A major histocompatibility Class I locus contributes to multiple sclerosis susceptibility independently from HLA-DRB1*15:01

Abstract

Background: In Northern European descended populations, genetic susceptibility for multiple sclerosis (MS) is associated with alleles of the human leukocyte antigen (HLA) Class II gene DRB1. Whether other major histocompatibility complex (MHC) genes contribute to MS susceptibility is controversial.

Methodology/principal findings: A case control analysis was performed using 958 single nucleotide polymorphisms (SNPs) spanning the MHC assayed in two independent datasets. The discovery dataset consisted of 1,018 cases and 1,795 controls and the replication dataset was composed of 1,343 cases and 1,379 controls. The most significantly MS-associated SNP in the discovery dataset was rs3135391, a Class II SNP known to tag the HLA-DRB1*15:01 allele, the primary MS susceptibility allele in the MHC (O.R. = 3.04, p < 1 x 10(-78)). To control for the effects of the HLA-DRB1*15:01 haplotype, case control analysis was performed adjusting for this HLA-DRB1*15:01 tagging SNP. After correction for multiple comparisons (false discovery rate = .05) 52 SNPs in the Class I, II and III regions were significantly associated with MS susceptibility in both datasets using the Cochran Armitage trend test. The discovery and replication datasets were merged and subjects carrying the HLA-DRB1*15:01 tagging SNP were excluded. Association tests showed that 48 of the 52 replicated SNPs retained significant associations with MS susceptibility independently of the HLA-DRB1*15:01 as defined by the tagging SNP. 20 Class I SNPs were associated with MS susceptibility with p-values < or = 1 x 10(-8). The most significantly associated SNP was rs4959039, a SNP in the downstream un-translated region of the non-classical HLA-G gene (Odds ratio 1.59, 95% CI 1.40, 1.81, p = 8.45 x 10(-13)) and is in linkage disequilibrium with several nearby SNPs. Logistic regression modeling showed that this SNP's contribution to MS susceptibility was independent of the Class II and Class III SNPs identified in this screen.

Conclusions: A MHC Class I locus contributes to MS susceptibility independently of the HLA-DRB1*15:01 haplotype.

Figure 1. Association test results for 958 SNPs spanning the MHC in the discovery dataset are shown.

The location of the SNPs is depicted on the X-axis and the statistical significance of the association is depicted on the Y-axis. A: Discovery dataset (1018 cases and 1795 controls), 958 common SNP subset, FDR = .05, adjusted for sex and center (US versus UK), trend test. B: Discovery dataset, 958 common SNP subset, FDR = .05, adjusted for the HLA-DRB1*15:01 tagging SNP rs3135391), sex and center (US versus UK), trend test.

Figure 2. LD map and associations for the 48 SNPs in the merged dataset that excludes all HLA-DRB1*15:01 subjects.

Each SNP's position in the MHC is shown on the X-axis with the most telomeric SNPs on the left and the most centromeric SNPs on the right. The lower portion of the figure depicts the strength of LD is in intensity from black to grey to white. Multiple SNPs in the Class I region associated with MS susceptibility independently from HLA-DRB1*15:01 are in moderate to strong LD with each other. These SNPs are in much weaker LD with the MS associated SNPs in the Class III and Class II regions. The degree of statistical significance is depicted in the upper portion of the figure where each SNP's –log₁₀ transformed p-value is depicted on the Y-axis. The most significant associations with MS susceptibility are in the Class I region and the Class III and Class II signals, although statistically significant, are considerably weaker. An algorithm used to cluster SNPs based on LD-R² grouped together SNPs in the Class III NOTCH4 gene (rs2071285, rs206015, rs384247) and Class II gene TSBP (rs9268148, rs3132958, rs3129904, rs3132963, rs2050191).