Association Of Variants Research Articles

Relevance of PNPLA3, TM6SF2, HSD17B13, and GCKR Variants to MASLD Severity in an Egyptian Population.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a frequent clinical condition globally. Single nucleotide polymorphisms (SNPs) associated with NAFLD have been proposed in the literature and based on bioinformatic screening. The association between NAFLD and genetic variants in Egyptians is still unclear. Hence, we sought to investigate the association of some genetic variants with NAFLD in Egyptians. Egyptians have been categorized into either the MASLD group (n = 205) or the healthy control group (n = 187). The severity of hepatic steatosis and liver fibrosis was assessed by a Fibroscan device. TaqMan-based genotyping assays were employed to explore the association of selected SNPs with MASLD. PNPLA3 rs738409 C>G variant is associated with the presence of MASLD with liver fibrosis, the severity of both hepatic steatosis and liver fibrosis, increased systolic and diastolic blood pressure and increased alanine aminotransferase (all p < 0.05), while the TM6SF2 rs58542926 C>T, HSD17B13 rs9992651 G>A, and GCKR rs1260326 T>C variants were not (all p > 0.05). The TM6SF2 rs58542926 T allele is associated with increased fasting blood glucose and a decreased waist circumference. The GCKR rs1260326 C allele is associated with decreased aspartate transaminase and diastolic blood pressure (all p < 0.05). Only after adjusting for the risk factors (age, sex, BMI, WC, HDL, TG, diabetes mellitus, and hypertension) F2 liver fibrosis score is negatively correlated with the HSD17B13 rs9992651 GA genotype. This study offers evidence for the association of the PNPLA3 rs738409 C>G variant with MASLD among Egyptians and for the association of the PNPLA3 rs738409 G allele, the TM6SF2 rs58542926 T allele, and the GCKR rs1260326 C allele with some parameters of cardiometabolic criteria.

A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals

Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes. We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N≤2,619,939), Latin American (N≤446,646) and African American (N≤146,776) populations to uncover new and perhaps unexpected associations. These SNPs have been consistently implicated by both candidate gene studies and genome-wide association studies of alcohol-related behaviours but have not been investigated in detail for other relevant phenotypes in a hypothesis-free approach in such a large cohort of multiple ancestries. To provide insight into potential causal effects of alcohol consumption on the outcomes significant in the PheWAS, we performed univariable two-sample and one-sample Mendelian randomisation (MR) analyses. The minor allele rs1229984-T, which is protective against alcohol behaviours, showed the highest number of PheWAS associations across the three cohorts (N=232, European; N=29, Latin American; N=7, African American). rs1229984-T influenced multiple domains of health. We replicated associations with alcohol-related behaviours, mental and sleep conditions, and cardio-metabolic health. We also found associations with understudied traits related to neurological (migraines, epilepsy), immune (allergies), musculoskeletal (fibromyalgia), and reproductive health (preeclampsia). MR analyses identified evidence of causal effects of alcohol consumption on liability for 35 of these outcomes in the European cohort. Our work demonstrates that polymorphisms in genes encoding alcohol metabolising enzymes affect multiple domains of health beyond alcohol-related behaviours. Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine. MVJ, NCK, SBB, SSR and AAP were supported by T32IR5226 and 28IR-0070. SSR was also supported by NIDA DP1DA054394. NCK and RBC were also supported by R25MH081482. ASH was supported by funds from NIAAA K01AA030083. JLMO was supported by VA 1IK2CX002095. JLMO and JJMM were also supported by NIDA R21DA050160. JJMM was also supported by the Kavli Postdoctoral Award for Academic Diversity. EGA was supported by K01MH121659 from the NIMH/NIH, the Caroline Wiess Law Fund for Research in Molecular Medicine and the ARCO Foundation Young Teacher-Investigator Fund at Baylor College of Medicine. MSA was supported by the Instituto de Salud Carlos III and co-funded by the European Union Found: Fondo Social Europeo Plus (FSE+) (P19/01224, PI22/00464 and CP22/00128).

Association of single nucleotide polymorphism rs3213119 variant of IL-12B gene in diagnosed Rheumatoid Arthritis patients.

To identify the IL12B gene variant (rs3213119) and to find its association in Pakistani clinical population of Rheumatoid Arthritis. It was a population association (unrelated) case control study, performed from January - December 2022 at Laboratory of Department of Biochemistry and Molecular Biology, Army Medical College, Rawalpindi. Blood samples were collected from all 150 study participants, followed by DNA extraction and Allele-specific polymerase chain reaction performed at Center for Research in Experimental and Applied Medicine (CREAM) Laboratory of Department of Biochemistry and Molecular Biology, Army Medical College Rawalpindi. Statistical analysis was done using 'SPSS' (version-22), followed by gene analysis on 'SNPstat'. About 28.0% of RA patients were smokers, 38.7% had history of RA in a first degree relative and 70.7% had positive history of consanguinity. Considering rs3213119 variant of IL12B gene, frequency of major allele C was 100%, minor allele A was 21%, genotype C/C was 79% and C/A was 21%. Applying the log additive model, the odds ratio of the genotype C/C was 1.00 (adjusted by age and gender with 95 % CI) and the odds ratio of the genotype C/A was 0.00, 52.0% of RA patients originated from four predominant ethnic groups, namely Awaans (18.7%), Rajputs (14.7%), Pathans (12.0%) and Araeens (6.7%). The study findings suggest the role of minor allele 'A' as risk allele in our clinical population. CA genotype confers susceptibility towards the RA development.

ST2 and IL-33 polymorphisms and the development of childhood asthma: a prospective birth cohort study in Finnish children.

The ST2/IL-33 signaling pathway has an important role in the host inflammatory response. Here we aimed to study the association of ST2 and IL-33 polymorphisms with serum soluble (s) ST2 and IL-33 concentrations in healthy Finnish children and, in addition, their association with childhood asthma. In total, 146 children were followed from birth to the age 7 years for the development of asthma. Single-nucleotide polymorphisms (SNPs) in ST2 and IL-33 were determined, and associations of the SNP variants with serum levels of sST2 and IL-33 at age of 13 months and with recurrent wheezing and childhood asthma at 7 years of age were analyzed. Children with ST2 rs1041973 AC/AA genotypes had significantly lower level of serum sST2 (2453 pg/mL; IQR 2265) than those with CC genotype (5437 pg/mL; IQR 2575; p = < 0.0001). Similar difference was also observed with ST2 rs13408661. No differences were observed between subjects with studied IL-33 SNPs. Children who carried genetic variants of ST2 rs1041973 or rs13408661 seemed to have a higher risk of asthma. In contrast, children who carried genetic variants of IL-33 rs12551268 were less often diagnosed with asthma. Even though these SNPs seemed to associate with asthma, the differences were not statistically significant.

Exome-wide analysis implicates rare protein-altering variants in human handedness

Handedness is a manifestation of brain hemispheric specialization. Left-handedness occurs at increased rates in neurodevelopmental disorders. Genome-wide association studies have identified common genetic effects on handedness or brain asymmetry, which mostly involve variants outside protein-coding regions and may affect gene expression. Implicated genes include several that encode tubulins (microtubule components) or microtubule-associated proteins. Here we examine whether left-handedness is also influenced by rare coding variants (frequencies ≤ 1%), using exome data from 38,043 left-handed and 313,271 right-handed individuals from the UK Biobank. The beta-tubulin gene TUBB4B shows exome-wide significant association, with a rate of rare coding variants 2.7 times higher in left-handers than right-handers. The TUBB4B variants are mostly heterozygous missense changes, but include two frameshifts found only in left-handers. Other TUBB4B variants have been linked to sensorineural and/or ciliopathic disorders, but not the variants found here. Among genes previously implicated in autism or schizophrenia by exome screening, DSCAM and FOXP1 show evidence for rare coding variant association with left-handedness. The exome-wide heritability of left-handedness due to rare coding variants was 0.91%. This study reveals a role for rare, protein-altering variants in left-handedness, providing further evidence for the involvement of microtubules and disorder-relevant genes.

Associations of MEFV gene variants, IL-33, and sST2 with the risk of Henoch-Schönlein purpura in children

ObjectiveHenoch-Schönlein purpura (HSP) is the most common systemic vasculitis in children. HSP is a multifactorial inflammatory disease, but its pathogenesis is still unclear. The pathogenicity of familial Mediterranean fever gene (MEFV) variants in HSP remains controversial. The objective of this study was to evaluate relationships between MEFV variants and susceptibility to HSP and their associations with clinical outcomes. We also investigated levels of IL-33 and soluble suppression of tumorigenicity 2 (sST2) in children with HSP and their clinical significance. MethodsWe selected 100 children with HSP as the case group. The control group consisted of 50 children who visited the hospital for physical health examinations. All subjects were screened for MEFV gene exon mutations, and levels of IL-33 and sST2 were measured. ResultsThe frequency of MEFV variants was significantly greater in HSP patients than in healthy controls. The variant with the highest frequency was E148Q. The frequency of the C allele of the MEFV variant E148Q was 32 % in HSP patients and 18 % in controls (P-adjust = 0.04). Patients with the MEFV E148Q variant had more frequent joint involvement and recurrent purpura and higher levels of IL-33 and C-reactive protein (CRP). Levels of IL-33 and sST2 in children with HSP were significantly higher than those in the control group, and the sST2/IL-33 ratio in children with HSP was unbalanced (P-adjust <0.05). Logistic regression analysis revealed the presence of E148Q and an unbalanced sST2/IL-33 ratio to be independent risk factors for HSP. ConclusionThe results of this study suggest that the MEFV variant E148Q is associated with HSP susceptibility in Chinese children and that carriers of the variant may have more severe clinical manifestations and greater inflammatory responses. E148Q and the sST2/IL-33 ratio may play important roles in the pathogenesis of HSP.

Genetic associations of protein-coding variants in venous thromboembolism

Previous genetic studies of venous thromboembolism (VTE) have been largely limited to common variants, leaving the genetic determinants relatively incomplete. We performed an exome-wide association study of VTE among 14,723 cases and 334,315 controls. Fourteen known and four novel genes (SRSF6, PHPT1, CGN, and MAP3K2) were identified through protein-coding variants, with broad replication in the FinnGen cohort. Most genes we discovered exhibited the potential to predict future VTE events in longitudinal analysis. Notably, we provide evidence for the additive contribution of rare coding variants to known genome-wide polygenic risk in shaping VTE risk. The identified genes were enriched in pathways affecting coagulation and platelet activation, along with liver-specific expression. The pleiotropic effects of these genes indicated the potential involvement of coagulation factors, blood cell traits, liver function, and immunometabolic processes in VTE pathogenesis. In conclusion, our study unveils the valuable contribution of protein-coding variants in VTE etiology and sheds new light on its risk stratification.

Significance of single-nucleotide variants of anorexigenic hormone genes in childhood obesity

Obesity-induced dysregulation of hypothalamic neurons is not completely eliminated by restoring body weight, therefore the most urgent task of modern precision medicine is to predict the trajectory of development of metabolic disorders associated with obesity in children. The aim of the study was to determine the level of association of single-nucleotide variants of genes that determine eating behavior – Neuronal growth regulator 1, Fat mass and obesity associated gene, Glucagon-like peptide-1 receptor, ghrelin, leptin receptor, cholecystokinin, in the development of metabolically unhealthy obesity. 252 obese children aged 6-18 years were examined. The main group (n=152) consisted of children with metabolically unhealthy obesity (MUO) according to Identification and prevention of Dietary- and Lifestyle-induced Health Effects in Children and Infants 2014 criteria. The control group (n=100) consisted of children with metabolically healthy obesity (MHO). All children underwent a general clinical, immunobiochemical examination at the Synevo laboratory (Ukraine). Whole-genome sequencing (CeGat, Germany) was performed in 31 children of the primary and 21 children of the control group. Static analysis: variance analysis ANOVA, method of estimating data dispersion, ROC-analysis, method of testing statistical hypotheses. The level of single nucleotide variants association of anorexigenic hormone genes with MUO that exceeded the threshold accepted by 75% of the available data was, respectively, in ascending order: leptin receptor (LEPR) rs1137101 (40.38%), Glucagon-like peptide-1 receptor (GLP1R) rs1126476 (40.38%), GLP1R rs2235868 (42.31%), GLP1R rs1042044 (42.31%), LEPR rs3790435 (48.08%), cholecystokinin (CCK) rs754635 (50%), LEPR rs2186248 (55.76%), GLP1R rs6918287 (55.76%). Genotypes of the GLP1R gene, such as CC rs10305421 determine insulin resistance (F=5.6); GA/AA rs3765468 – meta-inflammation (F=5.8); AA rs6918287 – basal hyperglycemia (F=6.3) and triglyceridemia (F=51.3), p&lt;0.05. Single-nucleotide variants of the gene GLP1R rs6918287, LEPR rs2186248, CCK rs754635 of the anorexic hormones that control eating behavior are highly associated with the presence of metabolically unhealthy obesity in children.

Association of a genetic variant in angiopoietin-like 3 with serum HDL-C and risk of cardiovascular disease: A study of the MASHAD cohort over 6 years.

Loss-of-function (LOF) variants of the angiopoietin-like 3 (ANGPTL3) gene are reported to be associated with serum triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) concentrations and thereby affect the risk of cardiovascular disease (CVD). In the present study, we examined the association of rs10789117 in the ANGPTL 3 gene locus and the risk of CVD in the group of people who were part of the Mashhad-Stroke and Heart-Atherosclerotic-Disorders (MASHAD) cohort. One thousand and two healthy individuals enrolled in this study of whom 849 subjects were healthy and 153 subjects developed CVD outcomes after 6 years of follow-up. After a 12-h overnight fasting, 20 mL of blood samples were collected for the measurement of fasting blood glucose and lipid profile. DNA was extracted, and the Tetra-ARMS PCR (amplification refractory mutation system) was used for genotyping of rs10789117 in the ANGPTL3 gene. The genotype frequencies of the variant of rs10789117 in the ANGPTL3 gene were estimated using χ2 tests. Eventually, the statistical analysis was done by SPSS version 20. Individuals with AC/CC genotypes (rs10789117) were found to have to greater risk of CVD events compared to AA genotype (OR = 1.43, 95%CI = 1.01-2.02, p = 0.041). There was a 1.3-fold increase in cardiovascular events in individuals carrying the C allele of rs10789117 variant compared to non-carriers (OR = 1.32, 95%CI = 1.06-1.72, p value = 0.038). There were significant differences between different genotypes for serum triglyceride levels within the control group, but this difference was not significant in the group with CVD. Moreover, there was a significant association between CC genotype and CVD risk in the individuals with a normal serum HDL-C. We have found that a rs10789117 C>A in ANGPTL3 gene polymorphism was associated with incident CVD events, and this may be of value as a risk stratification biomarker in CVD in the Iranian population.

Autosomal Dominant Spastic Paraplegia With Dysregulation of Bowel Function Associated With Heterozygous AP4S1 Gene Mutation: Case Report.

The aim of our study was to examine the genetic variants already described in hereditary spastic paraplegia in a family where 2 members had spasticity, dysregulation of sphincter function, and dyspraxia in the proband. The study included 2 members of a non-consanguineous family with spastic gait, sphincter abnormalities, and neuropsychological characteristics. Whole-exome sequencing was used in the proband and his mother, both diagnosed with hereditary spastic paraplegia, to identify the underlying genetic cause. We identified a heterozygous variant already known in AP4S1 NM_007077.3: c.289C>T p. (Arg97*) in both patients. The AP4S1 gene on the 14q12 chromosome is responsible for directing proteins from the trans-Golgi network to the endosomal-lysosomal system. Homozygous AP4S1 mutations can cause a severe autosomal recessive phenotype with spasticity and intellectual disability in infants (SPG52). Interpretation: For the first time, a heterozygous pathogenic variant of the AP4S1 gene was observed in symptomatic individuals with hereditary spastic paraplegia. The clinical features of this heterozygous variant of the AP4S1 gene have little overlap with the severe clinical recessive features of SPG52. In this study, we delineated a heterozygous AP4S1 phenotype characterized by spasticity, dysregulation of sphincter functions, and developmental coordination disorder characteristics. Our results provided arguments for heterozygous variant associations in AP4S1 with hereditary spastic paraplegia and expanded the clinical spectrum of A4-related diseases.

Genetic Association of MSTN Gene Variant (18:66493737T&gt;C) with Track Performance &amp; Muscle Development in Pakistani Horses

The horse, revered for its diverse traits including racing prowess, gaitedness, and distinctive behavior, plays a pivotal role in various sports. Numerous studies have linked racing performance in horses to the MSTN gene across global populations. Objectives: To investigate the genetic variability of the 18:66493737T&gt;C variant in Pakistani random-bred horses. Methods: ARMS-PCR was employed where 24 horses sourced from UVAS equine clinic were genotyped. Results: Revealing a population distribution of 54% homozygous wild-type (TT), 41% heterozygous (TC), and 4% homozygous mutant (CC) at this locus. The alternative allele frequency within elite performers and control horses stood at 0.36 and 0.12, respectively. Application of the Chi-Square association test using the PLINK data toolset yielded a highly significant p-value of 7.832×10-6. Conclusions: This underscores significant genetic variability at the locus in the Pakistani horse population, aligning with global patterns. Future studies are advocated, incorporating racing performance data and encompassing diverse indigenous horse breeds with substantial sample sizes. Identification of subject markers can inform targeted breeding strategies, contributing to the enhancement and preservation of desirable traits across various horse breeds

Investigating the shared genetic architecture between attention-deficit/hyperactivity disorder and risk taking behavior: A large-scale genomewide cross-trait analysis

BackgroundThis study aims to explore the genetic architecture shared between Attention-Deficit/Hyperactivity Disorder (ADHD) and risk behavior. MethodsBased on the latest large-scale Genome-wide association studies (GWAS), we firstly employed Linkage disequilibrium score regression (LDSC) and Local Analysis of Variant Association (LAVA) to investigate the genetic correlation between risk behavior and ADHD. Then, we conducted cross-trait analysis to identified the Pleiotropic loci. Finally, bidirectional Mendelian randomization analysis (MR) was applied to examine the causal relationship. ResultsWe found a significant positive genetic correlation between ADHD and risk-taking behavior (rg = 0.351, p = 6.50E-37). The cross-trait meta-analysis identified 27 significant SNPs shared between ADHD and risk behavior. The most significant locus, located near the CADM2 gene on chromosome 3, had been identified associated with this two trait (pADHD = 3.07E-05 and prisk-taking behavior = 2.47E-30). The same situation can also be observed near the FOXP2 gene on chromosome 7 (rs8180817, pmeta = 5.72E-21). We found CCDC171 gene and other genes played a significant role in ADHD and risk behavior in mRNA level. Bidirectional MR analysis found a causal relationship between them. LimitationThe majority of our data sources were of European origin, which may limit the generalizability of our findings to other ethnic populations. ConclusionThis article reveals in depth the shared genetic structure between ADHD and risk-taking behavior, finding a significant positive genetic correlation between ADHD and risk-taking behavior. Providing insights for the future treatment and management of these two traits.

Genetic Associations of Primary Angle-Closure Disease

Effects of genetic variants on primary angle-closure disease remained uncertain. To systematically review the associations of common single-nucleotide variants (SNVs) and rare coding variants with primary angle-closure disease, its subtypes (including primary angle-closure glaucoma, primary angle-closure suspect, and primary angle-closure) and progression. Eligible studies from PubMed, Embase, and Web of Science were retrieved up to April 3, 2023. SNV information was extracted from eligible reports and 2 genome-wide association studies summary statistics, UK BioBank and FinnGen. Studies providing analyzable genotype or allele data in a case-control design for primary angle-closure disease association and longitudinal case-only design for primary angle-closure disease progression. PRISMA guidelines were used for literature screening and the Newcastle Ottawa Scale for data quality assessment. Pooled effect size with 95% CIs of SNV associations were calculated using fixed- or random-effect models according to I2 statistics. SNVs reported in 2 or more studies were meta-analyzed to generate pooled odds ratios and P values. Common and rare coding variants from single reports were summarized. Sixty-nine citations were eligible for meta-analysis on overall primary angle-closure disease, involving 206 SNVs in 64 genes or loci. Seventeen SNVs in 15 genes or loci showed associations with primary angle-closure disease, and 15 SNVs in 13 genes or loci showed associations with primary angle-closure glaucoma. Two SNVs, ABCA1 rs2422493 and ZNRF3 rs3178915, were associated only with primary angle-closure disease. Two SNVs, PCMTD1-ST18 rs1015213 and COL11A1 rs3753841, were associated with primary angle-closure suspect, and 1 SNV, MMP9 rs3918249, was associated with primary angle-closure. This systematic review and meta-analysis newly confirmed 7 genes or loci associated with primary angle-closure glaucoma: ATOH7, CALCRL, FBN1, IL6, LOXL1, MMP19, and VAV3. Common and rare coding variants in 16 genes or loci that have been associated with primary angle-closure disease were cataloged. Stratification analysis revealed different primary angle-closure disease-associated genes in different ethnic populations. Only 1 study regarding the genetic association of primary angle-closure glaucoma progression was identified. This study revealed the genetic complexity of primary angle-closure disease, involving common SNVs and rare coding variants in more than 30 genes or loci, with ethnic and phenotypic diversities. Further replication, genotype-phenotype correlation, and pathway analyses are warranted.

Association of genetic variants of the Fat Mass and Obesity (FTO) gene and obesity in children

Association of genetic variants of the Fat Mass and Obesity (FTO) gene and obesity in children

Genetic Associations of the Polymorphic Variant of the DRD2 (rs1800497) Gene with Forms of Suicidal Behavior in Patients with Alcohol Dependence

Suicide is a serious public health problem. A deeper understanding of the underlying mechanisms and processes that lead to suicidal behavior is crucial for the development of effective preventive strategies. The study and identification of biomarkers will help in understanding the underlying processes or changes associated with suicide, however, studies linking biomarkers to suicide are limited and fragmented. Objective- To study the genetic associations of the polymorphic variant of the DRD2 gene (rs1800497) with forms of suicidal behavior in patients with alcohol dependence. Materials and methods: The association of polymorphic variants of the gene DRD2 (rs1800497) was analysed in patients with alcohol dependence syndrome, with a history of suicidal behavior and without it, living in the Republic of Bashkortostan, who were treated at the Republican Narco-logical Dispensary in the period from 2019 to 2021. Results: the presence of suicidal tendencies was detected in 39% of patients (136/344). 30% (42/136) were classified as patients with ex-ternal and internal forms of suicidal behavior, 70% (94/136) had only internal forms of suicidal behavior. Carriages of the CC and TT genotypes of the DRD2 gene (rs1800497) are characterized by a lower frequency of occurrence of all forms of suicidal behavior than carriages of СТ genotype. Also, carriages of the CC genotype of the DRD2 gene (rs1800497) are characterized by a lower frequency of occurrence of external forms of suicidal behavior than carriages of СТ and TT genotypes. Conclusions. The data we present indicate the possible contribution of genetic factors to the risk of suicidal behavior in individuals with alcohol dependence syndrome. There is a need for further research to explain the relationships between the circadian rhythm system, alcohol use disorders and suicidal behavior.

Abstract 6130: Association of vitamin D-related genetic variants and prostate cancer risk in Black men

Abstract Background: What we know of the relationship between vitamin D status and prostate cancer has largely been characterized among men of European ancestry, hereafter referred to as “White”. Research among White men indicate positive associations between circulating vitamin D status, as measured by concentrations of 25-hydroxyvitamin D (25(OH)D), with prostate cancer risk, and that genetic scores based on genome-wide associated single nucleotide polymorphisms (SNPs) reflecting high vs. low 25(OHD) is positively associated with aggressive disease. Limited research exists elucidating this relationship among men of African ancestry, hereafter referred to as “Black”. This is despite the fact that Black populations experience chronically lower circulating 25(OH)D, and ancestry-specific differences in genetic variants in some vitamin D-related genes. Given the paucity of research in this area, we examined the role of genetic variants in six commonly studied genes in the vitamin D pathway involved in synthesis (CYP27A1 and CYP27B1), transport (GC), activity (VDR and RXR), and metabolism (CYP24A1) in relation to prostate cancer among Black men. Methods: We assessed a total of 78 candidate SNPs in six vitamin D pathway genes that were either previously associated with circulating 25(OHD) and/or associated with prostate cancer risk in studies of White men. We compared vitamin D gene SNP associations with prostate cancer in Black and White men using summary statistics from a large GWAS of over 10,000 prostate cancer cases and 10,000 controls among Black men and over 85,000 cases and 91,000 controls among White men. A statistical significance threshold of 0.00064 (0.05/78 candidate SNPs) was used to adjust for multiple comparisons. Results: None of the examined SNPs were significantly associated with prostate cancer risk among Black men after adjustment for multiple comparisons. However, four SNPs were nominally significant in Black men, including two in RXR [rs41400444 OR=1.09, 95% CI: 1.01-1.17, P = 0.024 and rs10881574 OR = 0.93, 0.867-0.999, P = 0.04556] and two in VDR [rs2853563 OR = 1.07, 1.012-1.13, P = 0.0173 and rs1156882 OR = 1.06, 1.00-1.12, P = 0.0495]. The latter SNP rs1156882 was also positively associated with prostate cancer risk in White men (OR = 1.035, 1.02-1.06, P = 0.00024), along with VDR SNP rs4516035 (OR = 1.027, 1.012-1.042, P = 0.00055), both after correction for multiple comparisons. Conclusions: We observed non-significant, though suggestive, associations between genetic variants in vitamin D pathway genes previously associated with prostate cancer or vitamin D levels in White populations and prostate cancer risk in Black men. Future research exploring the potential role of vitamin D pathway genes and prostate cancer in Black men – a population at high risk both for low circulating vitamin D and prostate cancer - will need to identify vitamin D-related genetic variants specific to carcinogenesis in Black men. Citation Format: Tracy M. Layne, Joseph H. Rothstein, Xiaoyu Song, Weiva Sieh, Robert J. Klein. Association of vitamin D-related genetic variants and prostate cancer risk in Black men [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 6130.

SRAGE levels are decreased in plasma and sputum of COPD secondary to biomass-burning smoke and tobacco smoking: Differences according to the rs3134940 AGER variant

The receptor for advanced glycation end products (RAGE) and its gene (AGER) have been related to lung injury and inflammatory diseases, including chronic obstructive pulmonary disease (COPD). We aimed to evaluate the association of rs2071288, rs3134940, rs184003, and rs2070600 AGER single-nucleotide variants and the soluble-RAGE plasma and sputum levels with COPD secondary to biomass-burning smoke (BBS) and tobacco smoking. Four groups, including 2189 subjects, were analyzed: COPD secondary to BBS exposure (COPD-BBS, n = 342), BBS-exposed subjects without COPD (BBES, n = 774), tobacco smoking-induced COPD (COPD-TS, n = 434), and smokers without COPD (SWOC, n = 639). Allelic discrimination assays determined the AGER variants. The sRAGE was quantified in plasma (n = 240) and induced-sputum (n = 72) samples from a subgroup of patients using the ELISA technique. In addition, a meta-analysis was performed for the association of rs2070600 with COPD susceptibility. None of the studied genetic variants were found to be associated with COPD-BBS or COPD-TS. A marginal association was observed for the rs3134940 with COPD-BBS (p = 0.066). The results from the meta-analysis, including six case-control studies (n = 4149 subjects), showed a lack of association of rs2070600 with COPD susceptibility (p = 0.681), probably due to interethnic differences. The sRAGE plasma levels were lower in COPD-BBS compared to BBS and in COPD-TS compared to SWOC. The sRAGE levels were also lower in sputum samples from COPD-BBS than BBES. Subjects with rs3134940-TC genotypes exhibit lower sRAGE plasma levels than TT subjects, mainly from the COPD-BBS and SWOC groups. The AGER variants were not associated with COPD-BBS nor COPD-TS, but the sRAGE plasma and sputum levels are related to both COPD-BBS and COPD-TS and are influenced by the rs3134940 variant.

Abstract 2845: Novel genetic risk loci for B-cell acute lymphoblastic leukemia in African American children: Findings from the Admixture and Risk of Acute Leukemia (ADMIRAL) Study

Abstract Background: Racial and ethnic disparities in incidence and outcomes for childhood B-cell acute lymphoblastic leukemia (B-ALL) are well established. While genome-wide association studies (GWASs) among children of European (EUR) genetic ancestry have identified robust risk loci, comparable studies in children of African (AFR) genetic ancestry do not exist. Here we report on results from the first GWAS of B-ALL exclusive to AFR children. Methods: A total of 840 AFR cases (diagnosis age &amp;lt;21y) and 3360 sex-/ancestry-matched controls (from ADMIRAL and ZOE 2.0, a childhood caries study) were evaluated. We used 656 cases from the Children’s Oncology Group (COG) ALL frontline trials for discovery and 184 non-COG cases for replication. Samples were genotyped with the Illumina Global Diversity Array and imputed with the TOPMed reference panel. Ancestry was ascertained with RFMix-inferred global ancestry values and principal components analysis. Logistic regression models adjusted for cryptic population substructure evaluated variant risk associations. Discovery and replication results were meta-analyzed using an inverse variance-weighted fixed effects model. Results: We identified 7 genome-wide significant (GWS, P&amp;lt;5 × 10−8) variants, including 2 novel B-ALL risk loci with replication evidence (P&amp;lt;0.05) and striking per allele effect sizes: CNTN4 (meta-analysis odds ratio [OR]=2.09, P=1.4 × 10−11) and FAM174A (OR=2.94, P=1.2 × 10−15). Established B-ALL EUR risk loci were corroborated in these data (ARIDB5, IKZF1; P&amp;lt;5 × 10−8). Five additional novel loci were GWS after meta-analysis including at SLC37A4 (OR=2.02, P=1.1 × 10−8) and CBWD1 (OR=2.69, P=2.7 × 10−9), with suggestive associations in discovery data (P&amp;lt;5 × 10−6) and nominal replication (P&amp;lt;0.05). Notably, all novel risk alleles were low-frequency in reference AFR populations and AFR-specific (minor allele frequencies of 2-9% in 1000 Genomes AFR and &amp;lt;0.1% in non-AFR). Top variants had relevant in silico annotations; variants at CNTN4 and SLC37A4 had high predicted functional probability (&amp;gt;0.8, RegulomeDb). For example, annotations for a top CNTN4 signal suggest a potential leukemogenesis mechanism, overlapping a ChIP-seq peak for CEBPA in transdifferentiated B cells. In our replication data, a polygenic risk score (PRS) with 5 novel AFR-specific GWS variants from discovery had an appreciably stronger B-ALL risk association (top 25% vs rest: OR=2.03, P=1.2 × 10−4) compared to a published B-ALL PRS from a GWAS in EUR children (top 25% vs rest: OR=1.59, P=0.014). Conclusions: Despite the modest number of AFR B-ALL cases, we successfully detected and replicated genotype risk associations with considerable effect sizes. These results demonstrate the critical importance of increasing diversity in genomic studies of childhood ALL to promote discovery and reduce disparities. Citation Format: Cindy Im, Andrew Raduski, Lauren J. Mills, Rebecca A. Johnson, Andrew DeWan, Xiaomei Ma, Joseph L. Wiemels, Catherine Metayer, Jun J. Yang, Heather H. Nelson, Tianzhong Yang, Saonli Basu, Lucie M. Turcotte, Nathan Pankratz, Michael E. Scheurer, Logan G. Spector. Novel genetic risk loci for B-cell acute lymphoblastic leukemia in African American children: Findings from the Admixture and Risk of Acute Leukemia (ADMIRAL) 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 2845.

The impact of genetic variants related to vitamin D and autoimmunity: A systematic review

Over the past few years, there has been a notable increment in scientific literature aimed at unraveling the genetic foundations of vitamin D signaling and its implications for susceptibility to autoimmunity, however, most of them address isolated diseases. Here, we conducted a systematic review of genetic variants related to vitamin D and autoimmune diseases and we discussed the current landscape of susceptibility and outcomes. Of 65 studies analyzed, most variants cited are in vitamin D binding protein (VDBP; rs2282679 GC gene), 25-hydroxylase (rs10751657 CYP2R1), 1α-hydroxylase (rs10877012, CYP27B1) and the nuclear hormone receptor superfamily [FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236) in VDR gene]. Therefore, our findings confirmed the associations of several genetic variants of vitamin D signaling with a broad spectrum of autoimmune diseases/traits. In addition, given the low number of papers found with functional analysis, further studies to elucidate the real effect that the variants exert on Vitamin D signaling are recommended.

Key variants via the Alzheimer's Disease Sequencing Project whole genome sequence data.

Genome-wide association studies (GWAS) have identified loci associated with Alzheimer's disease (AD) but did not identify specific causal genes or variants within those loci. Analysis of whole genome sequence (WGS) data, which interrogates the entire genome and captures rare variations, may identify causal variants within GWAS loci. We performed single common variant association analysis and rare variant aggregate analyses in the pooled population (N cases=2184, N controls=2383) and targeted analyses in subpopulations using WGS data from the Alzheimer's Disease Sequencing Project (ADSP). The analyses were restricted to variants within 100kb of 83 previously identified GWAS lead variants. Seventeen variants were significantly associated with AD within five genomic regions implicating the genes OARD1/NFYA/TREML1, JAZF1, FERMT2, and SLC24A4. KAT8 was implicated by both single variant and rare variant aggregate analyses. This study demonstrates the utility of leveraging WGS to gain insights into AD loci identified via GWAS.