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Background Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus marked by eosinophilic infiltration. Cumulative evidence indicates that the risk of EoE involves the complex interplay of both genetic and environmental factors. Because only a few genetic loci have been identified in EoE, the genetic underpinning of EoE remains largely elusive. Objective We sought to identify genetic loci associated with EoE. Methods Four EoE cohorts were genotyped using the Illumina single nucleotide polymorphism array platform, totaling 1,930 cases and 13,634 controls of European ancestry. Genotype imputation was performed with the Michigan Imputation Server using the Trans-Omics for Precision Medicine reference panel including whole-genome sequencing data from more than 100,000 individuals. Meta-analysis was conducted to identify potential novel genetic loci associated with EoE. Results Our study identified 11 new genome-wide significant loci, of which 6 are common variant loci, including 5q31.1 (rs2106984, P = 4.16 × 10−8; odds ratio [OR], 1.26, RAD50), 15q22.2 (rs2279293, P = 1.23 × 10−10; OR, 0.69, RORA), and 15q23 (rs56062135, P = 2.91 × 10−11; OR, 1.29, SMAD3), which have been previously associated with allergic conditions. Interestingly, a low-frequency synonymous mutation within the MATN2 gene was identified as the most significant single nucleotide polymorphism at the 8q22.1 locus. We also identified 5 sex-specific loci in the EoE cases, including an inflammatory bowel disease–associated locus at 9p24.1 (rs62541556, P = 4.4 × 10−8; OR, 1.11, JAK2). Conclusions Our findings demonstrate shared genetic underpinnings between EoE and other immune-mediated diseases and provide novel candidate genes for therapeutic target identification and prioritization.

Objective. The objective of this study was to determine the correlation between single-nucleotide polymorphism in filaggrin gene and expression of filaggrin mRNA in buccal epithelium and the phenotype of bronchial asthma with atopic dermatitis in medical history of children. Methods. Filaggrin genotyping (rs11204981) was carried out in group of patients with bronchial asthma and control group using real-time polymerase chain reaction (PCR). The level of mRNA expression was assessed by reverse transcription and subsequent real-time PCR. Results. We have found that 5 % of patients in the study group and 2 % in the control group had a minor allele (AA), 27 and 36 %, respectively, — heterozygous allele (GA), 67 and 61 % — major allele (GG). Variants with the AA genotype of the FLG rs11204981 were found 2.4 times more often in patients from the study group than in controls. Heterozygous variant had significantly higher expression in filaggrin in buccal epithelium. Conclusions. We believe that polymorphism in filaggrin gene (rs11204981) can serve as an important prognostic marker for the phenotype of bronchial asthma and atopic dermatitis, and that high levels of expression in the heterozygous state may indicate the protective role of this genotype in the development of allergy.

Мета цього дослідження — визначення зв’язку однонуклеотидних поліморфізмів в генах mTOR (mammalian target of rapamycin; мішень рапаміцину у ссавців) і ATG5 (autophagy related gene 5; ген автофагії 5) та розвитку алергічного фенотипу у дітей. Генотипування mTOR (rs11121704) та ATG5 (rs510432) проводили в групі хворих з атопічними захворюваннями і контрольній групі за допомогою полімеразної ланцюгової реакції у реальному часі. Виявлено, що у 50 (54,9 %) пацієнтів і 43 (49,4 %) здорових дітей наявна мажорна алель (ТТ) поліморфізму rs11121704; 36 (39,6 %) і 32 (36,8 %) відповідно мали гетерозиготну алель (ТС); у 5 (5,5 %) і 12 (13,8 %) виявлено мінорну алель (СС). Варіанти з генотипом СС rs11121704 у гені mTOR визначалися у 2,5 раза частіше у контрольній групі, ніж серед хворих. Алельні варіанти в гені ATG5 розподілилися так: 51 (52 %) пацієнт та 43 (44,3 %) здорових дитини мали гетерозиготну алель (СТ), 29 (29,6 %) і 21 (21,6 %) відповідно мав мінорну алель (ТТ), у 18 (18,4 %) та 33 (34 %) була мажорна алель (СС). ТТ-генотип асоціюється з підвищеним ризиком ранньої маніфестації бронхіальної астми (до 3 років життя). Вважаємо, що поліморфізми в генах mTOR (rs11121704) та ATG5 (rs510432) можуть служити корисними прогностичними маркерами для оцінки ризику виникнення бронхіальної астми та іншої алергічної патології у дітей.

The quantity of alcohol leading to alcohol-associated liver disease (ALD) varies individually. Genetic backgrounds contributing to the divergence in individual susceptibility to alcohol-induced liver damage have not been elucidated in detail.Based on the Korean Genome and Epidemiology Study Health Examination (KoGES_HEXA) cohort data, 21,919 participants (40-79 years old) were included and divided into cases and controls based on the ALD diagnostic criteria proposed by the American College of Gastroenterology. Data generated by a genome wide-association study were analyzed using logistic regression to assess the risk of ALD development in nondrinkers, light drinkers, and heavy drinkers. We detected three loci, gamma-glutamyltransferase 1 (GGT1), zinc protein finger 827 (ZNF827) and HNF1 homeobox A (HNF1A), which were significantly associated with ALD risk. The GGT1 rs2006227 minor allele was strongly associated with all groups. Among the minor alleles of single nucleotide polymorphisms (SNPs) in HNF1A, rs1183910 had the strongest association with a protective effect from ALD in light drinkers. However, this association was not observed in heavy drinkers. Five SNPs on chromosome 11 showed suggestive significance in protective effects against ALD.SNPs, including HNF1A rs1183910 minor allele, are the most promising genetic candidates for protection against ALD. The expression of genes contributing to ALD development may be altered by the amount of alcohol consumed.

Background Tumor mutational burden (TMB) measurements aid in identifying patients who are likely to benefit from immunotherapy; however, there is empirical variability across panel assays and factors contributing to this variability have not been comprehensively investigated. Identifying sources of variability can help facilitate comparability across different panel assays, which may aid in broader adoption of panel assays and development of clinical applications. Materials and methods Twenty-nine tumor samples and 10 human-derived cell lines were processed and distributed to 16 laboratories; each used their own bioinformatics pipelines to calculate TMB and compare to whole exome results. Additionally, theoretical positive percent agreement (PPA) and negative percent agreement (NPA) of TMB were estimated. The impact of filtering pathogenic and germline variants on TMB estimates was assessed. Calibration curves specific to each panel assay were developed to facilitate translation of panel TMB values to whole exome sequencing (WES) TMB values. Results Panel sizes >667 Kb are necessary to maintain adequate PPA and NPA for calling TMB high versus TMB low across the range of cut-offs used in practice. Failure to filter out pathogenic variants when estimating panel TMB resulted in overestimating TMB relative to WES for all assays. Filtering out potential germline variants at >0% population minor allele frequency resulted in the strongest correlation to WES TMB. Application of a calibration approach derived from The Cancer Genome Atlas data, tailored to each panel assay, reduced the spread of panel TMB values around the WES TMB as reflected in lower root mean squared error (RMSE) for 26/29 (90%) of the clinical samples. Conclusions Estimation of TMB varies across different panels, with panel size, gene content, and bioinformatics pipelines contributing to empirical variability. Statistical calibration can achieve more consistent results across panels and allows for comparison of TMB values across various panel assays. To promote reproducibility and comparability across assays, a software tool was developed and made publicly available.

Objective To assess predictors of subclinical RA-associated interstitial lung disease (RA-ILD) using quantitative lung densitometry (qLD). Methods RA patients underwent multi-detector row CT scanning at baseline and after an average of 39 months. Scans were analysed with qLD for the percentage of lung parenchyma with high attenuation areas (%HAA: the percentage of voxels of –600 to –250 Hounsfield units). Additionally, a pulmonary radiologist calculated an expert radiologist scoring (ERS) for RA-ILD features. Generalized linear models were used to identify indicators of baseline %HAA and predictors of %HAA change. Results Baseline %HAA was assessed in 193 RA patients and 106 had repeat qLD assessment. %HAA was correlated with ERS (Spearman’s rho = 0.261; P 10% of lung parenchyma with high attenuation) included female sex, higher pack-years of smoking, higher BMI and anti-CCP ≥200 units, collectively contributing an area under the receiver operator curve of 0.88 (95% CI 0.81, 0.95). Predictors of %HAA increase, occurring in 49% with repeat qLD, included higher baseline %HAA, presence of mucin 5B (MUC5B) minor allele and absence of HLA-DRB1 shared epitope (area under the receiver operator curve = 0.69; 95% CI 0.58, 0.79). The association of the MUC5B minor allele with %HAA change was higher among men and those with higher cumulative smoking. Within the group with increased %HAA, anti-CCP level was significantly associated with a greater increase in %HAA. Conclusions %HAA, assessed with qLD, was linked to several known risk factors for RA-ILD and may represent a more quantitative method to identify RA-ILD and track progression than expert radiologist interpretation.

BACKGROUND: Although DHA (22:6n–3) is critical for fetal development, results from randomized controlled trials (RCTs) of prenatal DHA supplementation report inconsistent effects on offspring health. Variants in fatty acid desaturase (FADS) genes that regulate the conversion of n–3 and n–6 essential fatty acids into their biologically active derivatives may explain this heterogeneity. OBJECTIVES: We investigated the effect of prenatal DHA supplementation on the offspring metabolome at age 3 mo and explored differences by maternal FADS single-nucleotide polymorphism (SNP) rs174602. METHODS: Data were obtained from a double-blind RCT in Mexico [POSGRAD (Prenatal Omega-3 Fatty Acid Supplementation and Child Growth and Development)] in which women (18–35 y old) received DHA (400 mg/d) or placebo from mid-gestation until delivery. Using high-resolution MS with LC, untargeted metabolomics was performed on 112 offspring plasma samples. Discriminatory metabolic features were selected via linear regression (P

Background Atopic dermatitis (AD) is the most common allergic disease in the world. While genetic components play critical roles in its pathophysiology, a large proportion of its genetic background is still unexplored. Objectives This study sought to illuminate the genetic associations with AD using genome-wide association study (GWAS) and its downstream analyses. Methods This study conducted a GWAS for AD comprising 2,639 cases and 115,648 controls in the Japanese population, followed by a trans-ethnic meta-analysis with UK Biobank data and downstream analyses including partitioning heritability analysis by linkage disequilibrium score regression. Results This study identified 17 significant susceptibility loci, among which 4 loci—AFF1, ITGB8, EHMT1, and EGR2—were novel in the Japanese GWAS. The trans-ethnic meta-analysis revealed 4 additional novel loci, namely—ZBTB38, LOC105755953/LOC101928272, TRAF3, andIQGAP1. This study found a missense variant (R243W) with a deleterious functional effect in NLRP10 and a variant altering expression of CCDC80 via enhancer expression as highly likely causal variants. These 2 regions were Asian-specific, and these population-specific associations could be explained by the frequency of causal variants. The gene-based test showed SMAD4 as an additional novel significant locus. Downstream analyses revealed substantial overlap of GWAS significant signals in enhancers of skin cells and immune cells, especially CD4 T cells. A highly shared polygenic architecture of AD between Europeans and Asians was also found. Conclusions This study identified Japanese-specific loci and novel significant loci shared by different populations. Two putative causal variants were illuminated in Japanese-specific loci. Trans-ethnic analyses revealed strong heritability enrichment in immune-related pathways, and relevant cell types shared among populations.

Preeclampsia (PE) is one of the major contributors to maternal and fetal mortality worldwide. Many host-related biomolecules regulate the pathophysiology of PE. The current study aims to examine the role of the renalase in PE manifestations. A total of 384 Chinese women consisting of subjects with normotensive pregnancy (n = 105), women with PE (n = 121), and healthy women (n = 158) were included in the study. Serum renalase level was measured in all subjects by ELISA. Renalase gene polymorphisms (rs10887800, rs2576178, and rs2296545) were genotyped by PCR-RFLP. The pregnant women had elevated renalase levels compared to healthy controls and subjects with PE. Renalase level was negatively correlated with systolic and diastolic blood pressure. Interestingly, renalase was positively correlated with the glomerular filtration rate. Prevalence of homozygous mutant (GG) and minor allele (G) for rs10887800 and rs2576178 renalase gene polymorphisms were significantly higher in PE patients compared to normotensive pregnant women and healthy controls. Furthermore, an association of G-G-C haplotype with susceptibility to PE was also noticed. A low level of renalase may be associated with an increased risk of PE during pregnancy. Renalase gene polymorphisms (rs10887800 and rs2576178) are correlated with serum renalase and are associated with predisposition to PE development in the Chinese cohort.

BACKGROUND CONTEXT Ossification of the posterior longitudinal ligament (OPLL) in the cervical spine is known as a rare, complex genetic disease, its complexity being partly because OPLL is diagnosed by radiological findings regardless of clinical or genetic evaluations. Although many genes associated with susceptibility have been reported, the exact causative genes are still unknown. PURPOSE We performed an analysis using next-generation sequencing and including only patients with a clear involved phenotype. STUDY DESIGN/SETTING This was a case control study. PATIENT SAMPLE A total of 74 patients with severe OPLL and 26 healthy controls were included. OUTCOME MEASURES Causal single-nucleotide variant (SNV), gene-wise variant burden (GVB), and related pathway METHOD We consecutively included the severe OPLL patients with continuous-/mixed-type and an occupying ratio of ≥ 40%, and performed whole-exome sequencing (WES) and bioinformatic analysis. Then, a validation test was performed for candidate variations. Participants were divided into 4 groups (rapidly-growing OPLL, growing rate ≥ 2.5%/y; slow-growing, RESULTS WES was performed on samples from 74 patients with OPLL (rapidly-growing, 33 patients; slow-growing, 37; and uncertain, 4) with 26 healthy controls. Analysis of 100 participants identified a newly implicated SNV and 4candidate genes based on GVB. The GVB of CYP4B1 showed a more deleterious score in the OPLL than the control group. Comparison between the rapidly growing OPLL and control groups revealed seven newly identified SNVs. We found significant association for 2 rare missense variants; rs121502220 (odds ratio [OR] = infinite; minor allele frequency [MAF] = 0.034) in NLRP1 and rs13980628 (OR= infinite; MAF = 0.032) in SSH2. The 3 genes are associated with inflammation control and arthritis, and SSH2 and NLRP1 are also related to vitamin D modulation. CONCLUSIONS Identification of unique variants in novel genes such as CYP4B1 gene may induce the development of OPLL. In subgroup analysis, NLRP1 and SSH2 genes coding inflammation molecules may related with rapidly-growing OPLL.

Risk factors for meningioma include female gender, African American race, high body mass index (BMI), and exposure to ionizing radiation. Although genome-wide association studies (GWAS) have identified two nuclear genome risk loci for meningioma (rs12770228 and rs2686876), the relation between mitochondrial DNA (mtDNA) sequence variants and meningioma is unknown. We examined the association of 42 common germline mtDNA variants (minor allele frequency ≥ 5%), haplogroups, and genes with meningioma in 1080 controls and 478 meningioma cases from a case–control study conducted at medical centers in the southeastern United States. Associations were examined separately for meningioma overall and by WHO grade (n = 409 grade I and n = 69 grade II/III). Overall, meningioma was significantly associated with being female (OR 2.85; 95% CI 2.21–3.69), self-reported African American race (OR 2.38, 95% CI 1.41–3.99), and being overweight (OR 1.48; 95% CI 1.11–1.97) or obese (OR 1.70; 95% CI 1.25–2.31). The variant m.16362T > C (rs62581341) in the mitochondrial control region was positively associated with grade II/III meningiomas (OR 2.33; 95% CI 1.14–4.77), but not grade I tumors (OR 0.99; 95% CI 0.64–1.53). Haplogroup L, a marker for African ancestry, was associated with meningioma overall (OR 2.92; 95% CI 1.01–8.44). However, after stratifying by self-reported race, this association was only apparent among the few self-reported Caucasians with this haplogroup (OR 6.35; 95% CI 1.56–25.9). No other mtDNA variant, haplogroup, or gene was associated with meningioma. Common mtDNA variants and major mtDNA haplogroups do not appear to have associations with the odds of developing meningioma.

Aim of the study – to establish the features of inheritance of the F5L:G(1961)A and F2:G(20210)A genotypes and to assess their influence on the course and outcomes of pregnancy.Materials and methods. The object of the study was 70 mother–child pairs: 50 women, carriers of the F5L:G(1961)A mutation, and their children; 20 female patients, carriers of the F2:G(20210)A mutation, their children. Additionally, 18 families of women, carriers of the factor V Leiden mutation, in three generations were studied.Results. Carriage of the F5:(1961)GA and F2:(20210)GA genotypes in fetuses is associated with the risk of developing gestational complications in their mothers, which are primarily realized when the maternal laboratory phenotype is manifested. A higher frequency of occurrence of the minor allele A20210 of the FII gene was determined in children than in the older generation (p = 0,0006).

The present study comprised of 100 lines derived from teosinte × maize (DI-103) hybridization, which were evaluated for morphological as well as molecular diversity. The slight difference in GCV and PCV estimates for all the traits except grain yield per plant reflects genotypic variation without much influence of environmental factors. The high heritability coupled with high genetic advance for most of the traits elucidated the presence of additive gene effect in the governance of these traits. Genotyping with 76 SSR markers resulted in 377 alleles with an average 5 alleles per marker loci. Wider polymorphic information content (PIC) range from 0.29 to 0.86, reflects higher allelic variation and wide distribution in the population. The average gene diversity, heterozygosity, major allele frequency, and minor allele frequency were 0.48, 0.85, 0.58, and 0.48 respectively. Cluster analysis allocated 102 lines including, maize inbred (DI-103) and teosinte-parviglumis into 14 genetic groups which indicate uniqueness of lines in terms of molecular makeup. Linkage analysis using SSR data revealed ten linkage groups in maize. Maximum allelic contribution from maize (65.2%) and teosinte (59.4%) parent was recorded in MT-26 and MT-19 respectively. With 14 and 3 heterozygous segments MT-44 and MT-26 reflected maximum (37.5%) and minimum (2.4%) heterozygosity respectively. The Maximum recombination (52%) was recorded in the case of MT-40, whereas, the line MT-81 expressed the least recombination (30%). The results reflected a quite significant variability among derived lines and governed by introgression of teosinte alleles, which can be visualized by graphical genotype.

Variability in the FADS2 gene, which codifies the Delta-6 Desaturases and modulates the conversion of essential n-3 and n-6 fatty acids into long-chain polyunsaturated fatty acids, might modify the impact of prenatal supplementation with n-3 docosahexaenoic acid (DHA) on neurodevelopment.To assess if maternal FADS2 single nucleotide polymorphisms (SNPs) modified the effect of prenatal DHA on offspring development at 5 years.We conducted a post-hoc interaction analysis of the POSGRAD randomized controlled trial (NCT00646360) of prenatal supplementation with algal-DHA where 1094 pregnant women originally randomized to 400 mg/day of preformed algal DHA or a placebo from gestation week 18-22 through delivery. In this analysis, we included offspring with information on maternal genotype and neurodevelopment at 5 years (DHA = 316; Control = 306) and used generalized linear models to assess interactions between FADS2 SNPs rs174602 or rs174575 and prenatal DHA on neurodevelopment at 5 years measured with McCarthy Scales of Children's Abilities (MSCA).Maternal and offspring characteristics were similar between groups. At baseline, mean (±standard deviation) maternal age was 26 ± 5 years and schooling was 12 ± 4 years. Forty-six percent (46%) of the children were female. Maternal minor allele frequencies were 0.37 and 0.33 for SNPs rs174602 and rs174575, respectively. There were significant variations by SNP rs174602 and intervention group (p for interactions0.05) where children in the intervention group had higher MSCA scores on the quantitative (DHA: mean ± SEM = 22.6 ± 0.9 vs. Control = 19.1 ± 0.9, mean difference (Δ) = 3.45; p = 0.01) and memory (DHA = 27.9 ± 1.1 vs. Control = 23.7 ± 1.1, Δ = 4.26; p = 0.02) scales only among offspring of TT (minor allele homozygotes).Maternal FADS2 SNP rs174602 modified the effect of prenatal DHA on cognitive development at 5 years. Variations in the genetic make-up of target populations could be an important factor to consider for prenatal DHA supplementation interventions.

Background Single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor A (VEGFA) are associated with susceptibility to several diseases including cancer. Correlations between VEGFA rs3025020 genotypes with clinical and laboratory features of primary myelofibrosis (PMF) are unstudied. Methods DNA was analyzed by real-time polymerase chain reaction for VEGFA rs3025020 genotypes in a cohort of 844 subjects with PMF and in two cohorts of normal subjects (N = 247 and N = 107). Results Frequency of rs3025020 minor allele (T) was not significantly different in subjects with PMF compared with normals; however, the T-allele was more frequent in PMF subjects with a calreticulin (CALR)-mutated genotype compared with normals (35 vs. 27%; OR = 1.47 [95% CI, 1.09, 1.98] p = 0.011), especially in subjects with a CALR-type 2/type 2-like mutation (43 vs. 27%; OR = 2.01 [1.25, 3.24] p = 0.004). CALR mutants with the rs3025020 TT genotype had higher CXCR4 expression on CD34-positive blood cells, and those who carried CT/TT genotypes had lower platelet concentrations compared with other genotypes at diagnosis. Overall, subjects with the rs3025020 CT/TT genotype had a lower cumulative incidence of deep vein thrombosis in typical sites (1.6 vs. 4.2%; OR = 0.37 [0.15, 0.90] p = 0.029) and longer interval from diagnosis to first thrombosis (HR = 0.37 [0.14, 0.95] p = 0.039). Conclusion Persons with PMF and the VEGFA rs3025020 minor T-allele are more likely to have a CALR mutation compared with other somatic driver mutations and lower cumulative incidence and hazard for deep vein thrombosis in typical sites.

Background Mitral valve prolapse (MVP) is largely considered a benign condition. However, MVP is over-represented consistently in sudden unexplained death in the young (SUDY) cohorts. Objective To determine the prevalence and potential genetic underpinnings of suspected arrhythmogenic MVP in a referral cohort of SUDY cases. Methods In this retrospective study, medical records/autopsy reports and whole exome molecular autopsy (WEMA) results for 77 SUDY victims (27 female; average age at death 20.6 ± 8.9 years) were reviewed for evidence of myxomatous MVP and left ventricle (LV) fibrosis. Variants detected in the prespecified 147 WEMA gene panel with a minor allele frequency ≤ 0.001 in public exomes/genomes were classified using the 2015 American College of Medical Genetics (ACMG) guidelines. Results Overall, 6 of 77 (7.8%; 2 female; average age at death 20.7 ± 6.9 years) SUDY cases had MVP as the lone abnormal postmortem finding. The majority had bileaflet involvement (5/6; 83%) and microscopic LV fibrosis (5/6; 83%). In 2 SUDY cases (33%), subjects were diagnosed with MVP by echocardiography prior to death. Unexpectedly, an ACMG pathogenic/likely pathogenic (P/LP) was more likely to be detected in SUDY cases with MVP than those without (3/6 [50%] vs 9/71 [13%]; P < .05). Interestingly, the 3 variants identified in MVP-positive SUDY cases localized to genes associated previously with a cardiomyopathy/channelopathy predisposition (p.E1518fsX25-DMD, p.S285N-RYR2, and p.R109X-TTN). Conclusion This WEMA series provides additional evidence that the combination of MVP and LV fibrosis underlies an unexpected number of SUDY cases. Whether P/LP variants in cardiomyopathy/channelopathy-susceptibility genes contribute to the pathogenesis of arrhythmogenic MVP requires further investigation.

Human genome wide association studies confirm the association of the rs738409 single nucleotide polymorphism (SNP) in the gene encoding protein patatin like phospholipase domain containing 3 (PNPLA...

The three-spot swimming crab (Portunus sanguinolentus) is one of the most important large size economic crabs in China. In this study, we first isolated and characterized a set of 84 SNP loci in P. sanguinolentus. PCR products from ten pairs of primers were sequenced and a total of 3181 bp high-quality DNA sequences were obtained. After genotyping, 84 polymorphic SNP loci were identified. The average frequency of SNP loci was one locus per 38 base pairs in P. sanguinolentus genome. Of these 84 SNP loci, each had bi-alleles with the minor allele frequency ranging from 0.0167 to 0.5000. The observed heterozygosity varied from 0.0333 to 0.7143, while the expected heterozygosity ranged from 0.0333 to 0.5085 per locus. 51 loci showed low variation (HO ≤ 0.3) and 14 SNP loci showed high variation (HO ≥ 0.5). Among 84 SNP loci, 11 loci showed significant deviation from Hardy–Weinberg equilibrium. The developed SNP markers herein will provide valuable information for elucidating population genetic diversity, population dynamics, and conservation genetics of this germplasm resource and other related crab species.

Background: The use of statins to lower high serum cholesterol levels may be associated with a number of adverse reactions, including severe myopathy. The solute carrier organic anion transporter 1B1 (SLCO1B1) gene, which encodes the organic anion-transporting polypeptide OATP1B1, is related to the intracellular transport of statins. The aim of this research was to study the association of rs2306283 and rs4149056 genetic polymorphism of the SLCO1B1 gene with the development of statin-induced myopathy in Jordanian diabetics receiving statins. Methods: We included 413 patients attending the Diabetes Clinics of the National Center for Diabetes, Endocrinology and Genetics, Amman, Jordan. The study was approved by the Institutional Review Board of NCDEG. Myopathy was defined as the elevation of creatine kinase more than 3 times the upper limit of normal. Every subject signed an informed consent form and donated 3-5 mL of venous blood. Genome DNA was extracted from lymphocytes of peripheral blood. Genotypes were identified using the Tetra Amplification Refractory Mutation System of SLCO1B1. Results: The minor allele frequencies of rs2306283 [G] and rs4149056 [C] were 0.38 and 0.23, respectively. The two SNPs followed the Hardy-Weinberg equilibrium. The development of SIM was significantly associated with the homozygous and heterozygous minor allele genotype of rs4149056 (CC and CT), and the homozygous wild type allele genotype of rs2306283 (AA). There was no linkage disequilibrium between the two SNPs in the studied subgroups. Conclusions: Genetic polymorphism in the SLCO1B1 Gene is a risk factor for the development of SIM in Jordanian patients.

The objective of this study was to determine the correlation between single-nucleotide polymorphism rs4769628 in POMP gene and the development of allergic disease in children. Methods. Genotyping of single nucleotide polymorphism rs4769628 in POMP gene in children with manifestations of atopic march and apparently healthy children using real-time polymerase chain reaction. Results. 62.26 % of children with atopic diseases and 53.06 % healthy children had major allele rs4769628 in POMP gene. 33.67 and 37.76 % of children, respectively, had heterozygous AG variant. Minor GG genotype was not detected in children with atopic diseases, 9.18 % of healthy people are carriers of minor allele (р < 0.05). Conclusions. Minor G allele of rs4769628 in РОМР gene is associated with reduced risk of atopic diseases in children. Polymorphism rs4769628 in РОМР gene can be used as an important prognostic marker for the development of atopic diseases in children.

Rationale: The contribution of the adiponectin gene polymorphisms (ADIPOQ, located at 3q27) in the residents of Nigeria and China to the risk of overweight and its association with the risk of arterial hypertension in the European population have been demonstrated.Aim: To identify associations between rs266729 and rs16861194 polymorphisms of the ADIPOQ gene with overweight and obesity in the Moscow region residents.Materials and methods: Identification of rs266729 and rs16861194 polymorphisms of the ADIPOQ gene was carried out in 222 people (140 women and 82 men, aged 25 to 65 years) living in the Moscow region. Genotyping was performed using allele-specific amplification with real-time detection of the results on the CFX96 Real-Time System amplifier (Bio-Rad, USA) and using TaqMan probes complementary to polymorphic DNA regions. To assess an association between these genetic polymorphisms and overweight/obesity, we performed a case control study, with the cases being subjects with body mass index (BMI) of ≥ 30 kg/m2, and the controls those with BMI of < 30 kg/m2.Results: The mean frequency of the minor allele G rs266729 polymorphism of the ADIPOQ gene in the subjects from the Moscow region was 26.8% and similar in men and women. Comparison of the CC and GG genotypes carriers of the rs266729 polymorphism of the ADIPOQ gene in men showed a statistically significant association of the GG genotype to the BMI value (p = 0.04). There were no statistically significant differences between anthropometric indicators (BMI, body fat mass) in the carriers of different rs16861194 polymorphism genotypes of the ADIPOQ. No association between the studied polymorphisms and blood glucose levels and lipid spectrum could be found.Conclusion: The frequency of the minor allele G of the rs266729 polymorphism of the ADIPOQ gene in the subjects from the Moscow region was similar to their rates in the Russian Federation and European countries. In Moscow residents, the rs266729 polymorphism of the ADIPOQ gene (G allele) contributes to the risk of obesity in homozygous carriers (genotype GG). No association of the rs16861194 polymorphism of the ADIPOQ gene with the BMI was found; therefore, this polymorphism cannot be considered as a genetic marker of the obesity risk.

Aims The aim of the present study was to consider whether the ultrastructural features of cardiomyocytes in dilated cardiomyopathy can be used to guide genetic testing. Methods and results Endomyocardial biopsy and whole‐exome sequencing were performed in 32 consecutive sporadic dilated cardiomyopathy patients [51.0 (40.0–64.0) years, 75% men] in initial phases of decompensated heart failure. The predicted pathogenicity of ultrarare (minor allele frequency ≤0.0005), non‐synonymous variants was determined using the American College of Medical Genetics guidelines. Focusing on 75 cardiomyopathy‐susceptibility and 41 arrhythmia‐susceptibility genes, we identified 404 gene variants, of which 15 were considered pathogenic or likely pathogenic in 14 patients (44% of 32). There were five sarcomeric gene variants (29% of 17 variants) found in five patients (16% of 32), involving a variant of MYBPC3 and four variants of TTN. A patient with an MYBPC3 variant showed disorganized sarcomeres, three patients with TTN variants located in the region encoding the A‐band domain showed sparse sarcomeres, and a patient with a TTN variant in encoding the I‐band domain showed disrupted sarcomeres. The distribution of diffuse myofilament lysis depended on the causal genes; three patients with the same TMEM43 variant had diffuse myofilament lysis near nuclei (P = 0.011), while two patients with different DSP variants had lysis in the peripheral areas of cardiomyocytes (P = 0.033). Conclusions Derangement patterns of myofilament and subcellular distribution of myofilament lysis might implicate causal genes. Large‐scale studies are required to confirm whether these ultrastructural findings are related to the causative genes.

Background Approximately 10%-20% of kidney transplant (KT) recipients suffer from acute rejection (AR); thus, sensitive and accurate monitoring of allograft status is recommended. We evaluated the clinical utility of donor-derived DNA (dd-DNA) detection in the urine of KT recipients as a non-invasive means for diagnosing AR. Methods Urine samples serially collected from 39 KT recipients were tested for 39 single-nucleotide variant loci selected according to technical criteria (i.e., high minor allele frequency and low analytical error) using next-generation sequencing. The fraction of dd-DNA was calculated and normalized by the urine creatinine (UCr) level (%dd-DNA/UCr). The diagnostic performance of %dd-DNA/UCr for AR was assessed by ROC curve analysis. Results There was an increasing trend of %dd-DNA/UCr in the AR group before subsequent graft injury, which occurred before (median of 52 days) histological rejection. The serum creatinine (SCr) level differed significantly between the AR and non-AR groups at two and four months of follow-up, whereas %dd-DNA/UCr differed between the groups at six months of follow-up. The combination of %dd-DNA/UCr, SCr, and spot urine protein (UPtn)/UCr showed high discriminating power, with an area under the ROC curve of 0.93 (95% confidence interval: 0.81-1.00) and a high negative predictive value of 100.0%. Conclusions Although the dd-DNA-based test cannot eliminate the need for biopsy, the high negative predictive value of this marker could increase the prebiopsy probability of detecting treatable injury to make biopsy an even more effective diagnostic tool.

Background High macular pigment optical density (MPOD) has been associated with improved eye health and better cognitive functions. Genetic variations have been associated with MPOD in adults. However, these associations between genetic variations and MPOD have not been studied in children. Objectives This was a secondary analysis of the FK2 (Fitness Improves Thinking in Kids 2) trial (n = 134, 41% male). The aim was to determine differences in MPOD among children (aged 7-9 y) based on genetic variants that either are biologically relevant to lutein (L) and zeaxanthin (Z) accumulation or have been associated with MPOD in adults. Methods MPOD was measured using customized heterochromatic flicker photometry via a macular densitometer. DXA was used to assess whole-body and visceral adiposity. DNA was extracted from saliva samples and was genotyped for 26 hypothesis-driven single nucleotide polymorphisms and 75 ancestry-informative markers (AIMs). Habitual diet history was obtained via 3-d food logs completed by parents (n = 88). General linear models were used to compare MPOD between different genotypes. Principal component analysis was performed for the AIMs to account for ethnic heterogeneity. Results Children carrying ≥1 minor allele on β-carotene-15,15'-monooxygenase (BCO1)-rs7501331 (T allele) (P = 0.045), cluster of differentiation 36(CD36)-rs1527483 (T allele) (P = 0.038), or CD36-rs3173798 (C allele) (P = 0.001) had significantly lower MPOD (range: 14.1%-26.4%) than those who were homozygotes for the major alleles. MPOD differences based on CD36-rs3173798 genotypes persisted after adjustment for dietary L and Z intake. Conclusions The findings indicate that genetic variations of CD36 and BCO1 contribute to MPOD in children. The influence of genetic variation in CD36-rs3173798 persisted after adjusting for variation in dietary intake.This trial was registered at clinicaltrials.gov as NCT01619826.

Acipenser baerii is one of the most important sources of caviar production. However, the population of the A. baerii is constantly being reduced in recent years due to dam construction, overfishing, and water pollution. Insufficient molecular markers have limited the effective conservation and management of this species; In the present study, we reported the isolation and characterization of 34 SNP markers in A. baerii; The minor allele frequency ranged from 0.050 to 0.483. The observed heterozygosity varied from 0.100 to 0.933, while the expected heterozygosity ranged from 0.097 to 0.508. Polymorphic information content ranged from 0.090 to 0.375. Seven loci showed significant deviations from the HWE after Bonferroni correction; The novel polymorphic SNPs will be helpful for the future study on molecular-aided breeding, population conservation, and construction of genetic linkage map for this species.

The dojo loach Misgurnus anguillicaudatus is an endemic freshwater species in Asia. The effective conservation and molecular-aided selection of M. anguillicaudatus were limited without sufficient molecular markers. In this study, 112 novel single nucleotide polymorphism (SNP) markers were screened based on 2b-RAD sequencing database, and 56 SNPs of them were developed and characterized by genotyping 40 individuals using SNaPshot method. The observed heterozygosity (Ho) ranged from 0.025 to 0.675, while the expected heterozygosity (He) varied from 0.025 to 0.500. The minor allele frequency (MAF) ranged from 0.013 to 0.500. Among these SNPs, 18 loci were found to deviate significantly from the Hardy–Weinberg equilibrium after Bonferroni correction (P

Hynobius amjiensis was considered as one of the 29 most threatened amphibian in China. To effectively conserve, manage and recover the population of this critically endangered species, 33 single nucleotide polymorphism (SNP) markers were developed using double digest restriction-site associated DNA (ddRAD) sequencing. The minor allele frequency per locus ranged from 0.0161 to 0.5000. The observed heterozygosity and expected heterozygosity varied from 0.0323 to 0.6667 (average 0.3303) and from 0.0317 to 0.5000 (average 0.2772), respectively. The inbreeding coefficient value ranged between − 0.3315 and 0.0000. No significant deviation from Hardy-Weinberg equlibrium (P > 0.05) were found in all loci. These novel SNPs will be helpful for the population genetic assessment and conservation of H. amjiensis.

The population of Hynobius yiwuensis has decreased dramatically due to urbanization and human activities. In order to better monitor and protect this species, 36 single nucleotide polymorphism (SNP) markers were developed using double digest restriction-site associated DNA sequencing (ddRAD-seq). The frequency of minor allele per locus ranged from 0.0132 to 0.3594, while the observed and expected heterozygosity varied from 0.0263 to 0.5278 (average 0.1565) and from 0.0260 to 0.4604 (average 0.1396), respectively. The inbreeding coefficient ranged from − 0.2643 to 0.0000. No loci showed significant departure from Hardy–Weinberg equilibrium (PHWE > 0.05). These polymorphic SNP markers will be useful for the study of conservation genetics in H. yiwuensis.

Objectives Evaluation of the association of PARP1 rs1136410 (A/G) polymorphism with gallbladder cancer susceptibility and its prognosis in the Indian population of eastern Uttar Pradesh and western Bihar. Methods PARP1 rs1136410 was genotyped by PCR-RFLP and its association with the prognosis of gallbladder cancer patients were analyzed using Kaplan-Meier plot and log-rank tests. Results Our results demonstrate that minor allele G is more frequent in gallbladder cancer patients than controls. The frequencies of minor allele G and GG genotype are significantly associated with increased risk of gallbladder cancer. Our data suggest that the minor allele G and homozygous genotype GG are significant predisposing factors for the early age of onset of gallbladder cancer. Similarly, women patients having AG and GG genotypes demonstrate an increased risk of gallbladder cancer. The risk group genotypes (AG + GG) are significantly more frequent in patients with thick gallbladder wall, with jaundice and with the presence of lymph node than in patients with normal gallbladder wall thickness, without jaundice and absence of lymph node involvement. Survival analysis data suggest that patients with risk group genotype (AG + GG) presenting jaundice have shorter overall survival. Conclusion Our study suggests that the minor allele G of PARP1 rs1136410 (A/G) is a predisposing factor for gallbladder carcinogenesis and is significantly associated with early onset of the disease. Interestingly, the minor allele G is significantly more frequent in the patients with jaundice, lymph node metastasis and gallbladder wall thickness.

The Aldabra giant tortoise (Aldabrachelys gigantea) is one of only two remaining giant tortoise species worldwide. Captive-bred A. gigantea are being used in rewilding projects in the Western Indian Ocean to functionally replace the extinct endemic giant tortoise species and restore degraded island ecosystems. Furthermore, large-scale translocations may become necessary as rising sea levels threaten the only wild population on the low-lying Aldabra Atoll. Critical management decisions would be greatly facilitated by insights on the genetic structure of breeding populations. We used a double-digest restriction-associated DNA sequencing (ddRAD-seq) approach to identify single nucleotide polymorphisms (SNP) among the wild population and two additional captive populations of A. gigantea. A total of 1674 unlinked, putatively neutral genome-wide SNPs were identified. The values of expected heterozygosity ranged from 0.33 to 0.5, whereas the minor allele frequency ranged from 0.20 to 0.5. These novel SNP markers will serve as useful tools for informing the conservation of A. gigantea.

INTRODUCTION Subjective tinnitus, a perception of phantom sound, is a common otological condition that affects almost 15% of the general population. It is known that noise-induced hearing loss (NIHL) and tinnitus exhibit a high level of comorbidity in individuals exposed to intense noise and music. However, the influence of genetic variants associated with NIHL on tinnitus remains elusive. We hypothesized that young musicians carrying genetic variants associated with NIHL would exhibit a higher prevalence of tinnitus than their counterparts. METHODS To test this hypothesis, we analyzed the database by Bhatt et al. (2020) (originally developed by Phillips et al., 2015) that investigated the genetic links to NIHL in young college-aged musicians. The present study identified 186 participants (average age = 20.3 yrs, range = 18-25 yrs) with normal tympanometry and otoscopic findings and with no missing data. We included 19 single nucleotide polymorphisms in 13 cochlear genes that were previously associated with NIHL. The candidate genes include: KCNE1, KCNQ1, CDH23, GJB2, GJB4, KCNJ10, CAT, HSP70, PCDH70, MYH14, GRM7, PON2, and ESRRB. RESULTS We find that individuals with at least one minor allele of rs163171 (C > T) in KCNQ1 exhibit significantly higher odds of reporting tinnitus compared to individuals carrying the major allele of rs163171. KCNE1 rs2070358 revealed a suggestive association (p = 0.049) with tinnitus, but the FDR corrected p-value did not achieve statistical significance (p

Many-lined sun skink (Eutropis multifasciata) is a medium sized viviparous scincid lizard. Insufficient molecular markers have limited the effective conservation and management of E. multifasciata. In the present study, 28 novel single nucleotide polymorphism (SNP) markers were developed from the transcriptome dataset of E. multifasciata using SNaPshot method. The minor allele frequency ranged from 0.117 to 0.483. The observed heterozygosity and expected heterozygosity ranged from 0.167 to 0.567 and from 0.210 to 0.508, respectively. Polymorphic information content ranged from 0.185 to 0.375. None of the loci deviated significantly from Hardy–Weinberg equilibrium and no significant linkage disequilibrium was found. Those polymorphic SNP markers will be helpful for the further studies on population structure and conservation genetics in E. multifasciata.

Exome association studies to date have generally been underpowered to systematically evaluate the phenotypic impact of very rare coding variants. We leveraged extensive haplotype sharing between 49,960 exome-sequenced UK Biobank participants and the remainder of the cohort (total N~500K) to impute exome-wide variants at high accuracy (R2>0.5) down to minor allele frequency (MAF) ~0.00005. Association and fine-mapping analyses of 54 quantitative traits identified 1,189 significant associations (P-8) involving 675 distinct rare protein-altering variants (MAFCOL16A1 and COL11A2. Across all traits, 49% of associations (578/1,189) occurred in genes with two or more hits; follow-up analyses of these genes identified long allelic series containing up to 45 distinct likely-causal variants within the same gene (on average exhibiting 93%-concordant effect directions). In particular, 24 rare coding variants in IFRD2 independently associated with reticulocyte indices, suggesting an important role of IFRD2 in red blood cell development, and 11 rare coding variants in NPR2 (a gene previously implicated in Mendelian skeletal disorders) exhibited intermediate-to-strong effects on height (0.18-1.09 s.d.). Our results demonstrate the utility of within-cohort imputation in population-scale GWAS cohorts, provide a catalog of likely-causal, large-effect coding variant associations, and foreshadow the insights that will be revealed as genetic biobank studies continue to grow.

ObjectiveThe Māori and Pacific (Polynesian) population of Aotearoa New Zealand has a high prevalence of gout. Our aim was to identify potentially functional missense genetic variants in candidate inflammatory genes amplified in frequency that may underlie the increased prevalence of gout in Polynesian populations.MethodsA list of 712 inflammatory disease-related genes was generated. An in silico targeted exome set was extracted from whole genome sequencing data in people with gout of various ancestral groups (Polynesian, European, East Asian; n = 55, 780, 135, respectively) to identify Polynesian-amplified common missense variants (minor allele frequency > 0.05). Candidate functional variants were tested for association with gout by multivariable-adjusted regression analysis in 2528 individuals of Polynesian ancestry.ResultsWe identified 26 variants common in the Polynesian population and uncommon in the European and East Asian populations. Three of the 26 population-amplified variants were nominally associated with the risk of gout (rs1635712 [KIAA0319], ORmeta = 1.28, Pmeta = 0.03; rs16869924 [CLNK], ORmeta = 1.37, Pmeta = 0.002; rs2070025 [fibrinogen A alpha chain (FGA)], ORmeta = 1.34, Pmeta = 0.02). The CLNK variant, within the established SLC2A9 gout locus, was genetically independent of the association signal at SLC2A9.ConclusionWe provide nominal evidence for the existence of population-amplified genetic variants conferring risk of gout in Polynesian populations. Polymorphisms in CLNK have previously been associated with gout in other populations, supporting our evidence for the association of this gene with gout.

Purpose Age-related macular degeneration (AMD) is a common multifactorial disease in the elderly with a prominent genetic basis. Many risk variants have been identified, but the interpretation remains challenging. We investigated the genetic distribution of AMD-associated risk variants in a large European consortium, calculated attributable and pathway-specific genetic risks, and assessed the influence of lifestyle on genetic outcomes. Design Pooled analysis of cross-sectional data from the European Eye Epidemiology Consortium. Participants Seventeen thousand one hundred seventy-four individuals 45 years of age or older participating in 6 population-based cohort studies, 2 clinic-based studies, and 1 case-control study. Methods Age-related macular degeneration was diagnosed and graded based on fundus photographs. Data on genetics, lifestyle, and diet were harmonized. Minor allele frequencies and population-attributable fraction (PAF) were calculated. A total genetic risk score (GRS) and pathway-specific risk scores (complement, lipid, extra-cellular matrix, other) were constructed based on the dosage of SNPs and conditional β values; a lifestyle score was constructed based on smoking and diet. Main Outcome Measures Intermediate and late AMD. Results The risk variants with the largest difference between late AMD patients and control participants and the highest PAFs were located in ARMS2 (rs3750846) and CHF (rs570618 and rs10922109). Combining all genetic variants, the total genetic risk score ranged from –3.50 to 4.63 and increased with AMD severity. Of the late AMD patients, 1581 of 1777 (89%) showed a positive total GRS. The complement pathway and ARMS2 were by far the most prominent genetic pathways contributing to late AMD (positive GRS, 90% of patients with late disease), but risk in 3 pathways was most frequent (35% of patients with late disease). Lifestyle was a strong determinant of the outcome in each genetic risk category; unfavorable lifestyle increased the risk of late AMD at least 2-fold. Conclusions Genetic risk variants contribute to late AMD in most patients. However, lifestyle factors have a strong influence on the outcome of genetic risk and should be a strong focus in patient management. Genetic risks in ARMS2 and the complement pathway are present in most late AMD patients but are mostly combined with risks in other pathways.

Polyunsaturated fatty acids (PUFA) influence many physiological functions. Associations have been found between single nucleotide polymorphisms (SNP) in the FADS1 (Fatty acid desaturase 1) gene and the relative abundance of PUFA in serum lipids. This study examines the relationship between two SNPs in the FADS1 gene (rs174546, rs174537) and the fatty acid (FA) composition of serum lipids in adolescents (13-18 years). We used DNA samples (670 children; 336 girls and 334 boys) from the Childhood Obesity Prevalence and Treatment (COPAT) project. Genomic DNA was extracted from peripheral blood leukocytes in whole blood samples. For genotype analysis, TaqMan SNP Genotyping assays (Applied Biosystems) were used. Fatty acid composition of serum lipids was assessed using gas chromatography. The T-statistic and regression were used for statistical evaluations. Minor allele T carriers in both SNPs had significant lower level of palmitic acid (16:0, phospholipids) and arachidonic acid (20:4[n-6], phospholipids) in both sexes. In girls, we found a significant positive association between minor allele T carriers and eicosadienoic acid (20:2[n-6], cholesteryl esters) in both SNPs. Being a minor allele T carrier was significantly positively associated with dihomo-γ-linolenic acid (20:3[n-6], phospholipids) in boys in both SNPs. SNPs (including rs174546, rs174537) in the FADS gene cluster should have impacted desaturase activity, which may contribute to different efficiency of PUFA synthesis.

Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are biomarkers for liver health. Here we report the largest genome‐wide association analysis to date of serum ALT and AST levels in over 388k people of European ancestry from UK biobank and DiscovEHR. Eleven million imputed markers with a minor allele frequency (MAF) ≥ 0.5% were analyzed. Overall, 300 ALT and 336 AST independent genome‐wide significant associations were identified. Among them, 81 ALT and 61 AST associations are reported for the first time. Genome‐wide interaction study identified 9 ALT and 12 AST independent associations significantly modified by body mass index (BMI), including several previously reported potential liver disease therapeutic targets, for example, PNPLA3, HSD17B13, and MARC1. While further work is necessary to understand the effect of ALT and AST‐associated variants on liver disease, the weighted burden of significant BMI‐modified signals is significantly associated with liver disease outcomes. In summary, this study identifies genetic associations which offer an important step forward in understanding the genetic architecture of serum ALT and AST levels. Significant interactions between BMI and genetic loci not only highlight the important role of adiposity in liver damage but also shed light on the genetic etiology of liver disease in obese individuals.

Human leukocyte antigen (HLA) system is the most polymorphic and gene dense region of human DNA that has shown many disease associations. It has been further divided into HLA classes I, II, and III. Polymorphism in HLA class II genes has been reported to play an important role in the pathogenesis of type 1 diabetes (T1D). It also showed association with T2D in different ethnic populations. However, a little is known about the relationship of HLA class I gene polymorphism and T2D. This study has evaluated the association of HLA-B (class I gene) variants with T2D in Pashtun ethnic population of Khyber Pakhtunkhwa. In the first phase of the study, whole exome sequencing (WES) of 2 pooled DNA samples was carried out, and DNA pools used were constructed from 100 diabetic cases and 100 control subjects. WES results identified a total of n = 17 SNPs in HLA-B gene. In the next phase, first 5 out of n = 17 reported SNPs were genotyped using MassARRAY® system in order to validate WES results and to confirm association of selected SNPs with T2D. Minor allele frequencies (MAFs) and selected SNPs×T2D association were determined using chi-square test and logistic regression analysis. The frequency of minor C allele was significantly higher in the T2D group as compared to control group (45.0% vs. 13.0%) ( p = 0.006 ) for rs2308655 in HLA-B gene. No significant difference in MAF distribution between cases and controls was observed for rs1051488, rs1131500, rs1050341, and rs1131285 ( p > 0.05 ). Binary logistic regression analyses showed significant results for SNP rs2308655 ( OR = 2.233 , CI 95 % = 1.223 ‐ 4.077 , and p = 0.009 ), while no considerable association was observed for the other 4 SNPs. However, when adjusted for these variants, the association of rs2308655 further strengthened significantly ( adjusted OR = 7.485 , CI 95 % = 2.353 ‐ 23.812 , and p = 0.001 ), except for rs1131500, which has no additive effect. In conclusion, the finding of this study suggests rs2308655 variant in HLA-B gene as risk variant for T2D susceptibility in Pashtun population.

The vitamin B group, including riboflavin, plays paramount roles in one-carbon metabolism (OCM), and disorders related to this pathway have been linked to cancer development. The variants of genes encoding OCM enzymes and the insufficiency of B vitamins could contribute to carcinogenesis. Very few observational studies have revealed a relationship between riboflavin and gastric cancer (GC), especially under conditions of modified genetic factors. We carried out a study examining the association of riboflavin intake and its interaction with MTRR (rs1532268) genetic variants with GC risk among 756 controls and 377 cases. The OR and 95 % CI were evaluated using unconditional logistic regression models. We observed protective effects of riboflavin intake against GC, particularly in the female subgroup (OR = 0·52, 95 % CI 0·28, 0·97, Ptrend = 0·031). In the MTRR (rs1532268) genotypes analysis, the dominant model showed that the effects of riboflavin differed between the CC and CT + TT genotypes. Compared with CC carriers, low riboflavin intake in T+ carriers was significantly associated with a 93 % higher GC risk (OR = 1·93, 95 % CI 1·09, 3·42, Pinteraction = 0·037). In general, higher riboflavin intake might help reduce the risk of GC in both CC and TC + TT carriers, particularly the T+ carriers, with marginal significance (OR = 0·54, 95 % CI 0·28, 1·02, Pinteraction = 0·037). Our study indicates a protective effect of riboflavin intake against GC. Those who carry at least one minor allele and have low riboflavin intake could modify this association to increase GC risk in the Korean population.

Background: Chemotherapy-related adverse events may restrain taxane/cisplatin administration as a regimen for patients with esophageal squamous cell carcinoma. Genetic polymorphisms may contribute to adverse event susceptibility. Method & results: The authors genotyped ten SNPs from five genes (rs1045642, rs2032582 and rs3213619 of ABCB1; rs2231137 and rs2231142 of ABCG2; rs246221 of ABCC1; rs3740066 of ABCC2; and rs10771973, rs12296975 and rs1239829 of FGD4) in 219 patients with esophageal squamous cell carcinoma treated with taxane/cisplatin. Patients with severe toxicities were compared with those with minor or no adverse events by unconditional logistic regression models and semi-Bayesian shrinkage. After adjustment for age and sex, with the null prior, FGD4 rs1239829 was statistically significantly related to grade 3–4 leukopenia (odds ratio [95% CI] in dominant model = 1.77 [1.04–3.03]). Conclusion: The minor allele of FGD4 rs1239829 was related to grade 3–4 leukopenia in patients with esophageal squamous cell carcinoma treated with taxane/cisplatin, with unclear biological mechanism.

PURPOSE: Unpredictability in acquiring an adequate number of high-quality oocytes following ovarian stimulation is one of the major complications in controlled ovarian hyperstimulation (COH). Genetic predispositions of variations could alter the immunological profiles and consequently be implicated in the variability of ovarian response to the stimulation. DESIGN: Uncovering the influence of variations in AMHR2, LHCGR, MTHFR, PGR, and SERPINE1 genes with ovarian response to gonadotrophin stimulation in COH of infertile women. METHODS: Blood samples of the women with a good ovarian response (GOR) or with a poor ovarian response (POR) were collected. Genomic DNA was extracted, and gene variations were genotyped by TaqMan SNP Genotyping Assays using primer-probe sets or real-time PCR Kit. RESULTS: Except for PGR (rs10895068), allele distributions demonstrate that the majority of POR patients carried minor alleles of AMHR2 (rs2002555, G-allele), LHCGR (rs2293275, G-allele), MTHFR (rs1801131, C-allele, and rs1801133, T-allele), and SERPINE1 (rs1799889, 4G allele) genes compared to the GOR. Similarly, genotypes with a minor allele in AMHR2, LHCGR, MTHFR, and SERPINE1 genes had a higher prevalence among POR patients with the polymorphic genotypes. However, further genotype stratification indicated that the minor alleles of these genes are not associated with poor response. Multivariate logistic analysis of clinical−demographic factors and polymorphic genotypes demonstrated a correlation between FSH levels and polymorphic genotypes of SERPINE1 in poor response status. CONCLUSIONS: Despite a higher prevalence of AMHR2, LHCGR, MTHFR, and SERPINE1 variations in the patients with poor ovarian response, it seems that these variations are not associated with the ovarian response.

Identification of genetic factors leading to increased risk of suicide death is critical to combat rising suicide rates, however, only a fraction of the genetic variation influencing risk has been accounted for. To address this limitation, we conducted the first comprehensive analysis of rare genetic variation in suicide death leveraging the largest suicide death biobank, the Utah Suicide Genetic Risk Study (USGRS). We conducted a single-variant association analysis of rare (minor allele frequency

Background The "Foafoaga O le Ola (Beginning of Life)" study is a prospective birth cohort of n = 160 Samoan mother-infant dyads established in 2017-2018. A primary study aim is to explore how a missense variant at CREBRF rs373863828 impacts growth in early life, given its association with increased body size but lower risk of diabetes in adult Samoans. Here, we examine body size and composition by genotype among toddlers aged 18.7-24.5 months. Methods Height, weight, head circumference, mid-upper-arm circumference, and abdominal circumference, as well as subscapular, triceps, iliac crest and thigh skinfold thickness were measured among 107 toddlers with known rs373863828 genotype; 42 of these toddlers completed dual-energy X-ray absorptiometry (DXA) scans from which body composition (total body less head fat mass, lean mass, bone mass, % fat mass and % fat-free mass) was estimated. Results After controlling for sex and age, toddlers with at least one copy of the CREBRF minor allele (AA/AG) were 1.31 cm taller (SE = 0.64, p = 0.045) than toddlers with the GG genotype. Conclusion Whether greater linear growth in early childhood could contribute to the metabolically protective effects associated with the CREBRF variant in adulthood should be explored in future studies.

BACKGROUND While evidence indicates that familial predisposition influences the risk of developing degenerative rotator cuff disease (RCD), knowledge of specific genetic markers is limited. We conducted a genome-wide association study of RCD surgery using the UK Biobank, a prospective cohort of 500,000 people (40 to 69 years of age at enrollment) with genotype data. METHODS Cases with surgery for degenerative RCD were identified using linked hospital records. The cases were defined as an International Classification of Diseases, Tenth Revision (ICD-10) code of M75.1 determined by a trauma/orthopaedic specialist and surgery consistent with RCD treatment. Cases were excluded if a diagnosis of traumatic injury had been made during the same hospital visit. For each case, up to 5 controls matched by age, sex, and follow-up time were chosen from the UK Biobank. Analyses were limited to European-ancestry individuals who were not third-degree or closer relations. We used logistic regression to test for genetic association of 674,405 typed and >10 million imputed markers, after adjusting for age, sex, population principal components, and follow-up. RESULTS We identified 2,917 RCD surgery cases and 14,158 matched controls. We observed 1 genome-wide significant signal (p < 5 × 10-8) for a novel locus tagged by rs2237352 in the CREB5 gene on chromosome 7 (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.11 to 1.24). The single-nucleotide polymorphism (SNP) rs2237352 was imputed with a high degree of confidence (info score = 0.9847) and is common, with a minor allele frequency of 47%. After expanding the control sample to include additional unmatched non-cases, rs2237352 and another SNP in the CREB5 gene, rs12700903, were genome-wide significant. We did not detect genome-wide significant signals at loci associated with RCD in previous studies. CONCLUSIONS We identified a novel association between a variant in the CREB5 gene and RCD surgery. Validation of this finding in studies with imaging data to confirm diagnoses will be an important next step. CLINICAL RELEVANCE Identification of genetic RCD susceptibility markers can guide understanding of biological processes in rotator cuff degeneration and help inform disease risk in the clinical setting. LEVEL OF EVIDENCE Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

BACKGROUND Familial pseudohyperkalemia (FP) is characterized by an increased rate of potassium leakage in refrigerated red cells and is associated with the minor allele of the single nucleotide polymorphism rs148211042 (R723Q) in the ABCB6 gene. The study aims were to obtain the minor allele frequencies of ABCB6 variants and to measure supernatant potassium accumulation, and other red cell storage parameters, in red cell concentrates (RCC) from carriers of variant rs148211042 under standard blood bank conditions. STUDY DESIGN Whole blood units were collected from 6 FP individuals and 11 controls and processed into RCC in additive solution. RCC were sampled and tested over cold storage for full blood count, extracellular potassium, glucose, lactate, microvesicle release, deformability, hemolysis, pH, adenosine triphosphate, and 2,3-diphosphoglycerate. RESULTS Screening of genotyped cohorts identified that variant rs148211042 is present in 1 in 394 British citizens of European ancestry. FP RCC had significantly higher supernatant potassium at all time points from day 3 onwards (p

Background Several studies correlated elevated B-cell activating factor (BAFF) levels and its polymorphisms (SNPs) in patients with autoimmunity. Limited data existed regarding the role of BAFF in Crohn's Disease (CD) susceptibility and/or treatment response to infliximab. Aim This study aims to evaluate BAFF expression in CD patients, investigate if its expression can predict response to infliximab treatment, and examine the association of BAFF SNPs with CD susceptibility. Methods One hundred twelve CD patients and 164 healthy controls were recruited. Serum BAFF levels were determined using an enzyme-linked immunosorbent assay. Participants were genotyped for rs9514828, rs1041569 and rs2893321 SNPs. Results Serum BAFF concentration was elevated in CD patients (472.86 ± 223.60 pg/ml) compared with controls (128.16 ± 70.10 pg/ml) before treatment. Responders to IFX treatment had increased serum BAFF levels at baseline (610.03 ± 167.55 pg/ml) compared to non-responders (267.09 ± 107 pg/ml). In responders, BAFF concentration reduced after IFX administration, while increased in non-responders. The rs1041569, TA and AA genotypes frequencies, and the minor allele A were increased significantly in CD patients, indicating an association of the SNP with CD susceptibility. Conclusions Our study suggests that BAFF could be a potential biomarker of CD, while SNP rs1041569 was associated with CD susceptibility.

Birsen Can Demirdöğen,1 Yağmur Miçooğulları,2 Aysun Türkanoğlu Özçelik,3 Orhan Adalı4 1Department of Biomedical Engineering, TOBB University of Economics and Technology, Ankara, Turkey; 2Institute of Natural and Applied Sciences, Department of Biology, Middle East Technical University, Ankara, Turkey; 3Food Safety and Agricultural Research Center, Akdeniz University, Antalya, Turkey; 4Department of Biological Sciences, Joint Graduate Program in Biochemistry, Middle East Technical University, Ankara, TurkeyCorrespondence: Birsen Can DemirdöğenDepartment of Biomedical Engineering, TOBB University of Economics and Technology, Ankara, TurkeyTel +90 312 292 42 79Email birsencan.demirdogen@gmail.comPurpose: Soluble epoxide hydrolase (sEH) and microsomal epoxide hydrolase (mEH) both catalyze the metabolism of epoxyeicosatrienoic acids (EETs), lipid signaling molecules that are protective against ischemic brain injury owing to their participation in the regulation of vascular tone and cerebral blood flow. In addition, mEH metabolizes polycyclic aromatic hydrocarbons, one of the causative factors of atherosclerotic lesion development. In this study, we aimed to investigate the association of enzyme activity-modifying missense single nucleotide polymorphisms (SNPs) of the sEH gene (EPHX2) and mEH gene (EPHX1) and ischemic stroke risk in a Turkish population.Patients and Methods: Genomic DNA of patients with large artery atherosclerotic ischemic stroke (n=237) and controls (n=120) was isolated from blood samples, and genotypes for Tyr113His (rs1051740) and His139Arg (rs2234922) SNPs of EPHX1 and Arg287Gln (rs751141) SNP of EPHX2 were attained by the PCR/RFLP method.Results: Minor allele frequency and genotype distributions for Arg287Gln, Tyr113His and His139Arg SNPs did not differ significantly between stroke patients and controls. However, hypertension- and diabetes-associated ischemic stroke risk was decreased by EPHX1 and increased by EPHX2 variants in stratification analyses.Conclusion: This study has shown for the first time that the polymorphic alleles of EPHX1 were unlikely to be associated with large artery atherosclerotic ischemic stroke susceptibility; however, protective effects were evident within subgroups of hypertension and diabetes. In addition, EPHX2 Arg287Gln polymorphism, which has been studied for the first time in a Turkish population, was not significantly related to ischemic stroke, but increased the stroke risk in subgroup analysis.Keywords: Arg287Gln, epoxyeicosatrienoic acids, EETs, His139Arg, SNP, Tyr113His

Summary The proportion of variation in complex traits that can be attributed to non-additive genetic effects has been a topic of intense debate. The availability of biobank-scale datasets of genotype and trait data from unrelated individuals opens up the possibility of obtaining precise estimates of the contribution of non-additive genetic effects. We present an efficient method to estimate the variation in a complex trait that can be attributed to additive (additive heritability) and dominance deviation (dominance heritability) effects across all genotyped SNPs in a large collection of unrelated individuals. Over a wide range of genetic architectures, our method yields unbiased estimates of additive and dominance heritability. We applied our method, in turn, to array genotypes as well as imputed genotypes (at common SNPs with minor allele frequency [MAF] > 1%) and 50 quantitative traits measured in 291,273 unrelated white British individuals in the UK Biobank. Averaged across these 50 traits, we find that additive heritability on array SNPs is 21.86% while dominance heritability is 0.13% (about 0.48% of the additive heritability) with qualitatively similar results for imputed genotypes. We find no statistically significant evidence for dominance heritability (p

Single nucleotide polymorphisms (SNPs) are the most abundant and richest form of genomic polymorphism and, hence, are highly favorable markers for genetic map construction and genome-wide association studies. Based on the DNA specific-locus amplified fragment sequencing (SLAF-seq) for large-scale SNP detection, the genetic diversity and population structure of Salix gordejevii Y. L. Chang et Skv., a valuable sand-fixing shrub, was assessed in 199 accessions from 20 populations in Hunshandake Sandland of northern China. A total of 623.15 M reads resulted in 30.49 × sequencing depth on average and a mean Q30 of 95.70%, and 2,287,715 SNPs in 178,509 polymorphic SLAF tags were obtained. By discarding minor allele frequency > 0.05 and integrity > 0.8, a total of 93,600 SNPs were retained for population genetic analyses, which revealed that 199 individuals could be divided into six groups based on cross-validation errors. However, this grouping pattern did not match the geographical distribution, indicating that there is no apparent geographic barrier in the blank areas where S. gordejevii was not distributed in Hunshandake Sandland. In addition, the physical distance of linkage disequilibrium decay in the analyzed S. gordejevii individuals was 18.5 kb when r2 = 0.1. The linkage disequilibrium decay distances for different chromosomes varied from 4.6 kb (chromosome 16) to 37.8 kb (chromosome 3). The obtained SNPs offer suitable marker resources for further genetic and genomic studies and will benefit S. gordejevii breeding programs.

Background The quantification of mitochondrial DNA heteroplasmy for the diagnosis of mitochondrial disease or after mitochondrial donation, is performed mainly using next-generation sequencing strategies (NGS). Digital PCR (dPCR) has the potential to offer an accurate alternative for mutation load quantification. Methods We assessed the mutation load of 23 low-input human samples at the m.11778 locus, which is associated with Leber’s hereditary optic neuropathy (LHON) using 2 droplet digital PCR platforms (Stilla Naica and Bio-Rad QX200) and the standard NGS strategy. Assay validation was performed by analyzing a titration series with mutation loads ranging from 50% to 0.01%. Results A good concordance in mutation rates was observed between both dPCR techniques and NGS. dPCR established a distinctly lower level of background noise compared to NGS. Minor alleles with mutation loads lower than 1% could still be detected, with standard deviations of the technical replicates varying between 0.07% and 0.44% mutation load. Although no significant systematic bias was observed when comparing dPCR and NGS, a minor proportional bias was detected. A slight overestimation of the minor allele was observed for the NGS data, most probably due to amplification and sequencing errors in the NGS workflow. Conclusion dPCR has proven to be an accurate tool for the quantification of mitochondrial heteroplasmy, even for samples harboring a low mutation load (