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Objective  To determine the relationship between highly-conserved extended-haplotypes (CEHs) in the major histocompatibility complex (MHC) and MS-susceptibility.    Background  Among the ~200 MS-susceptibility regions, which are known from genome-wide analyses of single nucleotide polymorphisms (SNPs), the MHC accounts for roughly a third of the currently explained variance and the strongest MS-associations are for certain Class II alleles (e.g.,  HLA-DRB1*15 : 01; HLA-DRB1*03 : 01;  and  HLA-DRB1*13 : 03 ), which frequently reside on CEHs within the MHC.    Design/Methods  Autosomal SNPs (441,547) from 11,376 MS cases and 18,872 controls in the WTCCC dataset were phased. The most significant MS associated SNP haplotype was composed of 11 SNPs in the MHC Class II region surrounding the  HLA-DRB1 gene . We also phased alleles at the  HLA-A ,  HLA-C ,  HLA-B ,  HLA-DRB1 , and  HLA-DQB1  loci. This data was used to probe the relationship between CEHs and MS susceptibility.    Results  We phased a total of 59,884 extended haplotypes ( HLA-A ,  HLA-C ,  HLA-B ,  HLA-DRB1 ,  HLA-DQB1  and SNP haplotypes) from 29,942 individuals. Of these, 10,078 unique extended haplotypes were identified. The 10 most common CEHs accounted for 22% (13,302) of the total. By contrast, the 8,446 least common extended haplotypes also accounted for approximately 20% (12,298) of the total. This extreme frequency-disparity among extended haplotypes necessarily complicates interpretation of reported disease-associations with specific HLA alleles. In particular, the HLA motif  HLA-DRB1*15 : 01~HLA-DQB1*06 : 02  is strongly associated with MS risk. Nevertheless, although this motif is almost always found on the  a1  SNP haplotype, it can rarely be found on others (e.g.,  a27  and  a36 ), and, in these cases, it seems to have no apparent disease-association (OR = 0.7; CI = 0.3–1.3 and OR = 0.7; CI = 0.2–2.2, respectively). Furthermore, single copy carriers of the  a1  SNP-haplotype without this HLA motif still have an increased disease risk (OR = 2.2; CI = 1.2–3.8). In addition, even among the set of CEHs, which carry the Class II motif of  HLA-DRB1*15 : 01~HLA-DQB1*06 : 02~a1 , different CEHs have differing strengths in their MS-associations.    Conclusions  The MHC in diverse human populations consists, primarily, of a very small collection of very highly-selected CEHs. Our findings suggest that the MS-association with the  HLA-DRB1*15 : 01~HLA-DQB1*06 : 02  haplotype may be due primarily to the combined attributes of the CEHs on which this particular HLA-motif often resides.

Highly conserved extended haplotypes of the major histocompatibility complex and their relationship to multiple sclerosis susceptibility