Cytokine gene polymorphisms and human autoimmune disease in the era of genome-wide association studies

Abstract

Cytokine (receptor) genes have traditionally attracted great interest as plausible genetic risk factors for autoimmune disease. Since 2007, the implementation of genome-wide association studies has facilitated the robust identification of allelic variants in more than 35 cytokine loci as susceptibility factors for a wide variety of over 15 autoimmune disorders. In this review, we catalog the gene loci of interleukin, chemokine, and tumor necrosis factor receptor superfamily and ligands that have emerged as autoimmune risk factors. We examine recent progress made in the clarification of the functional mechanisms by which polymorphisms in the genes coding for interleukin-2 receptor alpha (IL2RA), IL7R, and IL23R may alter risk for autoimmune disease, and discuss opposite autoimmune risk alleles found, among others, at the IL10 locus.

FIG. 1.

GWAS-based identification of cytokine gene loci as risk factors for 17 autoimmune/chronic inflammatory disorders. Included are chemokine and cytokine (receptor) and ligands/receptors of the TNF superfamily. Genes are considered to be associated with a disease, if they contain an associated SNP in the coding/intronic/3′ or 5′ regulatory sequences, or in the surrounding region within reach of linkage disequilibrium with the gene. Only GWAS and meta-analyses of GWAS that include validation of the associated variant through independent replication were examined. GWAS were accessed via the NHGRI Catalog of Published GWAS (www.genome.gov/gwastudies), and additional searches were performed in PubMed (up to August 2011). Black squares denote association of the gene locus with genome-wide significance, white numbers refer to the times the gene locus has turned up in independent GWAS, be it not necessarily with the same SNPs. Notes: ¹Gene cluster on chr17q12 (pos 29606409–29672532) containing the following contiguous chemokine genes: CCL2–CCL7–CCL11–CCL8. ²Gene cluster on chr2q12.1 (position 101974738–102435458) containing the following contiguous cytokine genes: IL1R2–IL1R1–IL1RL2–IL1RL1–IL18R1–IL18RAP. GWAS, genome-wide association studies.