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 <110 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 110 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 =8.4510 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.

... 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 110 8 . The most significantly associated SNP was rs4959039, a SNP in the downstream un-translated region of the

... by combining the discovery and replication datasets. The MAF for each SNP is reported for cases and controls in the merged dataset as well as the strength of association using the trend test ( Table S3 ). A SNP in the downstream non-coding region of HLA-G (rs4959039) was the most significantly associated marker ( p <8.6510 12 ) in the merged cohort analysis, after adjusting for the HLA-DRB1*15:01 tagging SNP rs3135391 and potential stratification effects caused by sex, location (US versus UK

... controls. Association tests were performed in this merged HLA-DRB1*15:01 (-) dataset and significant associations were found for 48 of the 52 SNPs identified in the case control screens including all previously identified Class I and Class III SNPs ( Table S4 ). Using the genotype test for association in the HLA-DRB1*15:01 (-) dataset, 20 Class I SNPs had p -values 10 8 ( Table 1 ). The HLA-G linked rs4959039:A>G allele (rs4959039) continued to have the strongest association in this HLA-DRB1*15:01 (-) dataset (odds ratio 1.59, 95% confidence intervals 1.40, 1.81, p <8.4510 13 ). Importantly, rs4959039 and the other Class I SNPs associated with MS susceptibility are poorly correlated with the SNPs in the Class III and Class II regions as illustrated by the LD map ( Figure 2 ). For example, the average (range) r 2 for rs4959039 with the Class III SNPs was .081 (.014 to .149) and for the Class II SNPs was .024 (.002 to .085). 10.1371/journal.pone.0011296.g002 Figure 2 LD map and associations for the

... LD with each other (as defined by LD-R 2 0.5) include: rs2523822, rs2517701 ( HLA-80 ), rs4713270 ( HCG2PG ), rs4713274 ( MICD ), rs2523946 ( MICD ), rs3823355 ( MICD ), rs4959039 (in between HLA-G and HLA-A ), rs4713281 ( HLA-J ), rs9357092 ( HCG9 ), and rs9393989 ( RNF39 ). Using an algorithm to define haplotype blocks by LD-R 2 0.5 an apparently separate Class I SNP cluster (rs1362126, rs2523393, rs2743951) emerges that includes a tagging SNP for the HLA-B*44:02 allele (rs2523393), a recently identified MS protective allele [12] , [14] . Tests for independent association using logistic regression models To confirm that the contribution to MS susceptibility of the rs4959039 SNP was independent of any residual Class II associations, logistic regression models were constructed. Because many of the 48 SNPs associated with MS susceptibility in the HLA-DRB1*15:01 (-) dataset are in moderate to strong LD with each other a clustering algorithm was used to group the 48 SNPs into 20 clusters (LD-R 2

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