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Non-synonymous variant (Gly307Ser) in CD226 is associated with susceptibility to multiple autoimmune diseases.

ABSTRACT: Recently, a non-synonymous (Gly307Ser) variant, rs763361, in the CD226 gene was shown to be associated with multiple autoimmune diseases (ADs) in European Caucasian populations. However, shared autoimmunity with CD226 has not been evaluated in non-European populations. The aim of the present study is to assess the association of this single nucleotide polymorphism (SNP) with ADs in non-European populations.To replicate this association in non-European populations, we evaluated case-control association between rs763361 and coeliac disease (CED) samples from Argentina; SLE, RA, type-1 diabetes (T1D) and primary SS (pSS) from Colombia; and SLE samples from China and Japan. We genotyped rs763361 and evaluated its genetic association with multiple ADs, using chi(2)-test. For each association, odds ratio (OR) and 95% CI were calculated.We show that rs763361 is significantly associated with Argentinean CED (P = 0.0009, OR = 1.60). We also observed a trend of possible association with Chinese SLE (P = 0.01, OR = 1.19), RA (P = 0.047, OR = 1.25), SLE (P = 0.0899, OR = 1.24) and pSS (P = 0.09, OR = 1.33) in Colombians. Meta-analyses for SLE (using our three populations) and T1D (our population and three published populations) yielded significant association with rs763361, P = 0.009 (OR = 1.16) and P = 1.1.46 x 10(-9) (OR = 1.14), respectively.Our results demonstrate that the coding variant rs763361 in CD226 gene is associated with multiple ADs in non-European populations.

SUBMITTER: Maiti AK

PROVIDER: S-EPMC2909799 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Non-synonymous variant (Gly307Ser) in CD226 is associated with susceptibility to multiple autoimmune diseases.

Maiti Amit K AK Kim-Howard Xana X Viswanathan Parvathi P Guillén Laura L Qian Xiaoxia X Rojas-Villarraga Adriana A Sun Celi C Cañas Carlos C Tobón Gabriel J GJ Matsuda Koichi K Shen Nan N Cherñavsky Alejandra C AC Anaya Juan-Manuel JM Nath Swapan K SK

Rheumatology (Oxford, England) 20100324 7

<h4>Objectives</h4>Recently, a non-synonymous (Gly307Ser) variant, rs763361, in the CD226 gene was shown to be associated with multiple autoimmune diseases (ADs) in European Caucasian populations. However, shared autoimmunity with CD226 has not been evaluated in non-European populations. The aim of the present study is to assess the association of this single nucleotide polymorphism (SNP) with ADs in non-European populations.<h4>Methods</h4>To replicate this association in non-European populatio ...[more]

PMID: 20338887

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Project description:BackgroundAutoimmune thyroid disease (AITD) is induced by various factors, including inheritability, which regulates gene expression. Multiple loci correlated with AITD have been discovered utilizing genome-wide association studies (GWASs). Nevertheless, demonstrating the biological relevance and function of these genetic loci is difficult.MethodsThe FUSION software was utilized to define genes that were expressed differentially in AITD using a transcriptome-wide association study (TWAS) method in accordance with GWAS summary statistics from the largest genome-wide association study of 755,406 AITD individuals (30,234 cases and 725,172 controls) and levels of gene expression from two tissue datasets (blood and thyroid). Further analyses were performed such as colocalization, conditional, and fine-mapping analyses to extensively characterize the identified associations, using functional mapping and annotation (FUMA) to conduct functional annotation of the summary statistics of 23329 significant risk SNPs (P < 5 × 10-8) recognized by GWAS, together with summary-data-based mendelian randomization (SMR) for identifying functionally related genes at the loci in GWAS.ResultsThere were 330 genes with transcriptome-wide significant differences between cases and controls, and the majority of these genes were new. 9 of the 94 unique significant genes had strong, colocalized, and potentially causal correlations with AITD. Such strong associations included CD247, TPO, KIAA1524, PDE8B, BACH2, FYN, FOXK1, NKX2-3, and SPATA13. Subsequently, applying the FUMA approach, novel putative AITD susceptibility genes and involved gene sets were detected. Furthermore, we detected 95 probes that showed strong pleiotropic association with AITD through SMR analysis, such as CYP21A2, TPO, BRD7, and FCRL3. Lastly, we selected 26 genes by integrating the result of TWAS, FUMA, and SMR analysis. A phenome-wide association study (pheWAS) was then carried out to determine the risk of other related or co-morbid phenotypes for AITD-related genes.ConclusionsThe current work provides further insight into widespread changes in AITD at the transcriptomic level, as well as characterized the genetic component of gene expression in AITD by validating identified genes, establishing new correlations, and uncovering novel susceptibility genes. Our findings indicate that the genetic component of gene expression plays a significant part in AITD.

Project description:Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.

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Non-synonymous variant (Gly307Ser) in CD226 is associated with susceptibility to multiple autoimmune diseases.

Publications

Non-synonymous variant (Gly307Ser) in CD226 is associated with susceptibility to multiple autoimmune diseases.

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