Common Single Nucleotide Polymorphisms Research Articles

Association between bronchial asthma and TSLP gene polymorphism: A Systematic review and Meta-analysis

Aims: This study entails an association between bronchial asthma and common single nucleotide polymorphisms (SNPs) in Thymic Stromal Lymphopoietin (TSLP) gene; rs2289278, rs3806933, rs2289276, and rs1837253. Methods: The databases of PubMed, Embase, Web of Science, and Google Scholar were searched for studies reporting TSLP polymorphisms and asthma from inception to January 2022. Hardy-Weinberg equilibriums (HWE) for each polymorphism of the control group were checked using the Chi-square test. The association was estimated by means of odds ratio (OR) with 95% confidence interval (CI) in both dominant and recessive modes of inheritance respectively. Results: Altogether, 11 studies with 3121 asthma cases and 3041 healthy controls were added. Results from six studies showed that the SNP rs2289278 had a protective role in asthma development (OR=0.65, 95% CI= 0.44 - 0.97, P=0.04). Pooling of four studies showed that the SNP rs3806933 had higher odds of developing asthma (OR=1.32, 95% CI=1.14 - 1.54, P < 0.01). However, the SNP rs2289276 and rs1837253 showed no significant association. From the subgroup analysis, SNPs rs2289278 and rs1837253 were protective against the development of asthma in Asia. However, SNP rs2289276 showed a risk association in Asia and in adults. Conclusion: This meta-analysis shows that the SNP rs2289278 has a protective effect on the development of asthma; whereas rs3806933 has a risk of asthma. Additionally, this study adds genomic-based support to the recent FDA approval of tezepelumab, an anti-TSLP agent.

Decoding Common Genetic alterations between Barrett’s Esophagus and Esophageal Adenocarcinoma: A Bioinformatics analysis

BackgroundEsophageal adenocarcinoma (EAC) is a common cancer with a poor prognosis in advanced stages. Therefore, early EAC diagnosis and treatment have gained attention in recent decades. It has been found that various pathological changes, particularly Barrett's Esophagus (BE), can occur in the esophageal tissue before the development of EAC. In this study, we aimed to identify the molecular contributor in BE to EAC progression by detecting the essential regulatory genes that are differentially expressed in both BE and EAC. Materials and MethodsWe conducted a comprehensive bioinformatics analysis to detect BE and EAC-associated genes. The common differentially expressed genes (DEGs) and common single nucleotide polymorphisms (SNPs) were detected using the GEO and DisGeNET databases, respectively. Then, hub genes and the top modules within the protein-protein interaction network were identified. Moreover, the co-expression network of the top module by the HIPPIE database was constructed. Additionally, the gene regulatory network was constructed based on miRNAs and circRNAs. Lastly, we inspected the DGIdb database for possible interacted drugs. ResultsOur microarray dataset analysis identified 92 common DEGs between BE and EAC with significant enrichment in skin and epidermis development genes. The study also identified 22 common SNPs between BE and EAC. The top module of PPI network analysis included SCEL, KRT6A, SPRR1A, SPRR1B, SPRR3, PPL, SPRR2B, EVPL, and CSTA. We constructed a ceRNA network involving three specific mRNAs, 23 miRNAs, and 101 selected circRNAs. According to the results from the DGIdb database, TD101 was found to interact with the KRT6A gene. ConclusionThe present study provides novel potential candidate genes that may be involved in the molecular association between Esophageal adenocarcinoma and Barrett's Esophagus, resulting in developing the diagnostic tools and therapeutic targets to prevent progression of BE to EAC.

The effect of single nucleotide polymorphisms on depression in combination with coronary diseases: a systematic review and meta-analysis.

Depression and coronary heart disease (CHD) have common risk mechanisms. Common single nucleotide polymorphisms (SNPs) may be associated with the risk of depression combined with coronary heart disease. This study was designed according to the PRISMA-P guidelines. We will include case-control studies and cohort studies investigating the relationship between gene SNPs and depression and coronary heart disease comorbidities. The Newcastle-Ottawa Scale (NOS) will be used to assess the risk of bias. When measuring dichotomous outcomes, we will use the odds ratio (OR) and 95% confidence interval (95%CIs) in a case-control study. Five genetic models (allele model, homozygous model, co-dominant model, dominant model, and recessive model) will be evaluated for each included study. Subgroup analysis by ethnicity will be performed. If necessary, post hoc analysis will be made according to different types. A total of 13 studies were included in this study, and the types of genes included are FKBP5 and SGK1 genes that act on glucocorticoid; miR-146a, IL-4-589, IL-6-174, TNF-α-308, CRP-717 genes that act on inflammatory mechanisms; eNOS genes from endothelial cells; HSP70 genes that act on the autoimmune response; ACE2 and MAS1 genes that act to mediate Ang(1-7) in the RAS system; 5-HTTLPR gene responsible for the transport of serotonin 5-HT and neurotrophic factor BDNF gene. There were three studies on 5-HTTLPR and BDNF genes, respectively, while there was only one study targeting FKBP5, SGK1, miR-146a, IL-4-589, IL-6-174, TNF-alpha-308, CRP-717, eNOS, HSP70, ACE2, and MAS1 genes. We did not perform a meta-analysis for genes reported in a single study, and meta-analysis was performed separately for studies exploring the 5-HTTLPR and BDNF genes. The results showed that for the 5-HTTLPR gene, there was a statistically significant association between 5-HTTLPR gene polymorphisms and depression in combination with coronary diseases (CHD-D) under the co-dominant model (LS vs LL: OR 1.76, 95%CI 1.20-2.59; SS vs LL: OR 2.80, 95%CI 1.45 to 5.41), the dominant model (LS+SS vs LL: OR 2.06, 95%CI 1.44 to 2.96), and the homozygous model (SS vs LL: OR 2.80 95%CI 1.45 to 5.5.41) were statistically significant for CHD-D, demonstrating that polymorphisms in the 5-HTTLPR gene are associated with the development of CHD-D and that the S allele in the 5-HTTLPR gene is likely to be a risk factor for CHD-D. For the BDNF gene, there were no significant differences between one of the co-dominant gene models (AA vs GG: OR 6.63, 95%CI 1.44 to 30.64), the homozygous gene model (AA vs GG: OR 6.63,95% CI 1.44 to 30.64), the dominant gene model (GA+AA vs GG: OR4.29, 95%CI 1.05 to 17.45), recessive gene model (AA vs GG+GA: OR 2.71, 95%CI 1.16 to 6.31), and allele model (A vs G: OR 2.59, 95%CI 1.18 to 5.67) were statistically significant for CHD-D, demonstrating that BDNFrs6265 gene polymorphisms are associated with the CHD-D development and that the A allele in the BDNFrs6265 gene is likely to be a risk factor for CHD-D. We analyzed the allele frequencies of SNPs reported in a single study and found that the SNPs in the microRNA146a gene rs2910164, the SNPs in the ACE2 gene rs2285666 and the SNPs in the SGK1 gene rs1743963 and rs1763509 were risk factors for the development of CHD-D. We performed a subgroup analysis of three studies involving the BDNFrs6265 gene. The results showed that European populations were more at risk of developing CHD-D than Asian populations in both dominant model (GA+AA vs GG: OR 10.47, 95%CI 3.53 to 31.08) and co-dominant model (GA vs GG: OR 6.40, 95%CI 1.98 to 20.73), with statistically significant differences. In contrast, the studies involving the 5-HTTLPR gene were all Asian populations, so subgroup analyses were not performed. We performed sensitivity analyses of studies exploring the 5-HTTLPR and BDNF rs6265 genes. The results showed that the results of the allele model, the dominant model, the recessive model, the homozygous model and the co-dominant model for both 5-HTTLPR and BDNF rs6265 genes were stable. Due to the limited number of studies of the 5-HTTLPR and BDNF genes, it was not possible to determine the symmetry of the funnel plot using Begg's funnel plot and Egger's test. Therefore, we did not assess publication bias. SNPs of the microRNA146a gene at rs2910164, the ACE2 gene at the rs2285666 and the SGK1 gene at rs1743963 and rs1763509, and the SNPs at the 5-HTTLPR and BDNF gene loci are associated with the onset of comorbid depression in coronary heart disease. We recommend that future research focus on studying SNPs' impact on comorbid depression in coronary heart disease, specifically targeting the 5-HTTLPR and BDNF gene at rs6265. https://www.crd.york.ac.uk/prospero/, identifier CRD42021229371.

Leveraging functional genomic annotations and genome coverage to improve polygenic prediction of complex traits within and between ancestries.

We develop a method, SBayesRC, that integrates genome-wide association study (GWAS) summary statistics with functional genomic annotations to improve polygenic prediction of complex traits. Our method is scalable to whole-genome variant analysis and refines signals from functional annotations by allowing them to affect both causal variant probability and causal effect distribution. We analyze 50 complex traits and diseases using ∼7 million common single-nucleotide polymorphisms (SNPs) and 96 annotations. SBayesRC improves prediction accuracy by 14% in European ancestry and up to 34% in cross-ancestry prediction compared to the baseline method SBayesR, which does not use annotations, and outperforms other methods, including LDpred2, LDpred-funct, MegaPRS, PolyPred-S and PRS-CSx. Investigation of factors affecting prediction accuracy identifies a significant interaction between SNP density and annotation information, suggesting whole-genome sequence variants with annotations may further improve prediction. Functional partitioning analysis highlights a major contribution of evolutionary constrained regions to prediction accuracy and the largest per-SNP contribution from nonsynonymous SNPs.

Alzheimer Disease Associated Loci: APOE Single Nucleotide Polymorphisms in Marmara Region

Alzheimer’s disease (AD) is a major global health challenge, especially among individuals aged 65 or older. According to population health studies, Turkey has the highest AD prevalence in the Middle East and Europe. To accurately determine the frequencies of common and rare APOE single nucleotide polymorphisms (SNPs) in the Turkish population residing in the Marmara Region, we conducted a retrospective study analyzing APOE variants in 588 individuals referred to the Bursa Uludag University Genetic Diseases Evaluation Center. Molecular genotyping, clinical exome sequencing, bioinformatics analysis, and statistical evaluation were employed to identify APOE polymorphisms and assess their distribution. The study revealed the frequencies of APOE alleles as follows: ε4 at 9.94%, ε2 at 9.18%, and ε3 at 80.68%. The gender-based analysis in our study uncovered a tendency for females to exhibit a higher prevalence of mutant genotypes across various SNPs. The most prevalent haplotype observed was ε3/ε3, while rare APOE SNPs were also identified. These findings align with global observations, underscoring the significance of genetic diversity and gender-specific characteristics in comprehending health disparities and formulating preventive strategies.

Deciphering the Interplay between Genetic Risk Scores and Lifestyle Factors on Individual Obesity Predisposition.

Obesity's variability is significantly influenced by the interplay between genetic and environmental factors. We aimed to integrate the combined impact of genetic risk score (GRSBMI) with physical activity (PA), sugar-sweetened beverages (SSB), wine intake, and eating habits score (EHS) on obesity predisposition risk. Adults' (n = 5824) data were analyzed for common obesity-related single nucleotide polymorphisms and lifestyle habits. The weighted GRSBMI was constructed and categorized into quartiles (Qs), and the adjusted multivariate logistic regression models examined the association of GRSBMI with obesity (BMI ≥ 30) and lifestyle factors. GRSBMI was significantly associated with obesity risk. Each GRSBMI unit was associated with an increase of 3.06 BMI units (p ≤ 0.0001). PA markedly reduced obesity risk across GRSBMI Qs. Inactive participants' (≥90 min/week) mean BMI was higher in GRSBMI Q3-Q4 compared to Q1 (p = 0.003 and p < 0.001, respectively). Scoring EHS ≥ median, SSBs (≥1 cup/day), and non-wine drinking were associated with higher BMI within all GRSBMI Qs compared to EHS < median, non-SSBs, and non-wine drinkers. Mean BMI was higher in GRSBMI Q4 compared to other quartiles (p < 0.0001) in non-wine drinkers and compared to Q1 for SSB's consumers (p = 0.07). A higher GRSBMI augmented the impact of lifestyle factors on obesity. The interplay between GRSBMI and modifiable lifestyle factors provides a tailored personalized prevention and treatment for obesity management.

Association of common single-nucleotide polymorphism of HHEX with type 2 diabetes mellitus

Association of common single-nucleotide polymorphism of HHEX with type 2 diabetes mellitus

Expanding Access to Noninvasive Prenatal Diagnosis for Monogenic Conditions to Consanguineous Families.

Cell-free fetal DNA exists within the maternal bloodstream during pregnancy and provides a means for noninvasive prenatal diagnosis (NIPD). Our accredited clinical service offers definitive NIPD for several autosomal recessive (AR) and X-linked conditions using relative haplotype dosage analysis (RHDO). RHDO involves next-generation sequencing (NGS) of thousands of common single nucleotide polymorphism (SNPs) surrounding the gene of interest in the parents and an affected or unaffected offspring to conduct haplotype phasing of the high- and low-risk alleles. NGS is carried out in parallel on the maternal cell-free DNA, and fetal inheritance is predicted using sensitive dosage calculations performed at sites where the parental genotypes differ. RHDO is not currently offered to consanguineous couples owing to the shared haplotype between parents. Here we test the expansion of RHDO for AR monogenic conditions to include consanguineous couples. The existing sequential probability ratio test analysis pipeline was modified to apply to SNPs where both parents are heterozygous for the same genotype. Quality control thresholds were developed using 33 nonconsanguineous cases. The performance of the adapted RHDO pipeline was tested on 8 consanguineous cases. The correct fetal genotype was predicted by our revised RHDO approach in all conclusive cases with known genotypes (n = 5). Haplotype block classification accuracies of 94.5% and 93.9% were obtained for the nonconsanguineous and consanguineous case cohorts, respectively. Our modified RHDO pipeline correctly predicts the genotype in fetuses from consanguineous families, allowing the potential to expand access to NIPD services for these families.

Associations between COVID-19 and Glucose-6-Phosphate Dehydrogenase Activity in Brazil.

Glucose-6 phosphate dehydrogenase deficiency (G6PDd) was suggested as a risk factor for severe disease in patients with COVID-19. We evaluated clinical outcomes and glucose-6 phosphate dehydrogenase (G6PD) activity during and after illness in patients with COVID-19. This prospective cohort study included adult participants (≥18 years old) who had clinical and/or radiological COVID-19 findings or positive reverse transcription-polymerase chain reaction results. Epidemiological and clinical data were extracted from electronic medical records. Glucose-6 phosphate dehydrogenase activity was measured using SD Biosensor STANDARD G6PD® equipment on admission and 1 year after discharge. Samples were genotyped for the three most common single nucleotide polymorphisms for G6PDd in the Brazilian Amazon. Seven hundred fifty-three patients were included, of whom 123 (16.3%) were G6PD deficient. There was no difference between groups regarding the risks of hospitalization (P = 0.740) or invasive mechanical ventilation (P = 0.31), but the risk of death was greater in patients with normal G6PD levels (P = 0.022). Only 29 of 116 participants (25%) carried the African G6PDd genotype. Of 30 participants tested as G6PD deficient during disease, only 11 (36.7%) results agreed 1 year after discharge. In conclusion, this study does not demonstrate an association of G6PDd with severity of COVID-19. Limitations of the test for detecting enzyme levels during COVID-19 illness were demonstrated by genotyping and retesting after the disease period. Care must be taken when screening for G6PDd in patients with acute COVID-19.

Genetics and Genomics of Pulmonary Fibrosis: Charting the Molecular Landscape and Shaping Precision Medicine.

Recent genetic and genomic advancements have elucidated the complex etiology of idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases (ILDs), emphasizing the contribution of heritable factors. This state-of-the-art review synthesizes evidence on significant genetic contributors to pulmonary fibrosis (PF), including rare genetic variants and common single nucleotide polymorphisms (SNPs). The MUC5B promoter variant is unusual, a common SNP that markedly elevates the risk of early and established PF. We address the utility of genetic variation in enhancing understanding of disease pathogenesis, clinical phenotypes, improving disease definitions, and informing prognosis and treatment response. Critical research gaps are highlighted, particularly the underrepresentation of non-European ancestries in PF genetic studies and the exploration of PF phenotypes beyond usual interstitial pneumonia (UIP)/IPF. We discuss the role of telomere length, often critically short in PF, and its link to progression and mortality, underscoring the genetic complexity involving telomere biology genes (TERT, TERC) and others like SFTPC and MUC5B. Additionally, we address the potential of gene-by-environment interactions to modulate disease manifestation, advocating for precision medicine in PF. Insights from gene expression profiling studies and multi-omic analyses highlight the promise for understanding disease pathogenesis and offer new approaches to clinical care, therapeutic drug development, and biomarker discovery. Finally, we discuss the ethical, legal, and social implications of genomic research and therapies in PF, stressing the need for sound practices and informed clinical genetic discussions. Looking forward, we advocate for comprehensive genetic testing panels and polygenic risk scores to improve the management of PF and related ILDs across diverse populations.

Unraveling inbreeding patterns and selection signals in Alpine Grey cattle

Inbreeding plays a crucial role in livestock breeding, influencing genetic diversity and phenotypic traits. Genomic data have helped address limitations posed by incomplete pedigrees, providing deeper insights into breed genetic diversity. This study assesses inbreeding levels via pedigree and genomic approaches and analyzes old and recent inbreeding using runs of homozygosity (ROH), and selection signals in Alpine Grey cattle. Pedigree data from 165 575 individuals, analyzed with INBUPGF90 software, computed inbreeding coefficients. Genomic-based coefficients derived from PLINK v1.9. or DetectRUNS R package analyses of 1 180 individuals’ genotypes. Common single nucleotide polymorphisms within ROH pinpointed genomic regions, aggregating into “ROH islands” indicative of selection pressure. Overlaps with USCS Genome Browser unveiled gene presence. Moderate correlations (0.20–0.54) existed between pedigree and genomic coefficients, with most genomic estimators having higher (>0.8) correlation values. Inbreeding averaged 0.04 in <8 Mb ROH segments, and 0.03 in >16 Mb segments; >90% of ROHs were <8 Mb, indicating ancient inbreeding prevalence. Recent inbreeding proved less detrimental than in cosmopolitan breeds. Two major ROH islands on chromosomes 6 and 7 harbored genes linked to immune response, disease resistance (PYURF, HERC3), and fertility (EIF4EBP3, SRA1). This study underscores the need for detailed inbreeding analyses to understand genetic characteristics and historical changes in local breeds like Alpine Grey cattle. Genomic insights, especially from ROH, facilitated overcoming pedigree limitations, illuminating breed genetic diversity. Our findings reveal ancient inbreeding's enduring genetic impact and ROH islands potential for selective sweeps, elucidating traits in Alpine Grey cattle.

Evaluation of SNP in the CDH8 and CDH10 Genes Associated with Autism Using In-Silico Tools

Autism spectrum disorder (ASD) is defined as a pervasive and multifactorial neurodevelopmental disorder (ND). It is characterized by repetitive behavioral patterns as well as symptoms of social interaction and communication disorder. The cadherin (CDH) superfamily is a large group of synaptic cell adhesion molecules and has been widely related with ND, including autism. The aim of this study is to evaluate the potentially deleterious missense single nucleotide polymorphisms (SNPs) in CDH8 and CDH10 genes, which are related with ASD and cause amino acid changes, using internet-based software tools. To identify potentially harmful missense SNPs; all SNPs were screened using SIFT, PolyPhen-2, PROVEAN, SNPs&amp;GO, Meta-SNP, and SNAP2 software tools, and common deleterious ones were filtered out. Its effect on protein stabilization was investigated with I-Mutant 3.0 and MUpro tools. Three-dimensional models of these common damaging amino acid changes were evaluated with the HOPE software. As a result of in silico analysis of 577 missense SNPs in the CDH8 gene; The rs145143780 (Y572C) polymorphism common damaging ‎SNP has been detected by all software tools.‎ According to the results of the in silico analysis of 526 missense SNPs found in the CDH10 gene; The rs13174039 (V459G), rs147882578 (N485K), rs201423740 (Y306C), rs201956238 (F317L) and rs373340564 (R128C) common damaging SNPs have been identified in all polymorphisms by all software tools. As a result of this study, it is thought that the data obtained will make important contributions to future relevant experimental studies.

Low-frequency and rare genetic variants associated with rheumatoid arthritis risk.

Rheumatoid arthritis (RA) has an estimated heritability of nearly 50%, which is particularly high in seropositive RA. HLA alleles account for a large proportion of this heritability, in addition to many common single-nucleotide polymorphisms with smaller individual effects. Low-frequency and rare variants, such as those captured by next-generation sequencing, can also have a large role in heritability in some individuals. Rare variant discovery has informed the development of drugs such as inhibitors of PCSK9 and Janus kinases. Some 34 low-frequency and rare variants are currently associated with RA risk. One variant (19:10352442G>C in TYK2) was identified in five separate studies, and might therefore represent a promising therapeutic target. Following a set of best practices in future studies, including studying diverse populations, using large sample sizes, validating RA and serostatus, replicating findings, adjusting for other variants and performing functional assessment, could help to ensure the relevance of identified variants. Exciting opportunities are now on the horizon for genetics in RA, including larger datasets and consortia, whole-genome sequencing and direct applications of findings in the management, and especially treatment, of RA.

Molecular Parentage Analysis in Aquaculture: Principles, Applications, and Challenges: A Review

Molecular parentage analysis is a powerful tool for reconstructing pedigrees and estimating genetic parameters in aquaculture species. It is based on the comparison of DNA marker genotypes between offspring and potential parents. This review provides a concise overview of molecular parentage analysis in aquaculture, covering its principles, methods, applications, challenges, and limitations. It describes common DNA markers, including microsatellites and single nucleotide polymorphisms (SNPs), used in parentage analysis and the criteria for their selection. The software and statistical methods for assigning parentage and evaluating the accuracy and power of the assignment are also discussed. This review demonstrates applications for estimating genetic parameters, investigating inbreeding, evaluating reproductive success, and improving selective breeding programs. In conclusion, while molecular parentage analysis is a valuable tool for improving genetic management in aquaculture, careful planning, implementation, and interpretation are essential.

Abstract 7160: Germline predictors for bevacizumab induced hypertensive crisis in ECOG-ACRIN 5103 and BEATRICE

Abstract Introduction: Bevacizumab is a beneficial therapy in several advanced cancer types. Predictive biomarkers to better understand which patients are destined to benefit or experience toxicity are needed. Associations between bevacizumab induced hypertension and survival have been reported but with conflicting conclusions. Methods: We performed post-hoc analyses to evaluate the association in 3,124 patients from two phase III adjuvant breast cancer trials, E5103 and BEATRICE. Differences in invasive disease-free survival (IDFS) and overall survival (OS) between patients with hypertension and those without were compared. Hypertension was defined as systolic blood pressure (SBP) ≥ 160 mmHg (n=346) and SBP ≥ 180 mmHg (hypertensive crisis) (n=69). Genomic analyses were performed to evaluate germline genetic predictors for the hypertensive crisis. Results: Hypertensive crisis was significantly associated with superior IDFS (p = 0.015) and OS (p = 0.042), but only IDFS (p = 0.029; HR = 0.28) remained significant after correction for prognostic factors. SBP ≥ 160 mmHg was not associated with either IDFS or OS. A common single-nucleotide polymorphism, rs6486785, was significantly associated with hypertensive crisis (p = 8.4 × 10−9; OR = 5.2). Conclusion: Bevacizumab-induced hypertensive crisis is associated with superior outcomes and rs6486785 predicted an increased risk of this key toxicity. Citation Format: Fei Shen, Guanglong Jiang, Santosh Philips, Erica Cantor, Laura Gardner, Gloria Xue, Geneva Cunningham, Nawal Kassem, Anne Oneil, David Cameron, Thomas Suter, Kathy Miller, George Sledge, Bryan Schneider. Germline predictors for bevacizumab induced hypertensive crisis in ECOG-ACRIN 5103 and BEATRICE [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7160.

Abstract 6140: Gene-environment interactions for lifetime water arsenic exposure and bladder cancer risk in the New England Bladder Cancer study

Abstract Environmental arsenic and genetic susceptibility have both been shown to increase bladder cancer risk, yet little is known about their respective interaction. We conducted a gene-environment interaction (GxE) study to characterize lifetime arsenic exposure from drinking water, inherited susceptibility, and bladder cancer risk in the New England Bladder Cancer Study. Exposures were estimated from arsenic measured in water samples collected at home and workplace. We evaluated common single-nucleotide polymorphisms (SNPs) i) from the latest bladder cancer genome-wide association study (n= 28), ii) from candidate gene studies of arsenic or bladder cancer (n= 16 SNPs), and iii) SNPs from a large genome-wide association study of arsenic metabolism (n = 4 SNPs) as potential effect modifiers of the arsenic-bladder cancer relationship. We coded SNPs as the absence or presence of a risk/effect allele for bladder cancer or arsenic metabolism in 2,019 adults (928 bladder cancer cases and 1,091 controls) and arsenic exposures as tertiles. Odds ratios (OR) with 95% confidence intervals (CI) adjusted for age, sex, smoking status, high-risk occupation, and principal components of genetic ancestry were estimated using logistic regression models. P-values for multiplicative interaction were calculated. Out of 48 SNPs, we found evidence of interaction for 7 SNPs at the statistical significance level of P&amp;lt;0.05. Most SNPs involved in GxE interactions are mapped to genomic regions known or suspected to function in arsenic metabolism. For the association between cumulative lifetime water arsenic (mg) and bladder cancer, the strongest evidence of an interaction was with rs1046428 (near GSTZ1 on 14q23); among those with one or two copies of the T risk allele, ORT2vsT1: 1.52, CI: 1.11 - 2.07; ORT3 vsT1: 1.44, CI: 1.05 - 1.98, Pinteraction = 0.01; among those with no risk allele copy, ORT2vsT1: 0.91, CI: 0.62 - 1.35; ORT3 vsT1: 0.97, CI: 0.65 - 1.44. For average daily water arsenic (µg/day), we found evidence of interaction among those with risk allele for rs1801133 (A/A, A/G; MTHFR on 1p36) ORT2 vsT1: 1.70, CI: 1.18 - 2.44; ORT3 vsT1: 1.53, CI: 1.06 - 2.23, Pinteraction = 0.02, in those with no copies of risk allele ORT2vsT1: 0.85, CI: 0.61 - 1.17; ORT3 vsT1: 1.11, CI: 0.79 - 1.54; and rs1801131 (G/G; G/T; MTHFR ) ORT2 vsT1: 1.59, CI: 1.14 - 2.22; ORT3 vsT1: 1.63, CI: 1.16 - 2.29, Pinteraction = 0.01, whereas in those with no risk allele ORT2vsT1: 0.84, CI: 0.59 - 1.19; ORT3 vsT1: 1, CI: 0.69 - 1.44. For 40-year lagged cumulative lifetime water arsenic (mg) and average daily water arsenic (µg/day), we found suggestive interactions with rs2234636 (SLC39A2 on 14q11), and rs1495741 (NAT2 on 8p22). Our study provides evidence of interactions between lifetime arsenic exposure and genetic variants that function in xenobiotic metabolism on bladder cancer occurrence. Citation Format: Hugo Pomares-Millan, Stella Koutros, Nathaniel Rothman, Dalsu Baris, Molly Schwenn, Alison Johnson, Debra T. Silverman, Margaret R. Karagas, Michael N. Passarelli. Gene-environment interactions for lifetime water arsenic exposure and bladder cancer risk in the New England Bladder Cancer study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6140.

A common cis-regulatory variant impacts normal-range and disease-associated human facial shape through regulation of PKDCC during chondrogenesis.

Genome-wide association studies (GWAS) identified thousands of genetic variants linked to phenotypic traits and disease risk. However, mechanistic understanding of how GWAS variants influence complex morphological traits and can, in certain cases, simultaneously confer normal-range phenotypic variation and disease predisposition, is still largely lacking. Here, we focus on rs6740960, a single nucleotide polymorphism (SNP) at the 2p21 locus, which in GWAS studies has been associated both with normal-range variation in jaw shape and with an increased risk of non-syndromic orofacial clefting. Using in vitro derived embryonic cell types relevant for human facial morphogenesis, we show that this SNP resides in an enhancer that regulates chondrocytic expression of PKDCC - a gene encoding a tyrosine kinase involved in chondrogenesis and skeletal development. In agreement, we demonstrate that the rs6740960 SNP is sufficient to confer chondrocyte-specific differences in PKDCC expression. By deploying dense landmark morphometric analysis of skull elements in mice, we show that changes in Pkdcc dosage are associated with quantitative changes in the maxilla, mandible, and palatine bone shape that are concordant with the facial phenotypes and disease predisposition seen in humans. We further demonstrate that the frequency of the rs6740960 variant strongly deviated among different human populations, and that the activity of its cognate enhancer diverged in hominids. Our study provides a mechanistic explanation of how a common SNP can mediate normal-range and disease-associated morphological variation, with implications for the evolution of human facial features.

The primary ciliary dyskinesia-related genetic risk score is associated with susceptibility to adult-onset asthma.

Disturbance of mucociliary clearance is an important factor in the pathogenesis of asthma. We hypothesized that common variants in genes responsible for ciliary function may contribute to the development of asthma with certain phenotypes. Three independent adult Japanese populations (including a total of 1,158 patients with asthma and 2,203 non-asthmatic healthy participants) were studied. First, based on the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/), we selected 12 common single-nucleotide polymorphisms (SNPs) with molecular consequences (missense, nonsense, and 3'-untranslated region mutation) in 5 primary ciliary dyskinesia (PCD)-related genes and calculated a PCD-genetic risk score (GRS) as a cumulative effect of these PCD-related genes. Second, we performed a two-step cluster analysis using 3 variables, including PCD-GRS, forced expiratory volume in 1 second (%predicted FEV1), and age of asthma onset. Compared to adult asthma clusters with an average PCD-GRS, clusters with high and low PCD-GRS had similar overall characteristics: adult-onset, female predominance, preserved lung function, and fewer features of type 2 immunity as determined by IgE reactivity and blood eosinophil counts. The allele frequency of rs1530496, a SNP representing an expression quantitative trait locus (eQTL) of DNAH5 in the lung, showed the largest statistically significant difference between the PCD-GRS-High and PCD-GRS-Low asthma clusters (p = 1.4 x 10-15). Genes associated with PCD, particularly the common SNPs associated with abnormal expression of DNAH5, may have a certain influence on the development of adult-onset asthma, perhaps through impaired mucociliary clearance.

Abstract B052: Ovarian cancer risk prediction: a systematic assessment of the state of the art and development of a new model

Abstract B052: Ovarian cancer risk prediction: a systematic assessment of the state of the art and development of a new model

Common garden experiments and SNP genotyping at the extremes of a steep precipitation gradient suggest local adaptation in a Patagonian conifer

Abstract Plants inhabiting contrasting physical conditions might develop local adaptations overriding the homogenizing effects of gene flow. Hypotheses of local adaptation on phenotypic, genomic, and environmental variation under extreme precipitation regimes were tested in the Patagonian conifer Austrocedrus chilensis. Common garden experiments on progeny and genotype-to-environment association analysis on adults were conducted. Samples consisting of seeds and leaves from adult trees were collected from contrasting dry (DF) and humid (HF) forests along a steep but short precipitation gradient. Seeds were germinated and seedlings were grown under common garden conditions for 24 months. DNA was extracted from 75 randomly selected trees from DF and HF, and genotyped by sequencing to obtain single-nucleotide polymorphisms (SNPs). Seedlings from HF outgrew DF ones suggesting genetically based differences. Twenty-four outlier SNP loci differed between DF and HF, whereas neutral genes (3242) showed high levels of admixture. Eight out of the 24 outlier SNPs aligned with transcripts, half of them related to drought stress responses, and principal component analysis identified four precipitation-related marker–climate associations. Quantitative and genomic traits suggested that natural selection maintains divergence under contrasting climatic conditions regardless high gene flow. This underscores the importance of dry forests as reservoirs of drought-tolerant variants to cope with forecasted climate change.