPRK1) human genes. We analysed polymorphisms of these two genes to characterise their variation in Argentinian populations, as well as to evaluate their association with acute pain sensitivity. We studied 11 genetic markers in individuals from four locations in Argentina (Ciudad Autónoma de Buenos Aires, La Plata, Resistencia, and Misión Nueva Pompeya), calculated the population parameters, and evaluated the possible association among pain sensitivity, clinical, and genetic variables through a Generalised Estimating Equation model. High linkage disequilibrium was observed in the four populations for both genes, and significant differences were found among frequencies of Argentinian populations and those from other continents reported in the 1000 Genomes Project. Four PDYN gene polymorphisms from 3´ untranslated region and exon 4 showed association with acute pain sensitivity. One genotype of each of these polymorphisms was associated with a higher pain sensitivity, probably related with the activation of the N-methyl-D-aspartate (NMDA) receptors. We found a strong association with acute pain for the following clinical variables: 1) time after surgery, 2) intravenous klosidol supplied every 8 h, and 3) type of incision. Our results highlight the importance of a regional study of genetic variants which influence pain sensitivity and analgesic response., La asociación entre la sensibilidad al dolor y los polimorfismos que presentan los genes humanos de prodinorfina (PDYN) y receptor opioide kappa (OPRK1) se ha evidenciado en distintos estudios poblacionales. Con el objetivo de caracterizar la variación de estos genes y evaluar su asociación con dolor agudo en la población argentina, analizamos 11 polimorfismos en individuos provenientes de cuatro localidades argentinas (Ciudad Autónoma de Buenos Aires, La Plata, Resistencia, y Misión Nueva Pompeya). Calculamos los parámetros poblacionales y evaluamos la posible asociación entre sensibilidad al dolor, variables clínicas y variables genéticas a través de un modelo de ecuación generalizada de estimación. Se observó alto desequilibrio de ligamiento para ambos genes en las cuatro poblaciones analizadas, y se encontraron diferencias significativas entre las frecuencias de poblaciones argentinas y las reportadas en el Proyecto 1000 Genomes para poblaciones de otros continentes. Cuatro polimorfismos de la región 3´UTR y el exón 4 de PDYN mostraron asociación con la sensibilidad al dolor agudo. En cada uno de estos polimorfismos, un genotipo resultó asociado con alta sensibilidad al dolor, probablemente en relación con la activación de receptores N-metil-D-aspartato (NMDA). Encontramos una fuerte asociación con dolor agudo para las siguientes variables clínicas: 1) tiempo post-cirugía, 2) administración intravenosa de klosidol cada 8 h, y 3) tipo de incisión. Nuestros resultados resaltan la importancia de realizar estudios regionales de variables genéticas que influyen en la sensibilidad al dolor y la respuesta analgésica., Centro de Investigación de Proteínas Vegetales, Instituto Multidisciplinario de Biología Celular

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.

Purpose - to analyze the effectiveness of the timely appointment of pathogenetically justified secondary prevention in a patient with a burdened thrombotic and obstetric anamnesis based on the assessment of the course of pregnancy and the postpartum period in this woman. Clinical case. A woman with fetal loss syndrome and recurrent venous thrombosis applied for a consultation to plan pregnancy. The examination revealed a homozygous polymorphism of the F2-prothrombin gene (-20210 G>A), a decrease in protein S activity to the level of 35%, which indicated an extremely high risk of thromboembolic complications. Pregnancy occurred on the background of anticoagulant therapy in combination with pregravid cofactor vitamin therapy. During pregnancy, the patient received low molecular weight heparins in therapeutic doses in combination with acetylsalicylic acid at a dose of 150 mg per day, diosmin 600 mg and cofactor vitamin therapy. According to the results of combined screening in the I trimester, with the calculation of the risks of preeclampsia, the woman was classified as a high risk group for its development. At 23-24 and 32-33 weeks of gestation, an analysis was performed to calculate the risk of perinatal complications in the II-III trimesters by determining the ratio of water-soluble tyrosine kinase-1 / placental growth factor (Sflt-1/PlGF). The data obtained indicated that the preventive therapy prescribed to the patient was adequate and effective. The pregnancy was completed at the full 37 weeks of gestation by spontaneous delivery in cephalic presentation without complications. A boy was born weighing 2950 g, Apgar score - 7/8. Conclusions. The clinical case is a vivid example of how well-timed, adequate prophylactic therapy can work efficiently and effectively, even in women with a rather burdensome thrombotic and obstetric history. This case confirms the necessity and expediency of using the entire modern diagnostic arsenal that exists in Ukraine to predict the occurrence of «Great» obstetric syndromes, which to this day occupy one of the leading places in the structure of maternal and perinatal losses. The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors., Цель - проанализировать эффективность своевременного назначения патогенетически обоснованной вторичной профилактики у пациентки с отягощенным тромботическим и акушерским анамнезом на основании оценки беременности и послеродового периода у этой женщины. Клинический случай. Женщина с синдромом потери плода и рецидивирующими венозными тромбозами обратилась на консультацию с целью планирования беременности. При обследовании выявили гомозиготный полиморфизм гена F2-протромбин (-20210 G>A), снижение активности протеина S до уровня 35%, что свидетельствовало о крайне высоких рисках тромбоэмболических осложнений. Беременность наступила на фоне антикоагулянтной терапии в сочетании с прегравидарной кофакторной витаминотерапией. В течение беременности пациентка получала низкомолекулярные гепарины в лечебных дозах в сочетании с ацетилсалициловой кислотой в дозе 150 мг в сутки, диосмин 600 мг и кофакторную витаминотерапию. По результатам комбинированного скрининга в I триместре с расчетом рисков преэклампсии женщину отнесли к группе высокого риска ее развития. В сроке 23-24 и 32-33 недели гестации провели анализ на расчет риска перинатальных осложнений во II-III триместрах по определению соотношения водорастворимая тирозинкиназа-1 / плацентарный фактор роста (Sflt-1/PlGF). Полученные данные указывали на то, что профилактическая терапия, назначенная пациентке, была адекватной и эффективной. Беременность завершилась в сроке полных 37 недель беременности самостоятельными родами в головном предлежании без осложнений. Родился мальчик весом 2950 г, по шкале Апгар - 7/8 баллов. Выводы. Клинический случай - яркий пример того, как может качественно и эффективно работать своевременно назначенная, адекватная профилактическая терапия даже у женщин с достаточно отягощенным тромботическим и акушерским анамнезом. Этот случай подтверждает необходимость и целесообразность использования всего существующего в Украине современного диагностического арсенала для прогнозирования возникновения «больших» акушерских синдромов, которые по сей день занимают одно из ведущих мест в структуре материнских и перинатальных потерь. Исследование выполнено в соответствии с принципами Хельсинкской декларации. На проведение исследований получено информированное согласие женщины. Авторы заявляют об отсутствии конфликта интересов., Мета - проаналізувати ефективність своєчасного призначення патогенетично обґрунтованої вторинної профілактики в пацієнтки з обтяженим тромботичним та акушерським анамнезом на підставі оцінки перебігу вагітності й післяпологового періоду в цієї жінки. Клінічний випадок. Жінка із синдромом втрати плода та рецидивними венозними тромбозами звернулася на консультацію для планування наступної вагітності. Під час обстеження виявили гомозиготний поліморфізм гена F2-протромбін (-20210 G>A), зниження активності протеїну S до рівня 35%, що вказало на вкрай високі ризики тромбоемболічних ускладнень. Вагітність наступила на тлі антикоагулянтної терапії в поєднанні з прегравідарною кофакторною вітамінотерапією. Протягом вагітності пацієнтка отримувала низькомолекулярні гепарини в лікувальних дозах разом з ацетилсаліциловою кислотою в дозі 150 мг на добу, діосмін 600 мг і кофакторну вітамінотерапію. За результатами комбінованого скринінгу в І триместрі з розрахунком ризиків прееклампсії жінку віднесли до групи високого ризику її розвитку. У терміні 23-24 і 32-33 тижні гестації провели аналіз на розрахунок ризику перинатальних ускладнень у II-III триместрах щодо визначення співвідношення водорозчинна тирозинкіназа-1 / плацентарний фактор росту (Sflt-1/PlGF). За отриманими даними, профілактична терапія, призначена пацієнтці, була адекватною та ефективною. Вагітність завершилася в терміні повних 37 тижнів вагітності самостійними пологами в головному передлежанні, без ускладнень. Народився хлопчик масою тіла 2950 г, за шкалою Апгар - 7/8 балів. Висновки. Клінічний випадок - яскравий приклад того, як може якісно й ефективно працювати своєчасно призначена, адекватна профілактична терапія, навіть у жінок із досить обтяженим тромботичним та акушерським анамнезом. Цей випадок підтверджує необхідність і доцільність застосування всього сучасного діагностичного арсеналу, який існує в Україні, для прогнозування виникнення «великих» акушерських синдромів, що донині посідають одне з провідних місць у структурі материнських і перинатальних втрат. Дослідження виконано відповідно до принципів Гельсінської декларації. На проведення дослідження отримано інформовану згоду жінки. Автори заявляють про відсутність конфлікту інтересів.

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09–1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.

Preeclampsia (PE) is one of the most important problems of modern obstetrics. There is an opinion that the nature of PE is different when it starts before or after 34 weeks of pregnancy. Early onset of PE correlates with high neonatal morbidity and mortality and maternal complications. Being a multifactorial disease, PE has a number of candidate genes that are involved in the complex regulation of various endothelial functions. The article provides an overview of modern medical literature on the etiology and pathogenesis of PE. For a more detailed understanding of the pathogenesis, each angiogenesis factor is considered separately, as well as variations in the genes encoding them and the influence of these factors on the development of PE. Purpose - to clarify the causes of PE development, the role of timely diagnosis of genetic polymorphisms and angiogenesis markers for constructing an algorithm for diagnosing and predicting the development of PE. It has been established that the main pathogenetic moment in the development of PE is the lack of reconstruction of the junction of the spiral arteries and the trophoblast, which reflects a defect in deep placentation. This contributes to increased production of vasoconstrictor mediators from the very beginning of pregnancy and their progressive increase with gestational age. This does not allow the formation of adequate uteroplacental bleeding, which leads to relative hypoxia in the trophoblastic tissue, thereby causing oxidative stress of the entire placenta. This phenomenon further compromises placental villous angiogenesis and leads to an imbalance in the production of angiogenic and antiangiogenic growth factors. It has been proven that the presence of polymorphism in the angiogenesis genes worsens the pathomorphological conditions caused by PE. This is due to a genetically programmed decrease in the production of angiogenic factors, which further exacerbates the aforementioned imbalance. That is why a comprehensive genetic examination of a woman at the stage of preconception preparation will make it possible to predict the risks of developing PE. This prognosis will provide the possibility of earlier administration of drugs that can improve the effects of primary placentation and reduce rates of gestational complications and perinatal losses. No conflict of interests was declared by the authors., Преэклампсия (ПЭ) является одной из важнейших проблем современного акушерства. Существует мнение, что природа ПЭ различна при ее начале до или после 34 недель беременности. Раннее начало ПЭ коррелирует с высоким уровнем неонатальной заболеваемости и смертности, материнскими осложнениями. Будучи мультифакториальным заболеванием, ПЭ имеет целый ряд генов-кандидатов, вовлеченных в сложный процесс регулирования различных функций эндотелия. Представлен обзор современной медицинской литературы по этиологии и патогенезу ПЭ. Для более детального понимания патогенеза рассмотрен каждый фактор ангиогенеза отдельно, а также вариации кодирующих их генов и влияние именно этих факторов на развитие ПЭ. Цель - уточнить причины развития ПЭ, роль своевременной диагностики генетических полиморфизмов и маркеров ангиогенеза для построения алгоритма диагностики и прогнозирования развития ПЭ. Установлено, что основным патогенетическим моментом в развитии ПЭ является отсутствие реконструкции зоны стыка спиральных артерий и трофобласта, что отражает дефект глубокой плацентации. Это способствует повышенной продукции сосудосуживающих медиаторов с самого начала беременности и прогрессивному их увеличению со сроком беременности. Это не позволяет сформировать адекватное маточно-плацентарное кровотечение, что приводит к относительной гипоксии в трофобластической ткани, вызывая тем самым оксидативный стресс всей плаценты. Такое явление в дальнейшем компрометирует плацентарный ворсинчатый ангиогенез и приводит к дисбалансу продукции ангиогенных и антиангиогенных факторов роста. Доказано, что наличие полиморфизма в генах ангиогенеза ухудшает патоморфологические состояния, обусловленные ПЭ. Это объясняется генетически запрограммированным снижением выработки именно ангиогенных факторов, что еще больше усугубляет вышеупомянутый дисбаланс. Именно поэтому комплексное генетическое обследование женщины на этапе прегравидарной подготовки позволит прогнозировать риск развития ПЭ. Данный прогноз обеспечит возможность более раннего назначения препаратов, способных улучшить эффекты первичной плацентации и снизить показатели гестационных осложнений и перинатальных потерь. Авторы заявляют об отсутствии конфликта интересов., Прееклампсія (ПЕ) є однією з найважливіших проблем сучасного акушерства. Існує думка, що природа ПЕ різна в разі її початку до або після 34 тижнів вагітності. Ранній початок ПЕ корелює з високим рівнем неонатальної захворюваності і смертності, материнськими ускладненнями. Будучи мультифакторіальним захворюванням, ПЕ має ряд генів схильності, залучених до складного процесу регулювання різноманітних функцій ендотелію. Наведено огляд сучасної медичної літератури щодо етіології та патогенезу ПЕ. Для детальнішого розуміння патогенезу розглянуто кожний фактор ангіогенезу окремо, а також варіації генів, що їх кодують, і вплив саме цих факторів на розвиток ПЕ. Мета - уточнити причини розвитку ПЕ, роль своєчасної діагностики генетичних поліморфізмів і маркерів ангіогенезу для побудови алгоритму діагностики та прогнозування розвитку ПЕ. Встановлено, що основним патогенетичним моментом у розвитку ПЕ є відсутність реконструкції зони стику спіральних артерій та трофобласту, що відображає дефект глибокої плацентації. Це спричиняє підвищену продукцію судинозвужувальних медіаторів від початку вагітності та прогресивне їх збільшення з терміном вагітності. Це не дає змоги сформувати адекватний матково-плацентарний кровотік, що призводить до відносної гіпоксії в трофобластичній тканині, викликаючи тим самим оксидативний стрес усієї плаценти. Таке явище надалі компрометує плацентарний ворсинчастий ангіогенез і призводить до дисбалансу продукції ангіогенних та антиангіогенних факторів росту. Доведено, що поліморфізм у генах ангіогенезу погіршує патоморфологічні стани, обумовлені ПЕ. Це пояснюється генетично запрограмованим зниженням вироблення саме ангіогенних факторів, що посилює вищезазначений дисбаланс. Саме тому комплексне генетичне обстеження жінки на етапі прегравідарної підготовки дасть змогу прогнозувати ризик розвитку ПЕ. Такий прогноз забезпечить можливість більш раннього призначення препаратів, здатних поліпшити ефекти первинної плацентації та знизити показники гестаційних ускладнень і перинатальних втрат. Автори заявляють про відсутність конфлікту інтересів.

Objectives: The purpose of our study is to investigate the effects of apolipoprotein B (APOB) and APOE gene polymorphisms on bleeding complications in patients receiving direct oral anticoagulants (DOACs). Methods: A total of 16 single nucleotide polymorphisms (SNPs) in 468 patients were genotyped. Six SNPs of ABCB1 (rs3842, rs1045642, rs2032582, rs1128503, rs3213619, and rs3747802), one SNP of CYP3A5 (rs776746), seven SNPs of APOB (rs1042034, rs2163204, rs693, rs679899, rs13306194, rs13306198, and rs1367117), and two SNPs of APOE (rs429358 and rs7412) were analyzed by a TaqMan genotyping assay. Multivariable logistic regression analysis with selected variables was performed for the construction of a risk scoring system. Two risk scoring systems were compared (demographic factors only vs. demographic factors and genetic factors). Results: In the multivariable analyses, two models were constructed; only demographic factors were included in Model I and both demographic factors and genetic factors in Model II. Rivaroxaban and anemia showed significant association with bleeding in both models. Additionally, ABCB1 rs3842 variant homozygote carriers (CC) and APOB rs13306198 variant allele carriers (AG, AA) had a higher risk of bleeding risk compared with that of wild-type allele carriers (TT, TC) and wild-type homozygote carriers (GG), respectively. Whereas the area under the receiver operating characteristic curve (AUROC) value using demographic factors only was 0.65 (95% confidence interval (CI): 0.56–0.74), the AUROC increased to 0.72 by adding genetic factors (95% CI: 0.65–0.80). The predicted bleeding risks of bleeding in patients with 0, 1, 2, 3, 4, 5, 6, 7 and 8 points from the logistic regression curve were 0.8%, 2.0%, 5.4%, 5.2%, 12.5%, 26.9%, 47.0%, 64.3% and 82.3%, respectively. Conclusions: The study results can be used for enhancing individualized treatment strategies in patients taking DOACs, helping clinicians predict the bleeding risk.

Yuhao Zhang,1,2 Dawei Sun3 1Department of Otolaryngology Head and Neck Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People’s Republic of China; 2Department of Otolaryngology Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 3Department of Thyroid Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, People’s Republic of ChinaCorrespondence: Dawei SunDepartment of Thyroid Surgery, The Affiliated Hospital of Qingdao University, #16 Jiangsu Road, Qingdao, Shandong, 266000, People’s Republic of ChinaEmail sundawei18669@sina.comPurpose: 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.Keywords: head and neck cancer, HNC, Fc receptor-like 3, FCRL3, NLR family pyrin domain containing 3, NLRP3, interleukin 2, IL2, genetic polymorphisms

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.

An optimized method for bacterial strain differentiation, based on combination of Repeated Sequences and Whole Genome Alignment Differential Analysis (RS&WGADA), is presented in this report. In this analysis, 51 Acinetobacter baumannii multidrug-resistance strains from one hospital environment and patients from 14 hospital wards were classified on the basis of polymorphisms of repeated sequences located in CRISPR region, variation in the gene encoding the EmrA-homologue of E. coli, and antibiotic resistance patterns, in combination with three newly identified polymorphic regions in the genomes of A. baumannii clinical isolates. Differential analysis of two similarity matrices between different genotypes and resistance patterns allowed to distinguish three significant correlations (p A. baumannii isolates in different wards of the hospital in the time frame of several years, indicating that the optimized method may be useful in hospital epidemiological studies, particularly in identification of the source of primary infections.

We aimed to evaluate the effect of selected polymorphisms of the ACTN3, ACE, HIF1A and PPARA genes on the immediate supercompensation training effect of elite Slovak endurance runners and football players compared with a sedentary control group. Adaptation effect levels were evaluated by 10 s continuous vertical jump test parameters measured by Optojump. Genetic polymorphisms were determined by PCR and Sanger sequencing. We found significant differences in the effect of PPARA genotypes in the experimental group. C allele genotypes represented an advantage in immediate supercompensation (p < 0.05). We observed a significant combined effect of multiple genes on immediate supercompensation (p < 0.05): the RR genotype of the ACTN3 gene, the ID genotype of the ACE gene, the Pro/Pro genotype of HIF1A, and the GC and GG genotypes of PPARA genes. In the control group, we found a significant effect (p < 0.05) on immediate supercompensation of the II genotype of the ACE gene and the Pro/Ser genotype of the HIF1A gene. We found significant differences in genotype frequency of ACE (p < 0.01) and PPARA (p < 0.001) genes. We confirmed that individual genetic polymorphisms of ACTN3, ACE, HIF1A and PPARA genes have a different effect on the level of immediate supercompensation of the lower limbs depending on the training adaptation of the probands and the combination of genotypes.

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.

Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of antihyperglycemic drugs that enhance appropriate pancreatic β-cell secretion, pancreatic α-cell (glucagon) suppression, decrease liver glucose production, increase satiety through their action on the central nervous system, slow gastric emptying time, and increase insulin action on peripheral tissue. They are effective in the management of type 2 diabetes mellitus and have a favorable effect on weight loss. Their cardiovascular and renal safety has been extensively investigated and confirmed in many clinical trials. Recently, evidence has shown that in addition to the existing approaches for the treatment of obesity, semaglutide in higher doses promotes weight loss and can be used as a drug to treat obesity. However, some T2DM and obese patients do not achieve a desired therapeutic effect of GLP-1 receptor agonists. This could be due to the multifactorial etiologies of T2DM and obesity, but genetic variability in the GLP-1 receptor or signaling pathways also needs to be considered in non-responders to GLP-1 receptor agonists. This review focuses on the pharmacological, clinical, and genetic factors that may influence the response to GLP-1 receptor agonists in the treatment of type 2 diabetes mellitus and obesity.

Colorectal cancer (CRC) is a heterogeneous disease with evidence of distinct tumor types that develop through different somatically altered pathways. To better understand the impact of the host genome on somatically mutated genes and pathways, we assessed associations of germline variations with somatic events via two complementary approaches. We first analyzed the association between individual germline genetic variants and the presence of non-silent somatic mutations in genes in 1375 CRC cases with genome-wide SNPs data and a tumor sequencing panel targeting 205 genes. In the second analysis, we tested if germline variants located within previously identified regions of somatic allelic imbalance were associated with overall CRC risk using summary statistics from a recent large scale GWAS (n≃125 k CRC cases and controls). The first analysis revealed that a variant (rs78963230) located within a CNA region associated with TLR3 was also associated with a non-silent mutation within gene FBXW7. In the secondary analysis, the variant rs2302274 located in CDX1/PDGFRB frequently gained/lost in colorectal tumors was associated with overall CRC risk (OR = 0.96, p = 7.50e-7). In summary, we demonstrate that an integrative analysis of somatic and germline variation can lead to new insights about CRC.

Objective: analysis of the osteoarthritis (OA) comorbidity taking into account the microelement status and genetic polymorphisms of the examined patients, determination of the prospects for the OA prevention and therapy.Material and methods. A cross-sectional study of a multiethnic cohort (n=655, mean age 43±14 years, 95% CI 29–70) formed on the basis of the Institute of Microelements database, was carried out. For all participants, the content of the 62 elements of the Element Periodic Table profile in hair was identified and variants of 120 nucleotide polymorphisms associated with various pathologies were definedResults. The study found that 18 of the 27 ICD-10 diagnoses examined were comorbid with OA. Osteoarthritis was comorbid with pathologies with a pronounced component of inflammation (ulcerative colitis, atherosclerosis, unspecified encephalopathy, obesity, diabetes mellitus, essential (primary) hypertension, urine calculus, acute myocardial infarction, cholelithiasis, etc.). The core of OA comorbidity was established, which included following pathologies: chronic cerebral ischemia, diabetes mellitus, thrombophlebitis, atherosclerosis, cholelithiasis. Seven profiles of the most frequent combinations of these diagnoses were identified. The presence of 2 out of 5 of these pathologies was recorded in 92% of patients with OA (n=50) and only in 2% of control patients (n=600), which corresponded to an extreme increase in the risk of OA (OR 56.3, 95% CI 17.4–181.6, pConclusion. Based on the obtained results the prospects for the use of chondroitin sulfate and glucosamine sulfate in patients with an increased risk of OA development are shown.

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.

BackgroundVariation in host genetic factors may result in variation in the host immune response to the infection. Some chronic diseases may also affect individuals’ susceptibility to infectious diseases. The aim of this study was to evaluate the association of the host genetic factors mostly involved in inflammation, as well as hypercholesterolemia and diabetes with mild flu in an Iranian population.MethodsIn this cross-sectional study, nasopharyngeal swab samples were collected from 93 patients referred to primary care centers of Markazi, Semnan, and Zanjan provinces (central Iran) due to flu-like symptoms between March 2015 and December 2018. Of these, PCR test identified 49 influenza A/H1N1 and 44 flu-negative individuals. Twelve single-nucleotide polymorphisms (SNPs) in RPAIN, FCGR2A, MBL-2, CD55, C1QBP, IL-10, TNF-α and an unknown gene were genotyped using iPLEX GOLD SNP genotyping analysis. Hypercholesterolemia and diabetes status was determined based on the physician diagnosis. Association of the host genetic variants, hypercholesterolemia and diabetes with mild A/H1N1 flu was assessed with univariable and multivariable logistic regression analysis as implemented in Stata software (v.14). Statistical tests were considered as significant at 0.05 levels.ResultsFrequency of diabetes and hypercholesterolemia, as well as participants mean age was significantly higher in the flu-negative rather than the flu-positive group. Of 12 SNPs, nine did not show any significant association with mild flu in our study (rs1801274, rs1800451, rs2564978, rs361525, rs1800450, rs1800871, rs1800872, rs1800896, rs1800629). Possessing G vs. A allele in two SNPs (rs3786054 and rs8070740) was associated with a threefold increase in the chance of mild flu when compared to flu-negative patients (95% CI: 1.1, 22.0). Possessing C allele (vs. A) in the rs9856661 locus also increased the chance of mild flu up to 2 folds (95% CI: 1.0, 10.0).ConclusionThe results showed that possessing the G allele in either rs3786054 or rs8070740 loci in C1QBP and RPAIN genes, respectively, increased the risk of H1N1 infection up to 3.3 folds, regardless of the patient’s age, BMI, diabetes, and hypercholesterolemia. Complementary functional genomic studies would shed more light on the underlying mechanism of human immunity associated with these genetic markers. The identified genetic factors may have the same role in susceptibility to similar respiratory infections with RNA viruses, like SARS, MERS and COVID-19. Future genetic association studies targeting these RNA viruses, especially COVID-19 is recommended. Studies on other ethnic groups would also shed light on possible ethnic variations in genetic susceptibility to respiratory RNA viruses.Trial registryIR.PII.REC.1399.063

Objective: prognosis of thromboembolic complications using clinical diagnostic markers.Materials and methods. The study involved 151 patients who underwent total arthroplasty (TA) of large joints of the lower extremities. Blood serum was studied at the patient’s admission to the hospital, after surgery, and at discharge from the hospital. The following parameters were determined: cell-molecular marker vascular endothelial growth factor (VEGF), a genetic study was performed using the “Plasma screen. Plasma factors of the blood clotting system”. The content of VEGF was determined in blood serum using solid-phase enzyme immunoassay. The effectiveness of diagnostics based on sensitivity and specificity analysis was considered by constructing a ROC analysis at different points of separation of the values of the studied indicators.Results. Diagnostic significance of VEGF and the efficiency of determining PAI-1 were determined. In patients with elevated VEGF values (>183.6 pg/ml), PAI-1 gene polymorphism was detected, which reduces the fibrinolytic activity of the blood system and increases the risk of coronary disorders. This is especially important for patients in a hospital with a large number of risk factors for the development of VTEC due to prolonged immobilization of the limb. The study made it possible to determine that with VEGF values up to 183.6 pg/ml, a low probability of thromboembolic complications is predicted, and with values above 183.6 pg/ml — high.Conclusion. The course of DOA in athletes may be complicated by surgical intra-articular interventions of traumatological and orthopedic profile, which does not exclude the development of VTEO, significantly complicating drug therapy and the rehabilitation period. The presented data show that the determination of VEGF, 5G-675 4G polymorphism of the PAI 1 gene in blood serum can be used to assess the risk of venous thromboembolic complications (VTE), contributing to modern informative diagnostics, improving the quality of life of athletes and prolonging their sports career.

The pathogenesis of multiple sclerosis (MS) remains poorly understood. Presumably, MS is caused by multiple environmental, epigenetic, and genetic factors. Among them, human endogenous retroviruses (HERVs), Epstein-Barr virus (EBV) and vitamin D have been suggested to play a role in the pathogenesis and course of MS. Because vitamin D can affect the immune system and infections, it can be hypothesized that there is a close interplay between vitamins, EBV and ERV in the pathogenesis of MS. Here, we summarize the important data on vitamin D, including polymorphisms in genes related to vitamin D metabolism, EBV and ERV, in the pathogenesis of MS and create hypotheses regarding their interactions. Data indicate that vitamin D has a strong impact on viral infections and interferes with EBV infection, while EBV is capable of activating silent ERVs. We believe that EBV could be the missing link between vitamin D and ERV in MS pathogenesis.

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.

Prostate cancer is emerging as a significant global public health burden. The incidence and prevalence of prostate cancer has increased in Japan, as westernized lifestyles become more popular. Recent advances in genetic epidemiology, including genome-wide association studies (GWASs), have identified considerable numbers of human genetic factors associated with diseases. Several GWASs have reported significant loci associated with serum prostate-specific antigen (PSA) levels. One GWAS, which was based on classic GWAS microarray measurements, has been reported for Japanese so far. In the present study, we conducted a GWAS of serum PSA using 1000Genomes imputed GWAS data (n =1,216) from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study, to detect candidate novel genetic loci that influence serum PSA levels in Japanese. The association of SNPs/genetic variants with serum PSA as a continuous variable was tested using the linear Wald test. SNP rs10000006 in SGMS2 (sphingomyelin synthase 2) on chromosome 4 had genome-wide significance (P, This is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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

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

Breast cancer is the most common cancer in adult women aged 20 to 50 years. The therapeutic regimens that are commonly recommended to treat breast cancer are human epidermal growth factor receptor 2 (HER2) targeted therapy, endocrine therapy, and systemic chemotherapy. The selection of pharmacotherapy is based on the characteristics of the tumor and its hormone receptor status, specifically, the presence of HER2, progesterone receptors, and estrogen receptors. Breast cancer pharmacotherapy often gives different results in various populations, which may cause therapeutic failure. Different types of congenital drug resistance in individuals can cause this. Genetic polymorphism is a factor in the occurrence of congenital drug resistance. This review explores the relationship between genetic polymorphisms and resistance to breast cancer therapy. It considers studies published from 2010 to 2020 concerning the relationship of genetic polymorphisms and breast cancer therapy. Several gene polymorphisms are found to be related to longer overall survival, worse relapse-free survival, higher pathological complete response, and increased disease-free survival in breast cancer patients. The presence of these gene polymorphisms can be considered in the treatment of breast cancer in order to shape personalized therapy to yield better results.