Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk

Abstract

To discover novel RA risk loci, we systematically examined 370 SNPs from 179 independent loci with p<0.001 in a published meta-analysis of RA GWAS of 3,393 cases and 12,462 controls1. We used GRAIL2, a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci1,3-11. We identified 22 loci with a significant degree of functional connectivity. We genotyped 22 representative SNPs in an independent set of 7,957 cases and 11,958 matched controls. Three validate convincingly: CD2/CD58 (rs11586238, p=1×10−6 replication, p=1×10−9 overall), and CD28 (rs1980422, p=5×10−6 replication, p=1×10−9 overall), PRDM1 (rs548234, p=1×10−5 replication, p=2×10−8 overall). An additional four replicate (p<0.0023): TAGAP (rs394581, p=0.0002 replication, p=4×10−7 overall), PTPRC (rs10919563, p=0.0003 replication, p=7×10−7 overall), TRAF6/RAG1 (rs540386, p=0.0008 replication, p=4×10−6 overall), and FCGR2A (rs12746613, p=0.0022 replication, p=2×10−5 overall). Many of these loci are also associated to other immunologic diseases.

Vaccination and autoimmune diseases: is prevention of adverse health effects on the horizon?

“…Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown etiology, characterized by inflammatory polyarthritis affecting 1% of the adult population worldwide [112,113]. RA is caused by a combination of genetic susceptibility and environmental factors, including not only increased antibody levels of measles virus but also by vaccine strain [114].…”

PTPN22 polymorphisms associated with type 1 diabetes mellitus in ethnic populations of Russian Federation

“…Некото-рые из них играют критическую роль в предотвращении спонтанной активации T-клеток, а также в возвращении активированных T-клеток к состоянию покоя после уда-ления стимула активации [3]. Генетические исследования подтверждают, что гены по меньшей мере шести извест-ных тирозиновых фосфатаз ассоциированы с иммунопа-тологией: PTPN22, PTPN2, PTPRC, UBASH3A, PTPN11 и PTPRT [4][5][6][7][8][9][10]. Из них с диабетом первого типа макси-мально ассоциирован ген PTPN22, сообщая риск >2 [11].…”

ANKRD55 and DHCR7 are novel multiple sclerosis risk loci

“…8,25 Similarly, the PRDM1 SNPs emerging from the RA and SLE studies, rs548234 and rs6568431, respectively, are 21 kb apart, occur in LD (D 0 ¼ 0.92, r 2 ¼ 0.69), and both are located 3 0 from PRDM1. 22,24 Neither of the UC/CD PRDM1 SNPs occurs in LD with any of the RA/SLE SNPs (D 0 p0.54, r 2 p0.09), an observation that may be indicative for the existence of independent susceptibility effects conferred either by allelic variants at the PRDM1 locus, or at any neighboring locus within reach of these discrete LD patterns. Thus, in order to ascertain more complete assessment of the genetic diversity at PRDM1, both the RA rs548234 and the CD rs7746082 SNPs (Table 1) were genotyped.…”

“…20,23 The PRDM1 gene region was identified as susceptibility locus for CD, UC, SLE and RA through meta-analyses of GWAS coupled to replication exercises in independent sample sets. 8,22,24,25 The most strongly associated SNPs identified in the CD and UC studies, rs7746082 and rs6911490, respectively, are in partial LD (D 0 ¼ 0.76, r 2 ¼ 0.265), separated by a stretch of 87 kb and are located 5 0 from PRDM1. 8,25 Similarly, the PRDM1 SNPs emerging from the RA and SLE studies, rs548234 and rs6568431, respectively, are 21 kb apart, occur in LD (D 0 ¼ 0.92, r 2 ¼ 0.69), and both are located 3 0 from PRDM1.…”