High-Density SNP Screening of the Major Histocompatibility Complex in Systemic Lupus Erythematosus Demonstrates Strong Evidence for Independent Susceptibility Regions

Abstract

A substantial genetic contribution to systemic lupus erythematosus (SLE) risk is conferred by major histocompatibility complex (MHC) gene(s) on chromosome 6p21. Previous studies in SLE have lacked statistical power and genetic resolution to fully define MHC influences. We characterized 1,610 Caucasian SLE cases and 1,470 parents for 1,974 MHC SNPs, the highly polymorphic HLA-DRB1 locus, and a panel of ancestry informative markers. Single-marker analyses revealed strong signals for SNPs within several MHC regions, as well as with HLA-DRB1 (global p = 9.99×10−16). The most strongly associated DRB1 alleles were: *0301 (odds ratio, OR = 2.21, p = 2.53×10−12), *1401 (OR = 0.50, p = 0.0002), and *1501 (OR = 1.39, p = 0.0032). The MHC region SNP demonstrating the strongest evidence of association with SLE was rs3117103, with OR = 2.44 and p = 2.80×10−13. Conditional haplotype and stepwise logistic regression analyses identified strong evidence for association between SLE and the extended class I, class I, class III, class II, and the extended class II MHC regions. Sequential removal of SLE–associated DRB1 haplotypes revealed independent effects due to variation within OR2H2 (extended class I, rs362521, p = 0.006), CREBL1 (class III, rs8283, p = 0.01), and DQB2 (class II, rs7769979, p = 0.003, and rs10947345, p = 0.0004). Further, conditional haplotype analyses demonstrated that variation within MICB (class I, rs3828903, p = 0.006) also contributes to SLE risk independent of HLA-DRB1*0301. Our results for the first time delineate with high resolution several MHC regions with independent contributions to SLE risk. We provide a list of candidate variants based on biologic and functional considerations that may be causally related to SLE risk and warrant further investigation.

The HLA-DRβ1 amino acid positions 11–13–26 explain the majority of SLE–MHC associations

“…We observed some suggestive associations near HLA-B and -C and non-HLA genes (PZ1.37 Â 10 À 6 ) after conditioning on all HLA-DRB1 signals. This observation could be consistent with other fine-mapping studies that showed evidence of multiple independent associations in the MHC region [6][7][8][9] . Therefore, in the future, it is important to expand the same finemapping study on HLA alleles, HLA amino acids and SNPs with a larger sample size and multiple ancestral samples.…”

“…Several studies have attempted to dissect the SLE association within the extended MHC locus characterized by a high degree of linkage disequilibrium (LD) and genetic diversity [6][7][8][9][10] . Multiple HLA alleles and non-HLA variants in MHC locus have been suggested to have independent SLE-risk effects, as demonstrated by stepwise conditional analysis or HLA allele-allele haplotype analysis to control for the LD effect [6][7][8][9] .…”

“…Multiple HLA alleles and non-HLA variants in MHC locus have been suggested to have independent SLE-risk effects, as demonstrated by stepwise conditional analysis or HLA allele-allele haplotype analysis to control for the LD effect [6][7][8][9] . However, there were inconsistent observations among the studies in terms of the number and position of independent SLE-risk loci.…”

Cumulative association of eight susceptibility genes with systemic lupus erythematosus in a Japanese female population

“…For the same reason, we did not include the multiple SNPs in the HLA region, which were shown to be independently associated with SLE in other populations. 38 Therefore, our current model represents only a proportion of the whole genetic contribution to SLE, and should be improved in the future by incorporating additional susceptibility genes when their association was replicated in the Japanese.…”

Introductory Chapter: Systemic Lupus Erythematosus - Different Predisposing Factors

“…The defect in these genes is although rare but susceptibility in most patients arises from a combination of normal variation in different genes. High-density SNP screening of the major histocompatibility complex in SLE showed strong evidence for independent susceptibility regions including HLADR2, HLADR3, and HLA-DRB1 [24]. There are other types of genes that can regulate the immune system, are also implicated in SLE.…”