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

Abstract

ObjectiveTo determine the relationship between highly-conserved extended-haplotypes (CEHs) in the major histocompatibility complex (MHC) and MS-susceptibility.BackgroundAmong 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/MethodsAutosomal 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.ResultsWe 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.ConclusionsThe 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.

The complexity and diversity of major histocompatibility complex challenge disease association studies

“…Usually, there are a relatively small number of common, conserved haplotypes and a very large number of rare haplotypes (Table ), making the disease association studies challenging. In a recent large, multinational, case‐control study of almost 30 000 cases from the Wellcome trust study consortium (patients with multiple sclerosis and controls), 10 000 unique HLA haplotypes (HLA‐A, ‐B, ‐C, ‐DRB1 ‐DQB1, and 11 SNPs around DRB1) were identified (Table ) . In this study, although the 10 most common haplotypes represented 22% of all haplotypes, 60% of the haplotypes were observed only once, and 74% only in two or less individuals.…”

“…Low imputation accuracy for HLA‐DRB1 has also been described by other studies covering heterogeneous study cohorts or diverse ancestry groups . The reasons may be low HLA‐DRB1 tagging of the SNPs used due to the absence of the informative SNPs for HLA‐DRB1 region, inadequate numbers of reference SNPs and its poor representativeness for diverse populations …”

“…Considering the genetic architecture of the region, also non‐HLA genes and more subtle genetic polymorphisms such as SNPs and copy number variation may play an important part in the haplotype structure and function. HLA‐SNP haplotypes have been only very recently studied …”

“…We have challenged the drawbacks of the HLA‐DRB1 imputation in combining GWA SNP results with the allele copy numbers of HLA‐DRB1*01 determined by genomic quantitative polymerase chain reaction (PCR) as a priori candidate gene associated with the complex disease of coronary artery disease . However, combining SNP results with HLA‐typing results has just started to be acknowledged by the GWA research community …”

“…HLA-SNP haplotypes have been only very recently studied. 25,26 In a given population, the observed haplotypes are extremely polymorphic and are present in variable frequencies between different geographical regions. Usually, there are a relatively small number of common, conserved haplotypes and a very large number of rare haplotypes (Table 3), making the disease association studies challenging.…”