A Genome‐Wide Association Study Reveals ARL15, a Novel Non‐HLA Susceptibility Gene for Rheumatoid Arthritis in North Indians

Abstract

Objective. Genome-wide association studies (GWAS) and their subsequent meta-analyses have changed the landscape of genetics in rheumatoid arthritis (RA) by uncovering several novel genes. Such studies are heavily weighted by samples from Caucasian populations, but they explain only a small proportion of total heritability. Our previous studies in genetically distinct North Indian RA cohorts have demonstrated apparent allelic/genetic heterogeneity between North Indian and Western populations, warranting GWAS in nonEuropean populations. We undertook this study to detect additional disease-associated loci that may be collectively important in the presence or absence of genes with a major effect.Methods. High-quality genotypes for >600,000 single-nucleotide polymorphisms (SNPs) in 706 RA patients and 761 controls from North India were generated in the discovery stage. Twelve SNPs showing suggestive association (P < 5 ؋ 10 ؊5 ) were then tested in an independent cohort of 927 RA patients and 1,148 controls. Additional disease-associated loci were determined using support vector machine (SVM) analyses. Fine-mapping of novel loci was performed by using imputation.Results. In addition to the expected association of the HLA locus with RA, we identified association with a novel intronic SNP of ARL15 (rs255758) on chromosome 5 (P combined ‫؍‬ 6.57 ؋ 10 ؊6 ; odds ratio 1.42). Genotype-phenotype correlation by assaying adiponectin levels demonstrated the functional significance of this novel gene in disease pathogenesis. SVM analysis confirmed this association along with that of a few more replication stage genes.Conclusion. In this first GWAS of RA among North Indians, ARL15 emerged as a novel genetic risk factor in addition to the classic HLA locus, which suggests that population-specific genetic loci as well as those shared between Asian and European populations contribute to RA etiology. Furthermore, our study reveals the potential of machine learning methods in unraveling gene-gene interactions using GWAS data.

Genome-wide association scan in north Indians reveals three novel HLA-independent risk loci for ulcerative colitis

“…This was supported by a GWAS on rheumatoid arthritis that we recently conducted in an NI cohort in which we identified a novel non-HLA gene, ARL15 27. These findings reiterate the importance of conducting GWASs in different ethnic groups.…”

Genome-wide analysis of methotrexate pharmacogenomics in rheumatoid arthritis shows multiple novel risk variants and leads for TYMS regulation

“…This gene is also in a common network with the RA-associated gene ARL15 (Supplementary Fig. 3; Supplemental digital content 4, http://links.lww.com/FPC/A697), which correlates with serum adiponectin level and tissue inflammation [20]. Underexpression of WWOX genes is known for cancer pathogenesis [46] that acts through several p53 family proteins and participates in growth suppression, differentiation, and transcription modulation [47].…”

“…SNPs were ranked on the basis of their weight, where higher weight indicates more relevant SNPs for the phenotype. The SVM approach has been used successfully in many studies to identify susceptibility variants [20,[25][26][27] and the detailed methodology has been described elsewhere [20]. It is well known that when the number of SNPs are larger than the number of individuals, the performance of the SVM reduces.…”

“…Genome-wide genotype data generated using Illumina Infinium Human 660w quad array for first ever genomewide association study (GWAS) in a north Indian RA cohort [20] were available in the laboratory. Data for a total of 457 RA patients with known MTX response were obtained for this study.…”

Tespa1 is associated with susceptibility but not severity of rheumatoid arthritis in the Zhejiang Han population in China

“…The shared epitope (SE) theory provided insight into the association between the susceptibility of RA and some specific HLA class II genotypes such as DRB1 and DRQ1 [16][17][18][19]. However, recent investigations have indicated that more non-MHC genes may be associated with RA susceptibility, such as PTPN22, PADI4, TRAF1-C5, STAT4, and ARL15 [20][21][22][23][24][25][26][27]. In our previous work, we identified Tespa1 [7], a gene that interacted with the linker for activation of T cells (LAT) signalosome formed during TCR signaling, thus playing a key role in the regulation of T cell development.…”