A polymorphism in the HLA-DPB1 gene is associated with susceptibility to multiple sclerosis

Abstract

We conducted an association study across the human leukocyte antigen (HLA) complex to identify loci associated with multiple sclerosis (MS). Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each P ≤ 4 x 10(-6)). All associations were significant in an independent replication cohort of 2212 cases and 2251 controls (P ≤ 0.001) and were highly significant in the combined dataset (P ≤ 6 x 10(-8)). The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD) with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set P = 9 x 10(-9), replication set P = 7 x 10(-4), combined P = 2 x 10(-10)). HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genome-wide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association.

Figure 1. LD between the seven SNPs in the fitted model ( Table 1 ) and other MHC polymorphisms.

The plot shows LD between the 7 model SNPs and other SNPs and classical HLA alleles genotyped in the HapMap CEU population. Points are only plotted for SNP pairs where . Points are plotted at the genomic positions of the HLA alleles/other SNPs; named points at the top of the plot () show the locations of the SNPs in the model. The various colours are used to distinguish LD with different SNPs in the model (rs2394160 pink, rs2854050 khaki, rs3830041 green, rs3129939 blue, rs9271366 purple, rs2187668 brown, rs9277535 red). SNPs are shown as small dots and HLA alleles are shown as triangles: refer to Table 2 for the names of HLA alleles correlated with . Pink stars denote SNPs in LD with rs2394160 that were strongly associated with MS in the second stage of the model-building (just with adjustment for the DRB1*15:01 proxy SNP rs9271366). The black triangles and crossess show the locations of some classical HLA genes and other genes respectively that are mentioned in the text. The red bars at the bottom of the graph show recombination rates averaged over 25kb windows. The vertical dashed lines mark the boundaries of the class I, class III and class II regions of the MHC.