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Vitiligo is a dermatological disease characterized by loss of melanocytes, causing non-scaly white macules on the skin. Zinc, copper, and selenium are important micronutrients that play a role in the normal functioning of the body and have been found to potentially aid in vitiligo treatment, although the relationship between their serum levels and vitiligo is not yet fully understood. This is a systematic review aimed at assessing the levels of serum zinc, copper, and selenium and their association with vitiligo. This review was performed following the Preferred Reporting Items of the systematic Review and Meta-Analysis (PRISMA) checklist and Cochrane guidelines. A comprehensive literature search was conducted on PubMed, Google Scholar and 41 studies published between 1970 and 2022 including 3353 vitiligo cases and 10,638 controls were included in the meta-analysis conducted from August 2022 till September 2023. The quality of the studies was assessed using the National Heart Lung and Blood Institute Study Quality Assessment tool, and the risk of bias was represented using the RobVis tool. The statistical analysis was performed using Review Manager (RevMan) Version 5.4. This meta-analysis indicate a significant decline in serum zinc levels (Z = 4.97; P < 0.0001; SMD = − 0.86; 95% CI − 1.19 to − 0.52) in vitiligo group with high statistical heterogeneity (Tau2 = 0.74; Chi2 = 513.95, d.f. = 26 [P < 0.00001]; I2 = 95%). Similarly for serum copper levels there was decline (Z = 2.43; P < 0.0001; SMD = − 0.50; 95% confidence interval [CI] − 0.91 to − 0.10) in vitiligo group and high statistical heterogeneity (Tau2 = 0.92; Chi2 = 475.10, d.f. = 22 [P < 0.00001]; I2 = 95%). On the other hand, there was a increase of serum selenium levels in the vitiligo group (Z = 0.56; P < 0.0001; SMD = 0.23; 95% confidence interval [CI], 0.58 to 1.04) and the results reveals high statistical heterogeneity among studies (Tau2 = 1.93; Chi2 = 406.44, d.f. = 11 [P < 0.00001]; I2 = 97%) in vitiligo patients compared to healthy controls. Publication bias was not found for the studies analysed. This study analyses the association of serum micronutrient levels and vitiligo among patients and controls from published research along with sub-group analysis specific to Asian populations using a meta-analysis. Low serum levels of Zinc and copper and high selenium levels are associated with Vitiligo. [ABSTRACT FROM AUTHOR]

In the last decade, an incredible improvement has been made in elucidating the genetic bases of cardiomyopathies. Here we report the impact of either the European Society of Cardiology (ESC) guidelines or the use of whole exome sequencing (WES) in terms of a number of variants of uncertain significance (VUS) and missed diagnoses in a series of 260 patients affected by inherited cardiac disorders. Samples were analyzed using a targeted gene panel of 128 cardiac‐related genes and/or WES in a subset of patients, with a three‐tier approach. Analyzing (i) only a subset of genes related to the clinical presentation, strictly following the ESC guidelines, 20.77% positive test were assessed. The incremental diagnostic rate for (ii) the whole gene panel, and (iii) the WES was 4.71% and 11.67%, respectively. The diverse analytical approaches increased the number of VUSs and incidental findings. Indeed, the use of WES highlights that there is a small percentage of syndromic conditions that standard analysis would not have detected. Moreover, the use of targeted sequencing coupled with "narrow" analytical approach prevents the detection of variants in actionable genes that could allow for preventive treatment. Our data suggest that genetic testing might aid clinicians in the diagnosis of inheritable cardiac disorders. [ABSTRACT FROM AUTHOR]

Background: Cascade testing can offer improved surveillance and timely introduction of clinical management for the at-risk biological relatives. Data on cascade testing and costs in mitochondrial diseases are lacking. To address this gap, we performed a cross-sectional retrospective study to provide a framework for cascade testing in mitochondrial diseases, to estimate the eligibility versus real-time uptake of cascade testing and to evaluate the cost of the genetic diagnosis of index cases and the cost of predictive cascade testing. Methods: Data was collected through retrospective chart review. The variant inheritance pattern guided the identification of eligible first-degree relatives: (i) Males with mitochondrial DNA (mtDNA) single nucleotide variants (SNVs) – siblings and mothers. (ii) Females with mtDNA SNVs – siblings, mothers and offspring. (iii) Autosomal Dominant (AD) nuclear DNA (nDNA) variants – siblings, offspring and both parents. (iv) Autosomal Recessive (AR) nDNA variants – siblings. Results: We recruited 99 participants from the Adult Mitochondrial Disease Clinic in Sydney. The uptake of cascade testing was 55.2% in the mtDNA group, 55.8% in the AD nDNA group and 0% in AR nDNA group. Of the relatives in mtDNA group who underwent cascade testing, 65.4% were symptomatic, 20.5% were oligosymptomatic and 14.1% were asymptomatic. The mean cost of cascade testing for eligible first-degree relatives (mtDNA group: $694.7; AD nDNA group: $899.1) was lower than the corresponding index case (mtDNA group: $4578.4; AD nDNA group: $5715.1) (p < 0.001). Conclusion: The demand for cascade testing in mitochondrial diseases varies according to the genotype and inheritance pattern. The real-time uptake of cascade testing can be influenced by multiple factors. Early diagnosis of at-risk biological relatives of index cases through cascade testing, confirms the diagnosis in those who are symptomatic and facilitates implementation of surveillance strategies and clinical care at an early stage of the disease. [ABSTRACT FROM AUTHOR]

Background Evidence about a potential link between current and lifetime night shift work and risk of incident asthma is insufficient. Aim To investigate the association of current and lifetime night shift work with risk of incident asthma, and the modified effect of genetic susceptibility on this association. Design and methods We included 253 773 individuals with complete night shift work information in the UK biobank. We calculated the standard polygenetic risk score (PRS) for asthma. The Cox proportional hazard models were conducted to estimate hazard ratios and 95% CIs. Results After multivariable adjustments, we found that current night shift work was associated with an increased risk of incident asthma in a dose–response fashion (P for trend < 0.001). Compared with day workers, those working usual/permanent night shifts had a 17% (95% CI: 1.04–1.33) higher risk of asthma incidence. In addition, we observed significant dose-dependent relationships of longer lifetime duration or frequency of night shift work with elevated risk of asthma incidence (all P for trend < 0.05). Compared with never night shift workers, those with a duration (≥5 years) or frequency (≥8 nights/month) of night shift work exhibited a 20% (95% CI: 1.03–1.39) or 22% (95% CI: 1.03–1.44) higher risk of incident asthma, respectively. Moreover, the elevated risk of incident asthma related to current and lifetime night shift work exposure was strengthened by high PRS, although no significant shift work–PRS interactions were detected. Conclusion Both current and lifetime night shift work may increase the risk of incident asthma, regardless of genetic predisposition to asthma. [ABSTRACT FROM AUTHOR]

Background and Objectives: The aim of the following cross-sectional study is to determine the association between human leukocyte antigen (HLA) alleles and outcomes in patients presenting to the emergency department (ED) with SARS-CoV-2 infection. Methods and Materials: Genotyping was made using the Axiom Human Genotyping SARS-CoV-2 Research Array. Statistical analysis was made with Fisher's exact test and multivariable logistic regression, adjusted for sex, age and clinical variables. Results: Of 190 patients, 11.1% were discharged from the ED; 57.9% were admitted to the COVID-19 ward, without intensive care unit (ICU) admission; 15.3% survived an ICU admission; and 15.8% died. After multivariable analysis, two HLA alleles protected against hospital admission (HLA-C*05:01, adjusted odds ratio [aOR] 0.2, 95% confidence interval [CI] 0.055–0.731; and HLA-DQB1*02:02, aOR 0.046, CI 0.002–0.871) and one was associated with higher risk for ICU admission or death (HLA-DQA1*05:01, aOR 2.517, CI 1.086–5.833). Conclusions: In this population, HLA-C*05:01 and HLA-DQB1*02:02 are associated with a protective effect against hospital admission and HLA-DQA1*05:01 is associated with higher risk of ICU admission or death in the multivariable analysis. This may help stratify risk in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Background: CDH1 and CTNNA1 remain as the main genes for hereditary gastric cancer. However, they only explain a small fraction of gastric cancer cases with suspected inherited basis. In this study, we aimed to identify new hereditary genes for early-onset gastric cancer patients (EOGC; < 50 years old). Methods: After germline exome sequencing in 20 EOGC patients and replication of relevant findings by gene-panel sequencing in an independent cohort of 152 patients, CTNND1 stood out as an interesting candidate gene, since its protein product (p120ctn) directly interacts with E-cadherin. We proceeded with functional characterization by generating two knockout CTNND1 cellular models by gene editing and introducing the detected genetic variants using a lentiviral delivery system. We assessed β-catenin and E-cadherin levels, cell detachment, as well as E-cadherin localization and cell-to-cell interaction by spheroid modeling. Results: Three CTNND1 germline variants [c.28_29delinsCT, p.(Ala10Leu); c.1105C > T, p.(Pro369Ser); c.1537A > G, p.(Asn513Asp)] were identified in our EOGC cohorts. Cells encoding CTNND1 variants displayed altered E-cadherin levels and intercellular interactions. In addition, the p.(Pro369Ser) variant, located in a key region in the E-cadherin/p120ctn binding domain, showed E-cadherin mislocalization. Conclusions: Defects in CTNND1 could be involved in germline predisposition to gastric cancer by altering E-cadherin and, consequently, cell-to-cell interactions. In the present study, CTNND1 germline variants explained 2% (3/172) of the cases, although further studies in larger external cohorts are needed. [ABSTRACT FROM AUTHOR]

Primary osteoarthritis (POA) is a complex hereditary disease that involves the interplay between genetics and epigenetics. MicroRNA molecules play important roles in epigenetic mechanisms. MicroRNA‐146a (miR‐146a) is a negative regulator of the immune response in osteoarthritis (OA). So, variations in the miR‐146a gene could affect OA risk. The aim of this study was to investigate the relationships between single nucleotide polymorphisms (SNPs) in the miR‐146a, interleukin‐6 (IL‐6), Toll‐like receptor 10 (TLR10), and tumor necrosis factor‐alpha (TNFA) genes and the risk for development of advanced‐stage primary hip osteoarthritis (PHOA) and primary knee osteoarthritis (PKOA) in the Croatian population. A total of 609 POA patients and 656 healthy donors were genotyped for SNPs in the miR‐146a (rs2910164, G>C). Since we used same patients and controls as two studies before us, we already had information about IL‐6 (rs1800795, C>G), TLR10 (rs11096957, C>T), and TNFA (rs1800629, C>T) genotypes of our subjects. None of the differences were statistically significant comparing either allelic or genotypic frequencies of miR‐146a SNP rs2910164 (G>C) between the PHOA and PKOA patients and controls. However, we found a significant association with risk to PHOA for the combination of genotypes (stratified miR‐146a genotype with the IL‐6, and stratified miR‐146a genotype with the TNFA). In a multifactorial disease such as POA, we have shown the indirect relevance of a second modifying factor (miR‐146a), which apparently contributes to the overall risk of PHOA. There was no risk association with the PKOA, indicating that these two localities (hip and knee) might have different risk‐modifying factors. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) dural arteriovenous fistulas (DAVF) have been reported in PTEN‐related hamartoma tumor syndrome (PHTS). However, PHTS‐associated DAVF remain an underexplored field of the PHTS clinical landscape. Here, we studied cases with a PTEN pathogenic variant identified between 2007 and 2020 in our laboratory (n = 58), and for whom brain imaging was available. Two patients had DAVF (2/58, 3.4%), both presenting at advanced stages: a 34‐year‐old man with a left lateral sinus DAVF at immediate risk of hemorrhage, and a 21‐year‐old woman with acute intracranial hypertension due to a torcular DAVF. Interestingly, not all patients had 3D TOF/MRA, the optimal sequences to detect DAVF. Early diagnosis of DAVF can be lifesaving, and is easier to treat compared to developed, proliferative, or complex lesions. As a result, one should consider brain MRI with 3D TOF/MRA in PHTS patients at genetic diagnosis, with subsequent surveillance on a case‐by‐case basis. [ABSTRACT FROM AUTHOR]

Background Associations between germline alterations in women and cancer risks among their relatives are largely unknown. Methods We identified women from 2 Swedish cohorts Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) and prevalent KARMA (pKARMA), including 28 362 women with genotyping data and 13 226 with sequencing data. Using Swedish Multi-Generation Register, we linked these women to 133 389 first-degree relatives. Associations between protein-truncating variants in 8 risk genes and breast cancer polygenic risk score in index women and cancer risks among their relatives were modeled via Cox regression. Results Female relatives of index women who were protein-truncating variant carriers in any of the 8 risk genes had an increased breast cancer risk compared with those of noncarriers (hazard ratio [HR] = 1.85, 95% confidence interval [CI] = 1.52 to 2.27), with the strongest association found for protein-truncating variants in BRCA1 and 2. These relatives had a statistically higher risk of early onset than late-onset breast cancer (P  = .001). Elevated breast cancer risk was also observed in female relatives of index women with higher polygenic risk score (HR per SD = 1.28, 95% CI = 1.23 to 1.32). The estimated lifetime risk was 22.3% for female relatives of protein-truncating variant carriers and 14.4% for those related to women in the top polygenic risk score quartile. Moreover, relatives of index women with protein-truncating variant presence (HR = 1.30, 95% CI = 1.06 to 1.59) or higher polygenic risk score (HR per SD = 1.04, 95% CI = 1.01 to 1.07) were also at higher risk of nonbreast hereditary breast and ovary cancer syndrome-related cancers. Conclusions Protein-truncating variants of risk genes and higher polygenic risk score in index women are associated with an increased risk of breast and other hereditary breast and ovary syndrome–related cancers among relatives. [ABSTRACT FROM AUTHOR]

Simple Summary: Hereditary breast cancer represents a significant proportion of breast cancer cases worldwide, and BRCA1 and BRCA2 explain the majority of these. Less frequent genes with variable penetrance remain less characterized in Colombia. This study explores the characteristics and outcomes of 82 breast cancer patients with germline pathogenic/likely pathogenic variants (PVs) treated and followed at the Instituto Nacional de Cancerología, Colombia (INC-C) from 2018 to 2021 as part of an Institutional Hereditary Cancer Program implementation. We described the distribution of germline PVs among the different breast cancer molecular subtypes in this cohort of carriers. We observed that most PVs were in known breast cancer susceptibility genes, and PVs in BRCA2 were the most frequent. Notably, we observed that patients with disease progression were predominantly carriers of PVs in the BRCA2 gene. This study aimed to investigate prognosis and survival differences in 82 breast cancer patients with germline pathogenic/likely pathogenic variants (PVs) treated and followed at the Breast Unit of the Instituto Nacional de Cancerología, Colombia (INC-C) between 2018 and 2021. Median age at diagnosis was 46 years, with 62.2% presenting locally advanced tumors, 47.6% histological grade 3, and 35.4% with triple-negative breast cancer (TNBC) subtype. Most carriers, 74.4% (61/82), had PVs in known breast cancer susceptibility genes (i.e., "associated gene carriers" group, considered inherited breast cancer cases): BRCA2 (30), BRCA1 (14), BARD1 (4), RAD51D (3), TP53 (2), PALB2 (2), ATM (2), CHEK2 (1), RAD51C (1), NF1 (1), and PTEN (1). BRCA1-2 represented 53.7%, and homologous recombination DNA damage repair (HR-DDR) genes associated with breast cancer risk accounted for 15.9%. Patients with PVs in non-breast-cancer risk genes were combined in a different category (21/82; 25.6%) (i.e., "non-associated gene carriers" group, considered other breast cancer cases). Median follow-up was 38.1 months, and 24% experienced recurrence, with 90% being distant. The 5-year Disease-Free Survival (DFS) for inherited breast cancer cases was 66.5%, and for other breast cancer cases it was 88.2%. In particular, for carriers of PVs in the BRCA2 gene, it was 37.6%. The 5-year Overall Survival (OS) rates ranged from 68.8% for those with PVs in BRCA2 to 100% for those with PVs in other HR-DDR genes. Further studies are crucial for understanding tumor behavior and therapy response differences among Colombian breast cancer patients with germline PVs. [ABSTRACT FROM AUTHOR]

Interleukin‐6 (IL‐6), a pivotal pro‐inflammatory cytokine, is closely linked to vascular wall thickening and atherosclerotic lesion. Since serum IL‐6 levels are largely determined by the genetic variant in IL‐6, this study was conducted to investigate whether the IL‐6 variant impacts cardiometabolic profile and the risk of premature coronary artery disease (PCAD). PubMed, Cochrane Library, Central, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and ClinicalTrials.gov were searched from May 13, 2022 to June 28, 2023. In total, 40 studies (26,543 individuals) were included for the analysis. The rs1800795 (a function variant in the IL‐6 gene) C allele was linked to higher levels of low‐density lipoprotein cholesterol (LDL‐C), total cholesterol (TC), fasting plasma glucose (FPG), body mass index (BMI), and waist circumference (WC), and a lower levels of high‐density lipoprotein cholesterol (HDL‐C). However, no significant association was observed of rs1800795 with triglycerides (TG), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Interestingly, a significant association was detected between rs1800795 and PCAD. Subgroup analyses indicted that the impacts of rs1800795 on cardiometabolic risk factors were significant in Caucasians but stronger in obese patients. In contrast, the impact of rs1800795 on PCAD was significant in brown race population. In summary, rs1800795 had a slight but significant impact on cardiometabolic risk factors and PCAD. IL‐6 inhibition with ziltivekimab or canakinumab may benefit high‐risk populations (e.g. brown race population, Caucasians, obese patients, etc.) with rs1800795 to prevent PCAD. [ABSTRACT FROM AUTHOR]

The aim of this study was to associate FGFR4 rs1966265 and rs351855 variants with colorectal cancer (CRC) in a Mexican population and to perform in silico analysis. Genomic DNA from 412 healthy individuals and 475 CRC patients was analyzed. In silico analysis was performed using the PolyPhen-V2, GEPIA, GTEx, and Cytoscape platforms. The GA genotype dominant model (GAAA) of rs1966265 and the AA genotype dominant and recessive models of rs351855 were identified as CRC risk factors (p < 0.05). CRC patients aged ≥ 50 years at diagnosis who consumed alcohol had a higher incidence of the rs351855 GA genotype than the control group (p < 0.05). Associations were observed between the rs1966265 GA genotype and patients with rectal cancer and stage III–IV disease. The rs351855 AA genotype was a risk factor for partial chemotherapy response, and the GA + AA genotype for age ≥ 50 years at diagnosis and rectal cancer was associated with a partial response to chemotherapy (p < 0.05). The AA haplotype was associated with increased susceptibility to CRC. In silico analysis indicated that the rs351855 variant is likely pathogenic (score = 0.998). Genotypic expression analysis in blood samples showed statistically significant differences (p < 0.05). EFNA4, SLC3A2, and HNF1A share signaling pathways with FGFR4. Therefore, rs1966265 and rs351855 may be potential CRC risk factors. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Clinical Hepatology / Linchuang Gandanbing Zazhi is the property of Journal of Clinical Hepatology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Overgrowth syndromes (e.g., Beckwith–Wiedemann) are associated with an increased risk of pediatric cancer, although there are few population‐based estimates of risk. There are also limited studies describing associations between other overgrowth features (e.g., hepatosplenomegaly) and pediatric cancer. Therefore, cancer risk among children with these conditions was evaluated with data from a large, diverse population‐based registry linkage study. Methods: This study includes all live births in Texas during the years 1999–2017. Children with overgrowth features and syndromes were identified from the Texas Birth Defects Registry; children with cancer were identified by linkage to the Texas Cancer Registry. Cox regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the association between each overgrowth syndrome/feature and cancer, which were adjusted for infant sex and maternal age. Results: In the total birth cohort (n = 6,997,422), 21,207 children were identified as having an overgrowth syndrome or feature. Children with Beckwith–Wiedemann syndrome were 42 times more likely to develop pediatric cancer (95% CI, 24.20–71.83), with hepatoblastoma being the most common, followed by Wilms tumor. The presence of any isolated overgrowth feature was associated with increased cancer risk (HR, 4.70; 95% CI, 3.83–5.77); associations were strongest for hepatosplenomegaly (HR, 23.04; 95% CI, 13.37–39.69) and macroglossia (HR, 11.18; 95% CI, 6.35–19.70). Conclusions: This population‐based assessment confirmed prior findings that children with either overgrowth syndromes or features were significantly more likely to develop cancer. Overall, this study supports recommendations for cancer surveillance in children with these conditions and may also inform future research into cancer etiology. Children with either overgrowth syndromes or features are at a significantly increased risk for childhood cancer. Results from this study may ultimately be used to guide recommendations for cancer surveillance in children with overgrowth syndromes/features and may also inform future research into cancer etiology. [ABSTRACT FROM AUTHOR]

Background Transcriptome-wide association studies have been successful in identifying candidate susceptibility genes for colorectal cancer (CRC). To strengthen susceptibility gene discovery, we conducted a large transcriptome-wide association study and an alternative splicing transcriptome-wide association study in CRC using improved genetic prediction models and performed in-depth functional investigations. Methods We analyzed RNA-sequencing data from normal colon tissues and genotype data from 423 European descendants to build genetic prediction models of gene expression and alternative splicing and evaluated model performance using independent RNA-sequencing data from normal colon tissues of the Genotype-Tissue Expression Project. We applied the verified models to genome-wide association studies (GWAS) summary statistics among 58 131 CRC cases and 67 347 controls of European ancestry to evaluate associations of genetically predicted gene expression and alternative splicing with CRC risk. We performed in vitro functional assays for 3 selected genes in multiple CRC cell lines. Results We identified 57 putative CRC susceptibility genes, which included the 48 genes from transcriptome-wide association studies and 15 genes from splicing transcriptome-wide association studies, at a Bonferroni-corrected P  value less than  .05. Of these, 16 genes were not previously implicated in CRC susceptibility, including a gene PDE7B (6q23.3) at locus previously not reported by CRC GWAS. Gene knockdown experiments confirmed the oncogenic roles for 2 unreported genes, TRPS1 and METRNL , and a recently reported gene, C14orf166. Conclusion This study discovered new putative susceptibility genes of CRC and provided novel insights into the biological mechanisms underlying CRC development. [ABSTRACT FROM AUTHOR]

Copyright of European Journal of Psychotraumatology is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction: Polygenic score (PGS) is a valuable method for assessing the estimated genetic liability to a given outcome or genetic variability contributing to a quantitative trait. While polygenic risk scores are widely used for complex traits, their application in uncovering shared genetic predisposition between phenotypes, i.e., when genetic variants influence more than one phenotype, remains limited. Methods: We developed an R package, comorbidPGS, which facilitates a systematic evaluation of shared genetic effects among (cor)related phenotypes using PGSs. The comorbidPGS package takes as input a set of single nucleotide polymorphisms along with their established effects on the original phenotype (Po), referred to as Po-PGS. It generates a comprehensive summary of effect(s) of Po-PGS on target phenotype(s) (Pt) with customisable graphical features. Results: We applied comorbidPGS to investigate the shared genetic predisposition between phenotypes defining elevated blood pressure (systolic blood pressure, SBP; diastolic blood pressure, DBP; pulse pressure) and several cancers (breast cancer; pancreatic cancer, PanC; kidney cancer, KidC; prostate cancer, PrC; colorectal cancer, CrC) using the European ancestry UK Biobank individuals and GWAS meta-analyses summary statistics from independent set of European ancestry individuals. We report a significant association between elevated DBP and the genetic risk of PrC (β [SE] = 0.066 [0.017], p value = 9.64 × 10−5), as well as between CrC PGS and both, lower SBP (β [SE] = −0.10 [0.029], p value = 3.83 × 10−4) and lower DBP (β [SE] = −0.055 [0.017], p value = 1.05 × 10−3). Our analysis highlights two nominally significant relationships for individuals with genetic predisposition to elevated SBP leading to higher risk of KidC (OR [95% CI] = 1.04 [1.0039–1.087], p value = 2.82 × 10−2) and PrC (OR [95% CI] = 1.02 [1.003–1.041], p value = 2.22 × 10−2). Conclusion: Using comorbidPGS, we underscore mechanistic relationships between blood pressure regulation and susceptibility to three comorbid malignancies. This package offers valuable means to evaluate shared genetic susceptibility between (cor)related phenotypes through polygenic scores. [ABSTRACT FROM AUTHOR]

Background: The predictive relationship between mild-to-moderate alcohol consumption and the risk of incident atrial fibrillation (AF) remains controversial. Objective: We investigated whether the relationship between alcohol consumption and the risk of incident AF could be associated with the genetic predisposition to alcohol metabolism. Methods: A total of 399,329 subjects with genetic data from the UK Biobank database, enrolled between 2006 and 2010, were identified and followed for incident AF until 2021. Genetic predisposition to alcohol metabolism was stratified according to the polygenic risk score (PRS) tertiles. Alcohol consumption was categorized as non-drinkers, mild-to-moderate drinkers (< 30 g/day), and heavy drinkers (≥ 30 g/day). Results: During the follow-up (median 12.2 years), 19,237 cases of AF occurred. When stratified by PRS tertiles, there was a significant relationship between genetic predisposition to alcohol metabolism and actual alcohol consumption habits (P < 0.001). Mild-to-moderate drinkers showed a decreased risk of AF (HR 0.96, 95% CI 0.92–0.99), and heavy drinkers showed an increased risk of AF (HR 1.06, 95% CI 1.02–1.10) compared to non-drinkers. When stratified according to PRS tertiles for genetic predisposition to alcohol metabolism, mild-to-moderate drinkers had equivalent AF risks, and heavy drinkers showed increased AF risk in the low PRS tertile group. However, mild-to-moderate drinkers had decreased AF risks and heavy drinkers showed similar risks of AF in the middle/high PRS tertile groups. Conclusions: Differential associations between alcohol consumption habits and incident AF across genetic predisposition to alcohol metabolism were observed; individuals with genetic predisposition to low alcohol metabolism were more susceptible to AF. [ABSTRACT FROM AUTHOR]

Acquired hemophilia A (AHA) is a rare bleeding disorder caused by the presence of autoantibodies against factor VIII (FVIII). As with other autoimmune diseases, its etiology is complex and its genetic basis is unknown. The aim of this study was to identify the immunogenetic background that predisposes individuals to AHA. HLA and KIR gene clusters, as well as KLRK1, were sequenced using next-generation sequencing in 49 AHA patients. Associations between candidate genes involved in innate and adaptive immune responses and AHA were addressed by comparing the alleles, genotypes, haplotypes, and gene frequencies in the AHA cohort with those in the donors' samples or Spanish population cohort. Two genes of the HLA cluster, as well as rs1049174 in KLRK1, which tags the natural killer (NK) cytotoxic activity haplotype, were found to be linked to AHA. Specifically, A*03:01 (p = 0.024; odds ratio (OR) = 0.26[0.06–0.85]) and DRB1*13:03 (p = 6.8 × 103, OR = 7.56[1.64–51.40]), as well as rs1049174 (p = 0.012), were significantly associated with AHA. In addition, two AHA patients were found to carry one copy each of the low-frequency allele DQB1*03:09 (nallele = 2, 2.04%), which was completely absent in the donors. To the best of our knowledge, this is the first time that the involvement of these specific alleles in the predisposition to AHA has been proposed. Further molecular and functional studies will be needed to unravel their specific contributions. We believe our findings expand the current knowledge on the genetic factors involved in susceptibility to AHA, which will contribute to improving the diagnosis and prognosis of AHA patients. [ABSTRACT FROM AUTHOR]

IgA nephropathy (IgAN) is an autoimmune disorder which is believed to be non-monogenic. We performed an exome-wide association study of 70 children with IgAN and 637 healthy donors. The HLA allele frequencies were compared between the patients and healthy donors from the bone marrow registry of the Pirogov University. We tested 78,020 gene markers for association and performed functional enrichment analysis and transcription factor binding preference detection. We identified 333 genetic variants, employing three inheritance models. The most significant association with the disorder was observed for rs143409664 (PRAG1) in the case of the additive and dominant models (PBONF = 1.808 × 10−15 and PBONF = 1.654 × 10−15, respectively), and for rs13028230 (UBR3) in the case of the recessive model (PBONF = 1.545 × 10−9). Enrichment analysis indicated the strongly overrepresented "immune system" and "kidney development" terms. The HLA-DQA1*01:01:01G allele (p = 0.0076; OR, 2.021 [95% CI, 1.322–3.048]) was significantly the most frequent among IgAN patients. Here, we characterized, for the first time, the genetic background of Russian IgAN patients, identifying the risk alleles typical of the population. The most important signals were detected in previously undescribed loci. [ABSTRACT FROM AUTHOR]

Background: To describe the indications and outcomes of BRCA mutation carriers undergoing nipple-sparing mastectomy (NSM). Methods: In this retrospective study, 76 BRCA mutation carriers with no cancer who opted to undergo risk reduction NSM or diagnosed with breast cancer (BC) who opted to undergo therapeutic NSM were included. Results: Indications for NSM: cancer treatment (n = 33), bilateral risk reduction (n = 39) and contralateral prophylactic NSM (n = 4). In a mean follow-up of 45 months (median: 30 months), one patient (2.5%) undergoing risk-reducing NSM developed a new BC. One (3%) local, one (3%) ipsilateral axillary and one (3%) distant recurrence were observed in BC patients. No partial or total nipple necrosis occurred. Conclusion: NSM is safe for reducing the risk of BC development in BRCA mutation carriers and for treating cancer. [ABSTRACT FROM AUTHOR]

Copyright of Revista del Cuerpo Médico del Hospital Nacional Almanzor Aguinaga Asenjo is the property of Cuerpo Medico del Hospital Nacional Almanzor Aguinaga Asenjo and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Cancer is a multi-factorial disease, and the etiology of breast cancer (BC) is due to a combination of both genetic and environmental factors. Breast tissue shows a unique microbiota, Proteobacteria and Firmicutes are the most abundant bacteria in breast tissue, and several studies have shown that the microbiota of healthy breast differs from that of BC. Breast microbiota appears to be correlated with different characteristics of the tumor, and prognostic clinicopathologic features. It also appears that there are subtle differences between the microbial profiles of the healthy control and high-risk patients. Genetic predisposition is an extremely important risk factor for BC. BRCA1/2 germline mutations and Li-Fraumeni syndrome are DNA repair deficiency syndromes inherited as autosomal dominant characters that substantially increase the risk of BC. These syndromes exhibit incomplete penetrance of BC expression in carrier subjects. The action of breast microbiota on carcinogenesis might explain why women with a mutation develop cancer and others do not. Among the potential biological pathways through which the breast microbiota may affect tumorigenesis, the most relevant appear to be DNA damage caused by colibactin and other bacterial-derived genotoxins, β-glucuronidase-mediated estrogen deconjugation and reactivation, and HPV-mediated cancer susceptibility. In conclusion, in patients with a genetic predisposition, an unfavorable breast microbiota may be co-responsible for the onset of BC. Prospectively, the ability to modulate the microbiota may have an impact on disease onset and progression in patients at high risk for BC. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Clinical Hepatology / Linchuang Gandanbing Zazhi is the property of Journal of Clinical Hepatology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Genetic counselling (GC) is a key step in the identification of inherited germline mutations. However, the oncogenetic practices are poorly described for pancreatic adenocarcinoma (PA) in Europe. The CAPANCOGEN study aimed to describe the GC referral practices in France and assess the implementation of international guidelines in patients with PA. Information about GC referrals with PA was collected in 13 French centres from September 2019 to October 2021. In the 5 largest centres, personal and familial histories of cancers and diseases associated with a higher risk of germline mutations were collected in 460 patients, according to international, American, European and French GC referral guidelines. Univariate and multivariate logistic regression analysis were performed to identify the factors influencing GC referral. Among 833 patients, a total of 100 patients (12%) had an indication of GC according to local multidisciplinary tumour board meetings (MTBM). Among these patients, 41% did not undergo GC. The median time between MTBM and GC was 55 days (IQR: 14.5–112). Among 460 patients with collected personal and familial history, 31.5% were not referred to a GC despite an existing indication. In multivariate logistic regression analysis, suspected CDKN2A (p = 0.032) or BRCA mutation (p < 0.001), familial pancreatic cancer history (p < 0.001) and controlled disease with first-line platinum-based chemotherapy (p < 0.001) increased the referral rate. Conversely, older age (p = 0.002) and a locally advanced PA (p = 0.045) decreased the risk of GC referral. GC referral is inadequate despite valuable information in patients' medical files. [ABSTRACT FROM AUTHOR]

Introduction: Gout is an inflammatory, metabolic disease associated with a high comorbidity burden including cardiovascular disease, hypertension, type 2 diabetes, hyperlipidemia, renal disease, and metabolic syndrome. Approximately 9.2 million Americans have gout, making prognosis and treatment outcome predictors highly important. About 600,000 Americans have early-onset gout (EOG), generally defined as first gout attack at ≤ 40 years of age. However, data on EOG clinical features, comorbidity profile, and treatment response are sparse; this systematic literature review provides insight. Methods: PubMed and American College of Rheumatology (ACR)/European Alliance of the Associations for Rheumatology (EULAR) abstract archives were searched for early-onset gout, "early onset gout," and ("gout" AND "age of onset"). Duplicate, foreign language, single case report, older (before 2016), and irrelevant/data insufficient publications were excluded. The age of diagnosis categorized patients as having common gout (CG, generally > 40 years) or EOG (generally ≤ 40 years). Applicable publications were extensively reviewed/discussed among authors for inclusion/exclusion consensus. Results: A total of 283 publications were identified, with 46 (35 articles, 10 abstracts) reviewed and 17 (12 articles, 5 abstracts) ultimately included. Eleven reported clinical characteristics, with 6 EOG-CG retrospective/cross-sectional comparisons. Gout diagnosis preceded cardiometabolic comorbidity and renal comorbidities were less prevalent in EOG than CG patients. EOG patients had more severe disease (more gout flares, polyarticular disease), higher pre-therapy serum urate (SU), and worse oral urate-lowering therapy response. Genetics-focused publications reported higher incidences of dysfunctional urate transporter mutations in EOG patients. Conclusions: This review suggests that EOG is more recalcitrant to urate-lowering therapy, is associated with urate transporter defects, and carries heavy disease burden. Therefore, early rheumatology referral and urate-lowering in a treat-to-target fashion may benefit EOG patients. Interestingly, EOG patients had fewer cardiometabolic comorbidities at diagnosis than CG patients, presenting a potential "window of opportunity" to attenuate cardiometabolic comorbidity development with SU control. Preventing gout-related suffering and health burden is particularly important in these young EOG patients who will live with gout and its sequelae for decades. Plain Language Summary: Gout, an inflammatory arthritis caused by high urate levels in the blood (SU), is associated with medical issues, including heart disease, high blood pressure, type 2 diabetes, and kidney disease. Millions of Americans have gout, with some having early-onset gout (EOG), generally the first gout attack at or before 40 years of age. Little information on EOG has been published; this literature review provides insight. More recent articles and major rheumatology meeting presentations (2016 to August 2022) on EOG were reviewed. Publications that were duplicates, not in English, on a single patient, or were not relevant/did contain enough information were excluded. The age at gout diagnosis determined if patients had common gout (CG) or EOG. Of the 283 publications identified, 17 were included in this review. Gout-associated medical issues (heart, metabolic, and kidney-related) were less common in EOG than CG patients and occurred after gout diagnosis in EOG patients. Compared to CG patients, EOG patients more often had severe gout (more gout attacks and affected joints), higher SU, and worse response to oral SU-lowering medications. Genetics-focused publications showed that mutations affecting how urate is removed from the body are more common in EOG patients. Overall, the literature suggests that EOG may be difficult to treat, has a genetic component, and has a heavy disease burden. Therefore, early rheumatology referral and gout management may benefit EOG patients due to a potential "window of opportunity" where proper SU control may prevent gout-related suffering and health burden in young EOG patients who will live with gout and its consequences for decades. [ABSTRACT FROM AUTHOR]

PRSS1 was the first reported chronic pancreatitis (CP) gene. The existence of both gain-of-function (GoF) and gain-of-proteotoxicity (GoP) pathological PRSS1 variants, together with the fact that PRSS1 variants have been identified in CP subtypes spanning the range from monogenic to multifactorial, has made the classification of PRSS1 variants very challenging. All currently reported PRSS1 variants (derived primarily from two databases) were manually reviewed with respect to their clinical genetics, functional analysis and population allele frequency. They were classified by variant type and pathological mechanism within the framework of our recently proposed ACMG/AMP guidelines-based seven-category system. The total number of distinct germline PRSS1 variants included for analysis was 100, comprising 3 copy number variants (CNVs), 12 5′ and 3′ variants, 19 intronic variants, 5 nonsense variants, 1 frameshift deletion variant, 6 synonymous variants, 1 in-frame duplication, 3 gene conversions and 50 missense variants. Based upon a combination of clinical genetic and functional analysis, population data and in silico analysis, we classified 26 variants (all 3 CNVs, the in-frame duplication, all 3 gene conversions and 19 missense) as "pathogenic", 3 variants (missense) as "likely pathogenic", 5 variants (four missense and one promoter) as "predisposing", 13 variants (all missense) as "unknown significance", 2 variants (missense) as "likely benign", and all remaining 51 variants as "benign". We describe an expert classification of the 100 PRSS1 variants reported to date. The results have immediate implications for reclassifying many ClinVar-registered PRSS1 variants as well as providing optimal guidelines/standards for reporting PRSS1 variants. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a major global health challenge and one of the top 10 cancers in Mexico. Lifestyle and genetic factors influence CRC development, prognosis, and therapeutic response; identifying risk factors, such as the genes involved, is critical to understanding its behavior, mechanisms, and prognosis. The association between KRAS gene variants (rs8720 and rs12587) and CRC in the Mexican population was analyzed. We performed in silico analysis and analyzed 310 healthy individuals and 385 CRC patients using TaqMan assays and real-time PCR. The CC and GG genotypes of rs8720 and rs12587 were identified as CRC risk factors (p < 0.05). The CC and TC genotypes of the rs8720 were associated with rectal cancer, age over 50 years, moderately differentiated histology, and advanced cancer stage. TG and GG genotypes of the rs12587 variant were a risk factor in the CRC group, in patients with stage I–II, males, and stage III–IV non-chemotherapy response. The TG haplotype is protected against CRC. The combined CCGG genotype was linked to CRC risk. In silico analysis revealed that the rs12587 and rs8720 variants could influence KRAS gene regulation via miRNAs. In conclusion, rs8720 and rs12587 variants of the KRAS gene were associated with CRC risk and could influence KRAS regulation via miRNAs. [ABSTRACT FROM AUTHOR]

Purpose: Causal mechanisms underlying systemic inflammation in spinal & widespread pain remain an intractable experimental challenge. Here we examined whether: (i) associations between blood C-reactive protein (CRP) and chronic back, neck/shoulder & widespread pain can be explained by shared underlying genetic variants; and (ii) higher CRP levels causally contribute to these conditions. Methods: Using genome-wide association studies (GWAS) of chronic back, neck/shoulder & widespread pain (N = 6063–79,089 cases; N = 239,125 controls) and GWAS summary statistics for blood CRP (Pan-UK Biobank N = 400,094 & PAGE consortium N = 28,520), we employed cross-trait bivariate linkage disequilibrium score regression to determine genetic correlations (rG) between these chronic pain phenotypes and CRP levels (FDR < 5%). Latent causal variable (LCV) and generalised summary data-based Mendelian randomisation (GSMR) analyses examined putative causal associations between chronic pain & CRP (FDR < 5%). Results: Higher CRP levels were genetically correlated with chronic back, neck/shoulder & widespread pain (rG range 0.26–0.36; P ≤ 8.07E-9; 3/6 trait pairs). Although genetic causal proportions (GCP) did not explain this finding (GCP range − 0.32–0.08; P ≥ 0.02), GSMR demonstrated putative causal effects of higher CRP levels contributing to each pain type (beta range 0.027–0.166; P ≤ 9.82E-03; 3 trait pairs) as well as neck/shoulder pain effects on CRP levels (beta [S.E.] 0.030 [0.021]; P = 6.97E-04). Conclusion: This genetic evidence for higher CRP levels in chronic spinal (back, neck/shoulder) & widespread pain warrants further large-scale multimodal & prospective longitudinal studies to accelerate the identification of novel translational targets and more effective therapeutic strategies. [ABSTRACT FROM AUTHOR]

Objective: The present review describes how children experience hereditary cancer risk communication within the family. Methods: Searches for studies between 1990 and 2020 on PubMed and EBSCO were undertaken, and 15 studies met the inclusion criteria, following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. The findings informed: (1) how, when and what is discussed about hereditary cancer risk in the family; (2) how does family communication about hereditary cancer risk impact children on psychosocial and behavioral outcomes; (3) what are the child's preferences regarding hereditary cancer risk communication within the family. Results: Disclosure is done mostly by both parents, or mothers only, which is in accordance with the children's preferences. Children value open communication about cancer risk with their parents, although they report experiences of fear, surprise, feeling unhappy, and concern about the increased risk of cancer. Regardless of the method of disclosure, children may be particularly sensitive to their parent's emotional state at the time of disclosure, and they learn from their parents' experiences the potential implications of cancer risk. Children also report that it would be helpful to learn more about genetic cancer syndromes via written materials, and/or meet a genetic counselor. Conclusions: Children rely on their parents as the primary models of the hereditary cancer experience. Therefore, parents play a central role in the psychological adjustment of children. Findings point to the relevance of family‐centered care in hereditary cancer risk that targets not only the mutation carrier individually but also their children and partners. [ABSTRACT FROM AUTHOR]

Copyright of Journal of International Obstetrics & Gynecology is the property of TianJin Medical Information Center and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

PRSS1 and PRSS2 constitute the only functional copies of a tandemly-arranged five-trypsinogen-gene cluster (i.e., PRSS1 , PRSS3P1 , PRSS3P2 , TRY7 and PRSS2) on chromosome 7q35. Variants in PRSS1 and PRSS2, including missense and copy number variants (CNVs), have been reported to predispose to or protect against chronic pancreatitis (CP). We wondered whether a common trypsinogen pseudogene deletion CNV (that removes two of the three trypsinogen pseudogenes, PRSS3P2 and TRY7) might be associated with CP causation/predisposition. We analyzed the common PRSS3P2 and TRY7 deletion CNV in a total of 1536 CP patients and 3506 controls from France, Germany, India and Japan by means of quantitative fluorescent multiplex polymerase chain reaction. We demonstrated that the deletion CNV variant was associated with a protective effect against CP in the French, German and Japanese cohorts whilst a trend toward the same association was noted in the Indian cohort. Meta-analysis under a dominant model yielded a pooled odds ratio (OR) of 0.68 (95% confidence interval (CI) 0.52–0.89; p = 0.005) whereas an allele-based meta-analysis yielded a pooled OR of 0.84 (95% CI 0.77–0.92; p = 0.0001). This protective effect is explicable by reference to the recent finding that the still functional PRSS3P2/TRY7 pseudogene enhancers upregulate pancreatic PRSS2 expression. The common PRSS3P2 and TRY7 deletion CNV was associated with a reduced risk for CP. This finding provides additional support for the emerging view that dysregulated PRSS2 expression represents a discrete mechanism underlying CP predisposition or protection. [ABSTRACT FROM AUTHOR]

Purpose of Review: Therapy-related myeloid neoplasms (t-MNs) are aggressive leukemias that develop following exposure to DNA-damaging agents. A subset of patients developing t-MN may have an inherited susceptibility to develop myeloid neoplasia. Herein, we review studies reporting t-MN and their association with a germline or inherited predisposition. Recent Findings: Emerging evidence suggests that development of t-MN is the result of complex interactions including generation of somatic variants in hematopoietic stem cells and/or clonal selection pressure exerted by the DNA-damaging agents, and immune evasion on top of any inherited genetic susceptibility. Conventionally, alkylating agents, topoisomerase inhibitors, and radiation have been associated with t-MN. Recently, newer modalities including poly (ADP-ribose) polymerase inhibitors (PARPi) and peptide receptor radionucleotide therapy (PRRT) are associated with t-MN. At the same time, the role of pathogenic germline variants (PGVs) in genes such as BRCA1/2, BARD1, or TP53 on the risk of t-MN is being explored. Moreover, studies have shown that while cytotoxic therapy increases the risk of developing myeloid neoplasia, it may be exposing the vulnerability of an underlying germline predisposition. Summary: t-MN remains a disease with poor prognosis. Studies are needed to better define an individual's inherited neoplastic susceptibility which will help predict the risk of myeloid neoplasia in the future. Understanding the genes driving the inherited neoplastic susceptibility will lead to better patient- and cancer-specific management including choice of therapeutic regimen to prevent, or at least delay, development of myeloid neoplasia after treatment of a prior malignancy. [ABSTRACT FROM AUTHOR]

Short stature is considered a condition in which the height is 2 standard deviations below the mean height of a given age, sex, and population group. Human height is a polygenic and heterogeneous characteristic, and its heritability is reported to be approximately 80%. More than 600 variants associated with human growth were detected in the genome-wide association studies. Rare and common variants concurrently affect human height. The rare variations that play a role in human height determination and have a strong impact on protein functions lead to monogenic short stature phenotypes, which are a highly heterogeneous group. With rapidly developing technologies in the last decade, molecular genetic tests have begun to be used widely in clinical genetics, and thus, the genetic etiology of several rare diseases has been elucidated. Identifying the genetic etiology underlying idiopathic short stature which represents phenotypically heterogeneous group of diseases ranging from isolated short stature to severe and syndromic short stature has promoted the understanding of the genetic regulation of growth plate and longitudinal bone growth. In cases of short stature, definite molecular diagnosis based on genetic evaluation enables the patient and family to receive genetic counseling on the natural course of the disease, prognosis, genetic basis, and recurrence risk. The determination of the genetic etiology in growth disorders is essential for the development of novel targeted therapies and crucial in the development of mutation-specific treatments in the future. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is a significant public health concern worldwide with a complex etiology attributed to behavioural, environmental, and genetic causes. The worldwide prevalence of NAFLD is estimated to be 32.4% and constantly rising. Global data, however, indicate considerable heterogeneity among studies for both NAFLD prevalence and incidence. Identifying variables that affect the estimated epidemiological measures is essential to all stakeholders, including patients, researchers, healthcare providers, and policymakers. Besides helping with the research on disease etiology, it helps to identify individuals at risk of the disease, which in turn will outline the focus of the preventive measures and help to fittingly tailor individualized treatments, targeted prevention, screening, or treatment programs. Several studies suggest differences in the prevalence and severity of NAFLD by race or ethnicity, which may be linked to differences in lifestyle, diet, metabolic comorbidity profile, and genetic background, among others. Race/ethnicity research is essential as it can provide valuable information regarding biological and genetic differences among people with similar cultural, dietary, and geographical backgrounds. In this review, we examined the existing literature on race/ethnicity differences in susceptibility to NAFLD and discussed the contributing variables to such differences, including diet and physical activity, the comorbidity profile, and genetic susceptibility. We also reviewed the limitations of race/ethnicity studies in NAFLD. [ABSTRACT FROM AUTHOR]

Background: It is unclear whether the main antihypertensive medication classes (diuretics, calcium channel blockers, beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers (ARBs)) are associated with different risks of cognitive decline. Published evidence is conflicting and stems mainly from observational studies.Objective: To investigate the differential effects of antihypertensives on the risks of developing dementia and cognitive decline, with a specific focus on the vascular component of the mechanisms underlying these interactions.Methods: Older adults with a history of hypertension and without dementia were drawn from the population-based HELIAD cohort. Age-, gender-, education-, and antihypertensive medication- (five dichotomous exposures) adjusted Cox proportional-hazards models and generalized estimating equations were performed to appraise the associations of baseline antihypertensive therapy with dementia incidence and cognitive decline (quantified using a comprehensive neuropsychological battery). Analyses were subsequently adjusted for clinical vascular risk (dyslipidemia, diabetes mellitus, smoking, cardiovascular, and cerebrovascular history) and genetic susceptibility to stroke (using polygenic risk scores generated according to the MEGASTROKE consortium GWAS findings).Results: A total of 776 predominantly female participants (73.61±4.94 years) with hypertension and a mean follow-up of 3.02±0.82 years were analyzed. Baseline treatment was not associated with the risk of incident dementia. ARB users experienced a slower yearly global cognitive [2.5% of a SD, 95% CI = (0.1, 4.9)] and language [4.4% of a SD, 95% CI = (1.4, 7.4)] decline compared to non-users. The fully adjusted model reproduced similar associations for both global cognitive [β= 0.027, 95% CI =  (-0.003, 0.057)], and language decline [β= 0.063, 95% CI = (0.023, 0.104)].Conclusion: ARBs may be superior to other antihypertensive agents in the preservation of cognition, an association probably mediated by vascular-independent mechanisms. [ABSTRACT FROM AUTHOR]

Background: Glutathione is a tripeptide detoxifying a variety of exogenous and endogenous free radicals and carcinogens, and a deficiency of glutathione is associated with an increased host susceptibility to oxidative stress, a pathological condition implicated in the development and progression of cancer. The catalytic subunit of glutamate-cysteine ligase (GCLC) is an enzyme responsible for the initial and rate-limiting step of glutathione biosynthesis. Methods and results: The aim of this pilot study was to investigate whether genetic variation at the GCLC gene contributes to the risk of colorectal cancer (CRC). DNA samples from 681 unrelated Russian individuals (283 patients with CRC and 398 age- and sex-matched healthy controls) were genotyped for six common functional SNPs of the GCLC gene (SNPs) such as rs12524494, rs17883901, rs606548, rs636933, rs648595 and rs761142 of the GCLC gene using the MassARRAY-4 system. We found that genotype rs606548-C/T is significantly associated with increased risk of CRC regardless of sex and age (OR 2.24; 95% CI 1.24–4.03; P = 0.007, FDR = 0.04). Moreover, ten GCLC genotype combinations showed association with the risk of CRC (P < 0.05). Functional SNP annotation enabled establishing the CRC-associated polymorphisms are associated with a decreased GCLC expression that may be attributed to epigenetic effects of histone modifications operating in a colon-specific manner. Conclusions: The present study was the first to show that genetic variation at the catalytic subunit of glutamate-cysteine ligase may contribute to the risk of colorectal cancer risk. However, further genetic association studies with a larger sample size are required to substantiate the role of GCLC gene polymorphisms in the development of sporadic colorectal cancer. [ABSTRACT FROM AUTHOR]

Copyright of Revista de Investigación e Innovación en Ciencias de la Salud (RIICS) is the property of Fundacion Universitaria Maria Cano and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: By studying the odds of developing idiopathic subglottic stenosis in the isolated and genetically unique Hutterite population, this study sought to strengthen the hypothesis that an underlying genetic predisposition may exist for its development. Methods: A retrospective chart review examined the medical records of all adult patients treated for idiopathic subglottic stenosis in Saskatchewan between 2008 and 2018. Cases were segregated into Hutterite and non-Hutterite. Results: Four out of 36 cases of idiopathic subglottic stenosis occurred among Hutterites. The odds of a Hutterite developing idiopathic subglottic stenosis are 21.89 times higher than for non-Hutterites. Positive family history was only observed in the Hutterite population. Conclusion: The study strengthens the hypothesis that genetics may play a role in the aetiology of idiopathic subglottic stenosis by demonstrating that the genetically and socially unique Hutterites are more likely to develop this rare disease. This study is the first to demonstrate that a specific subpopulation is at a higher risk for developing idiopathic subglottic stenosis. [ABSTRACT FROM AUTHOR]

Single-nucleotide polymorphisms (SNPs) in C1q gene cluster were previously linked to autoimmunity and SLE, but data are scarce for their association with RA. In the present study, we evaluated associations of five SNPs (rs665691, rs682658, rs172378, rs292001 and rs294179) in the C1q genetic region with RA and some of its clinical and immunologic characteristics. Fifty-eight RA patients and 67 age- and gender-matched healthy controls, all Caucasian, participated in the study. They were genotyped for the five SNPs using TaqMan allelic discrimination assay, and their C1q levels were estimated by ELISA. Rheumatoid factor and anti-citrullinated peptide antibodies were measured (using latex agglutination and ELISA resp.) in the RA patients' group and relevant clinical information was collected. RA patients and healthy controls had similar frequencies of alleles and genotypes of rs665691, rs682658 and rs294179. Minor G-allele and GG genotype of rs172378 were associated with RA (OR = 2.80; 95% CI 1.62–4.81; p = 0.0002 and OR = 5.01; 95% CI 1.55–16.24; p = 0.007, resp.), as well as AA genotype of rs292001 (OR = 3.23; 95% CI 1.15–9.08; p = 0.026). C1q levels were significantly lower (still normal) in RA patients' group compared to healthy volunteers: 89 µg/ml (68–121) vs 114 µg/ml (60–169), p < 0.0001. Significant association was established between rs172378 and rs292001 and RA, in contrast to rs665691, rs682658 and rs294179. RA patients had lower C1q levels than healthy controls. Our findings correspond to the scientific knowledge so far and add additional clarity from a Bulgarian cohort. [ABSTRACT FROM AUTHOR]

Summary: Background: Few studies have focused on the role of adverse childhood experiences (ACEs) in relation to genetic susceptibility to obesity. Objective: We aimed to examine the interaction between the presence of ACEs (i.e., physical, psychological and sexual abuse) before the age of 18 and BMI polygenic score. Methods: Data came from the National Longitudinal Study of Adolescent to Adult Health (Add Health) Wave IV (2007/2008) where saliva samples were collected for DNA genotyping and information on BMI and ACEs were obtained from 5854 European American (EA), 2073 African American (AA) and 1448 Hispanic American (HA) participants aged 24 to 32 years old. Polygenic scores were calculated as the sum of the number of risk alleles of BMI‐related SNPs which were weighted by effect size. A race/ethnicity‐stratified mixed‐effects linear regression model was used to test for differential association between BMI polygenic score and BMI by the presence of ACEs. Results: We did not find any evidence of significant interaction between ACEs and polygenic score in relation to BMI among EA (p = 0.289), AA (p = 0.618) or HA (p = 0.870). In main effects models, polygenic score was positively associated with BMI in all race/ethnic groups, yet the presence of ACEs was associated with increased BMI only among EA. Conclusion: We did not find any evidence that ACEs exacerbate genetic predisposition to increased BMI in early adulthood. [ABSTRACT FROM AUTHOR]

The presence of a bidirectional risk for metachronous carcinomas among women with thyroid and breast cancer is well established. However, the underlying risk factors remain poorly understood. Two sisters developed papillary thyroid cancer (PTC) at age 32 and 34 years, followed by ductal carcinoma of the breast at 44 and 42 years. The 2 children of the younger sister developed ataxia-telangiectasia; the son also developed lymphoblastic lymphoma and his sister died secondary to acute lymphoblastic leukemia (ALL). They were found to be compound heterozygous for ataxia telangiectasia mutated (ATM) gene mutations (c.3848T>C, p.L1283P; and c.802C>T, p.Q268X). Exome sequencing of the 2 sisters (mother and aunt of the children with ataxia-telangiectasia) led to the detection of the pathogenic monoallelic ATM mutation in both of them (c.3848T>C; minor allele frequency [MAF] < 0.01) but detected no other variants known to confer a risk for PTC or breast cancer. The findings suggest that monoallelic ATM mutations, presumably in conjunction with additional genetic and/or nongenetic factors, can confer a risk for developing PTC and breast cancer. [ABSTRACT FROM AUTHOR]

Copyright of Colombia Medica is the property of Universidad del Valle and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Ovarian cancer (OC) is the leading cause of death among women with gynecologic malignancy. Breast Cancer Susceptibility Gene 1 (BRCA 1) and Breast Cancer Susceptibility Gene 2 (BRCA 2) germline mutations confer an estimated 20 to 40 times increased risk of OC when compared to the general population. The majority of BRCA-associated OC is identified in the late stage, and no effective screening method has been proven to reduce mortality. Several pharmacologic and surgical options exist for risk-reduction of gynecologic malignancy in BRCA 1/2 mutation carriers. This review summarizes up-to-date research on pharmacologic risk-reducing interventions, including the oral contraceptive pill, acetylsalicylic acid/nonsteroidal anti inflammatory drugs (ASA/NSAID) therapy, and denosumab, and surgical risk-reducing interventions, including risk-reducing bilateral salpingo-oophorectomy, salpingectomy with delayed oophorectomy, and hysterectomy at the time of risk-reducing bilateral salpingo-oophorectomy. [ABSTRACT FROM AUTHOR]

Introduction: Kidney dysfunction is a highly significant disease, both in the United Kingdom and globally. Many previous studies have reported associations between human leukocyte antigens (HLA) and renal function; this systematic review attempts to identify, summarize and appraise all published studies of these associations. Methods: A literature search was performed using Medline, Embase and Cochrane Central Register of Controlled Trials to identify papers whose keywords included each of the following concepts: HLA, renal failure and genetic association. A total of 245 papers were identified and assessed for eligibility; 35 of these were included in the final study. Results: A total of 95 HLA types and 14 three‐locus haplotypes were reported to be associated with either increased or decreased renal function. A number of these findings were replicated by independent studies that reported 16 types were protective against renal dysfunction and 15 types were associated with reduced renal function. A total of 20 HLA types were associated with both increased risk of renal disease and decreased risk by independent studies. Discussion: There is very little consensus on which HLA types have a protective or deleterious effect on renal function. Ethnicity may play a role, with HLA types possibly having different effects among different populations, and it is possible that the different primary diseases that lead to ESRD may have different HLA associations. Some of the studies may contain type I and type II errors caused by insufficient sample sizes, cohort selection and statistical methods. Although we have compiled a comprehensive list of published associations between renal function and HLA, in many cases, it is unclear which associations are reliable. Further studies are required to confirm or refute these findings. [ABSTRACT FROM AUTHOR]

Objectives: Human leukocyte antigen-DP beta 1 (HLA-DPB1) with a glutamic acid at the 69th position of the ß chain (E69) genotype and inhalational beryllium exposure individually contribute to risk of chronic beryllium disease (CBD) and beryllium sensitisation (BeS) in exposed individuals. This retrospective nested case-control study assessed the contribution of genetics and exposure in the development of BeS and CBD.Methods: Workers with BeS (n=444), CBD (n=449) and beryllium-exposed controls (n=890) were enrolled from studies conducted at nuclear weapons and primary beryllium manufacturing facilities. Lifetime-average beryllium exposure estimates were based on workers' job questionnaires and historical and industrial hygienist exposure estimates, blinded to genotype and case status. Genotyping was performed using sequence-specific primer-PCR. Logistic regression models were developed allowing for over-dispersion, adjusting for workforce, race, sex and ethnicity.Results: Having no E69 alleles was associated with lower odds of both CBD and BeS; every additional E69 allele increased odds for CBD and BeS. Increasing exposure was associated with lower odds of BeS. CBD was not associated with exposure as compared to controls, yet the per cent of individuals with CBD versus BeS increased with increasing exposure. No evidence of a gene-by-exposure interaction was found for CBD or BeS.Conclusions: Risk of CBD increases with E69 allele frequency and increasing exposure, although no gene by environment interaction was found. A decreased risk of BeS with increasing exposure and lack of exposure response in CBD cases may be due to the limitations of reconstructed exposure estimates. Although reducing exposure may not prevent BeS, it may reduce CBD and the associated health effects, especially in those carrying E69 alleles. [ABSTRACT FROM AUTHOR]

My Family Health Portrait is a tool from the United States Surgeon General to assist users with creating a family health history. This tool allows users to learn about health risks that reappear in families and can be taken to health care providers to assist with diagnoses and treatments. This tool was developed by the National Institutes of Health and is maintained by the Centers for Disease Control and Prevention. Utilizing the My Family Health Portrait can encourage people to stay healthy by being aware of their family health history. [ABSTRACT FROM AUTHOR]

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Background: About one third of patients with chronic polyneuropathy have no obvious underlying etiology and are classified as having idiopathic polyneuropathy. The lack of knowledge about pathomechanisms and predisposing factors limits the development of effective prevention and treatment for these patients. We report the first genome-wide association study (GWAS) of idiopathic polyneuropathy. Methods: Cases with idiopathic polyneuropathy and healthy controls were identified by linkage to hospital records. We performed genome-wide association studies using genetic data from two large population-based health studies, the Trøndelag Health Study (HUNT, 1,147 cases and 62,204 controls) and UK Biobank (UKB, 946 cases and 383,052 controls). In a two-stage analysis design, we first treated HUNT as a discovery cohort and UK Biobank as a replication cohort. Secondly, we combined the two studies in a meta-analysis. Downstream analyses included genetic correlation to other traits and diseases. We specifically examined previously reported risk loci, and genes known to cause hereditary polyneuropathy. Results: No replicable risk loci were identified in the discovery-replication stage, in line with the limited predicted power of this approach. When combined in a meta-analysis, two independent loci reached statistical significance (rs7294354 in B4GALNT3, P -value 4.51 × 10−8) and (rs147738081 near NR5A2, P -value 4.75 × 10−8). Idiopathic polyneuropathy genetically correlated with several anthropometric measures, most pronounced for height, and with several pain-related traits. Conclusions: In this first GWAS of idiopathic polyneuropathy we identify two risk-loci that indicate possible pathogenetic mechanisms. Future collaborative efforts are needed to replicate and expand on these findings. [ABSTRACT FROM AUTHOR]

Background: Epidemiological data have shown that vitamin D deficiency is highly prevalent in Korea. Genetic factors influencing vitamin D deficiency in humans have been studied in Europe but are less known in East Asian countries, including Korea. We aimed to investigate the genetic factors related to vitamin D levels in Korean people using a genome-wide association study (GWAS). Methods: We included 12,642 subjects from three different genetic cohorts consisting of Korean participants. The GWAS was performed on 7,590 individuals using linear or logistic regression meta- and mega-analyses. After identifying significant single nucleotide polymorphisms (SNPs), we calculated heritability and performed replication and rare variant analyses. In addition, expression quantitative trait locus (eQTL) analysis for significant SNPs was performed. Results: rs12803256, in the actin epsilon 1, pseudogene (ACTE1P) gene, was identified as a novel polymorphism associated with vitamin D deficiency. SNPs, such as rs11723621 and rs7041, in the group-specific component gene (GC) and rs11023332 in the phosphodiesterase 3B (PDE3B) gene were significantly associated with vitamin D deficiency in both meta- and mega-analyses. The SNP heritability of the vitamin D concentration was estimated to be 7.23%. eQTL analysis for rs12803256 for the genes related to vitamin D metabolism, including glutamine-dependent NAD(+) synthetase (NADSYN1) and 7-dehydrocholesterol reductase (DHCR7), showed significantly different expression according to alleles. Conclusion: The genetic factors underlying vitamin D deficiency in Korea included polymorphisms in the GC, PDE3B, NADSYN1, and ACTE1P genes. The biological mechanism of a non-coding SNP (rs12803256) for DHCR7/NADSYN1 on vitamin D concentrations is unclear, warranting further investigations. [ABSTRACT FROM AUTHOR]