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Genome-wide association studies in Sjogren's syndrome: What do the genes tell us about disease pathogenesis?

ABSTRACT: The pathogenesis of Sjögren's syndrome (SS) likely involves complex interactions between genes and the environment. While the candidate gene approach has been previously used to identify several genes associated with SS, two recent large-scale genome-wide association studies (GWAS) have implicated many more loci as genetic risk factors. Of particular relevance, was the significant association of SS with additional immune-related genes including IL12A, BLK, and CXCR5. GWAS has also uncovered other loci and suggestive gene associations in SS, but none are related to genes encoding salivary or lacrimal components, secretion machinery and neuronal proteins involved in innervations of the glands, respectively. In this review, we discuss these genetic findings with particular attention paid to the genes identified, the strength of associations, and how the SS-associated genes compare to what has been discovered previously in systemic lupus erythematosus (SLE). We also summarize the potential impact of these associated gene products on NF?B and immune pathways and describe how this new information might be integrated further for identifying clinical subsets and understanding the pathogenesis of SS.

SUBMITTER: Burbelo PD

PROVIDER: S-EPMC4018829 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Genome-wide association studies in Sjögren's syndrome: What do the genes tell us about disease pathogenesis?

Burbelo Peter D PD Ambatipudi Kiran K Alevizos Ilias I

Autoimmunity reviews 20140318 7

The pathogenesis of Sjögren's syndrome (SS) likely involves complex interactions between genes and the environment. While the candidate gene approach has been previously used to identify several genes associated with SS, two recent large-scale genome-wide association studies (GWAS) have implicated many more loci as genetic risk factors. Of particular relevance, was the significant association of SS with additional immune-related genes including IL12A, BLK, and CXCR5. GWAS has also uncovered othe ...[more]

PMID: 24657515

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Project description:ObjectiveThe Sjögren's International Collaborative Clinical Alliance (SICCA) is an international data registry and biorepository derived from a multisite observational study of participants in whom genotyping was performed on the Omni2.5M platform and who had undergone deep phenotyping using common protocol-directed methods. The aim of this study was to examine the genetic etiology of Sjögren's syndrome (SS) across ancestry and disease subsets.MethodsWe performed genome-wide association study analyses using SICCA subjects and external controls obtained from dbGaP data sets, one using all participants (1,405 cases, 1,622 SICCA controls, and 3,125 external controls), one using European participants (585, 966, and 580, respectively), and one using Asian participants (460, 224, and 901, respectively) with ancestry adjustments via principal components analyses. We also investigated whether subphenotype distributions differ by ethnicity, and whether this contributes to the heterogeneity of genetic associations.ResultsWe observed significant associations in established regions of the major histocompatibility complex (MHC), IRF5, and STAT4 (P = 3 × 10-42 , P = 3 × 10-14 , and P = 9 × 10-10 , respectively), and several novel suggestive regions (those with 2 or more associations at P < 1 × 10-5 ). Two regions have been previously implicated in autoimmune disease: KLRG1 (P = 6 × 10-7 [Asian cluster]) and SH2D2A (P = 2 × 10-6 [all participants]). We observed striking differences between the associations in Europeans and Asians, with high heterogeneity especially in the MHC; representative single-nucleotide polymorphisms from established and suggestive regions had highly significant differences in the allele frequencies in the study populations. We showed that SSA/SSB autoantibody production and the labial salivary gland focus score criteria were associated with the first worldwide principal component, indicative of higher non-European ancestry (P = 4 × 10-15 and P = 4 × 10-5 , respectively), but that subphenotype differences did not explain most of the ancestry differences in genetic associations.ConclusionGenetic associations with SS differ markedly according to ancestry; however, this is not explained by differences in subphenotypes.

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Genome-wide association studies in Sjogren's syndrome: What do the genes tell us about disease pathogenesis?

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Genome-wide association studies in Sjögren's syndrome: What do the genes tell us about disease pathogenesis?

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