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Genetic fixity in the human major histocompatibility complex and block size diversity in the class I region including HLA-E.

ABSTRACT: The definition of human MHC class I haplotypes through association of HLA-A, HLA-Cw and HLA-B has been used to analyze ethnicity, population migrations and disease association.Here, we present HLA-E allele haplotype association and population linkage disequilibrium (LD) analysis within the ~1.3 Mb bounded by HLA-B/Cw and HLA-A to increase the resolution of identified class I haplotypes. Through local breakdown of LD, we inferred ancestral recombination points both upstream and downstream of HLA-E contributing to alternative block structures within previously identified haplotypes. Through single nucleotide polymorphism (SNP) analysis of the MHC region, we also confirmed the essential genetic fixity, previously inferred by MHC allele analysis, of three conserved extended haplotypes (CEHs), and we demonstrated that commercially-available SNP analysis can be used in the MHC to help define CEHs and CEH fragments.We conclude that to generate high-resolution maps for relating MHC haplotypes to disease susceptibility, both SNP and MHC allele analysis must be conducted as complementary techniques.

SUBMITTER: Romero V

PROVIDER: S-EPMC1853106 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Genetic fixity in the human major histocompatibility complex and block size diversity in the class I region including HLA-E.

Romero Viviana V Larsen Charles E CE Duke-Cohan Jonathan S JS Fox Edward A EA Romero Tatiana T Clavijo Olga P OP Fici Dolores A DA Husain Zaheed Z Almeciga Ingrid I Alford Dennis R DR Awdeh Zuheir L ZL Zuñiga Joaquin J El-Dahdah Lama L Alper Chester A CA Yunis Edmond J EJ

BMC genetics 20070412

<h4>Background</h4>The definition of human MHC class I haplotypes through association of HLA-A, HLA-Cw and HLA-B has been used to analyze ethnicity, population migrations and disease association.<h4>Results</h4>Here, we present HLA-E allele haplotype association and population linkage disequilibrium (LD) analysis within the ~1.3 Mb bounded by HLA-B/Cw and HLA-A to increase the resolution of identified class I haplotypes. Through local breakdown of LD, we inferred ancestral recombination points b ...[more]

PMID: 17430593

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Project description:Until recently, human leucocyte antigen (HLA) class II-independent associations with type 1 diabetes (T1D) in the Major Histocompatibility Complex (MHC) region were not adequately characterized owing to insufficient map coverage, inadequate statistical approaches and strong linkage disequilibrium spanning the entire MHC. Here we test for HLA class II-independent associations in the MHC using fine mapping data generated by the Type 1 Diabetes Genetics Consortium (T1DGC).We have applied recursive partitioning to the modelling of the class II loci and used stepwise conditional logistic regression to test approximately 1534 loci between 29 and 34 Mb on chromosome 6p21, typed in 2240 affected sibpair (ASP) families.Preliminary analyses confirm that HLA-B (at 31.4 Mb), HLA-A (at 30.0 Mb) are associated with T1D independently of the class II genes HLA-DRB1 and HLA-DQB1 (P = 6.0 x 10(-17) and 8.8 x 10(-13), respectively). In addition, a second class II region of association containing the single-nucleotide polymorphism (SNP), rs439121, and the class II locus HLA-DPB1, was identified as a T1D susceptibility effect which is independent of HLA-DRB1, HLA-DQB1 and HLA-B (P = 9.2 x 10(-8)). A younger age-at-diagnosis of T1D was found for HLA-B*39 (P = 7.6 x 10(-6)), and HLA-B*38 was protective for T1D.These analyses in the T1DGC families replicate our results obtained previously in approximately 2000 cases and controls and 850 families. Taking both studies together, there is evidence for four T1D-associated regions at 30.0 Mb (HLA-A), 31.4 Mb (HLA-B), 32.5 Mb (rs9268831/HLA-DRA) and 33.2 Mb (rs439121/HLA-DPB1) that are independent of HLA-DRB1/HLA-DQB1. Neither study found evidence of independent associations at HLA-C, HLA-DQA1 loci nor in the UBD/MAS1L or ITPR3 gene regions. These studies show that to find true class II-independent effects, large, well-powered sample collections are required and be genotyped with a dense map of markers. In addition, a robust statistical methodology that fully models the class II effects is necessary. Recursive partitioning is a useful tool for modelling these multiallelic systems.

Dataset Information

Genetic fixity in the human major histocompatibility complex and block size diversity in the class I region including HLA-E.

Publications

Genetic fixity in the human major histocompatibility complex and block size diversity in the class I region including HLA-E.

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