Dataset Information

The frequent and conserved DR3-B8-A1 extended haplotype confers less diabetes risk than other DR3 haplotypes.

ABSTRACT: The goal of this study was to develop and implement methodology that would aid in the analysis of extended high-density single nucleotide polymorphism (SNP) major histocompatibility complex (MHC) haplotypes combined with human leucocyte antigen (HLA) alleles in relation to type 1 diabetes risk.High-density SNP genotype data (2918 SNPs) across the MHC from the Type 1 Diabetes Genetics Consortium (1240 families), in addition to HLA data, were processed into haplotypes using PedCheck and Merlin, and extended DR3 haplotypes were analysed.With this large dense set of SNPs, the conservation of DR3-B8-A1 (8.1) haplotypes spanned the MHC (>/=99% SNP identity). Forty-seven individuals homozygous for the 8.1 haplotype also shared the same homozygous genotype at four 'sentinel' SNPs (rs2157678 'T', rs3130380 'A', rs3094628 'C' and rs3130352 'T'). Conservation extended from HLA-DQB1 to the telomeric end of the SNP panels (3.4 Mb total). In addition, we found that the 8.1 haplotype is associated with lower risk than other DR3 haplotypes by both haplotypic and genotypic analyses [haplotype: p = 0.009, odds ratio (OR) = 0.65; genotype: p = 6.3 x 10(-5), OR = 0.27]. The 8.1 haplotype (from genotypic analyses) is associated with lower risk than the high-risk DR3-B18-A30 haplotype (p = 0.01, OR = 0.23), but the DR3-B18-A30 haplotype did not differ from other non-8.1 DR3 haplotypes relative to diabetes association.The 8.1 haplotype demonstrates extreme conservation (>3.4 Mb) and is associated with significantly lower risk for type 1 diabetes than other DR3 haplotypes.

SUBMITTER: Baschal EE

PROVIDER: S-EPMC2769935 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The frequent and conserved DR3-B8-A1 extended haplotype confers less diabetes risk than other DR3 haplotypes.

Baschal E E EE Aly T A TA Jasinski J M JM Steck A K AK Johnson K N KN Noble J A JA Erlich H A HA Eisenbarth G S GS

Diabetes, obesity & metabolism 20090201

<h4>Aim</h4>The goal of this study was to develop and implement methodology that would aid in the analysis of extended high-density single nucleotide polymorphism (SNP) major histocompatibility complex (MHC) haplotypes combined with human leucocyte antigen (HLA) alleles in relation to type 1 diabetes risk.<h4>Methods</h4>High-density SNP genotype data (2918 SNPs) across the MHC from the Type 1 Diabetes Genetics Consortium (1240 families), in addition to HLA data, were processed into haplotypes u ...[more]

PMID: 19143812

Similar Datasets

Project description:To determine the relationship between highly-conserved extended-haplotypes (CEHs) in the major histocompatibility complex (MHC) and MS-susceptibility.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.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.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.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.

Project description:Here we studied HLA blocks and haplotypes in a group of 218 Lacandon Maya Native American using a high-resolution next generation sequencing (NGS) method. We assessed the genetic diversity of HLA class I and class II in this population, and determined the most probable ancestry of Lacandon Maya HLA class I and class II haplotypes. Importantly, this Native American group showed a high degree of both HLA homozygosity and linkage disequilibrium across the HLA region and also lower class II HLA allelic diversity than most previously reported populations (including other Native American groups). Distinctive alleles present in the Lacandon population include HLA-A*24:14 and HLA-B*40:08. Furthermore, in Lacandons we observed a high frequency of haplotypes containing the allele HLA-DRB1*04:11, a relatively frequent allele in comparison with other neighboring indigenous groups. The specific demographic history of the Lacandon population including inbreeding, as well as pathogen selection, may have elevated the frequencies of a small number of HLA class II alleles and DNA blocks. To assess the possible role of different selective pressures in determining Native American HLA diversity, we evaluated the relationship between genetic diversity at HLA-A, HLA-B and HLA-DRB1 and pathogen richness for a global dataset and for Native American populations alone. In keeping with previous studies of such relationships we included distance from Africa as a covariate. After correction for multiple comparisons we did not find any significant relationship between pathogen diversity and HLA genetic diversity (as measured by polymorphism information content) in either our global dataset or the Native American subset of the dataset. We found the expected negative relationship between genetic diversity and distance from Africa in the global dataset, but no relationship between HLA genetic diversity and distance from Africa when Native American populations were considered alone.

Project description:The association of single nucleotide polymorphisms (SNPs) in the apolipoprotein (Apo) A1/C3/A4/A5 gene cluster and serum lipid profiles is inconsistent. The present study was undertaken to detect the association between the ApoA1/C3/A5 gene polymorphisms and their haplotypes with serum lipid levels in the general Chinese population.A total of 1030 unrelated subjects (492 males and 538 females) aged 15-89 were randomly selected from our previous stratified randomized cluster samples. Genotyping of the ApoA1 -75 bp G>A, ApoC3 3238C>G, ApoA5 -1131T>C, ApoA5 c.553G>T and ApoA5 c.457G>A was performed by polymerse chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Pair-wise linkage disequilibria and haplotype analysis among the five SNPs were estimated.The levels of high-density lipoprotein cholesterol (HDL-C) and ApoA1 were lower in males than in femailes (P < 0.05 for each). The allelic and genotypic frequencies of the SNPs were no significant difference between males and females except ApoC3 3238C>G. There were 11 haplotypes with a frequency >1% identified in the cluster in our population. At the global level, the haplotypes comprised of all five SNPs were significantly associated with all seven lipid traits. In particular, haplotype G-G-C-C-A (6%; in the order of ApoA5 c.553G>T, ApoA5 c.457G>A, ApoA5 -1131T>C, ApoC3 3238C>G, and ApoA1 -75bp G>A) and G-A-T-C-G (4%) showed consistent association with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), ApoA1, ApoB, and the ApoA1/ApoB ratio. In addition, carriers of haplotype G-G-T-C-G (26%) had increased serum concentration of HDL-C and ApoA1, whereas carriers of G-G-C-G-G (15%) had high concentrations of TC, triglyceride (TG) and ApoB. We also found that haplotypes with five SNPs explain much more serum lipid variation than any single SNP alone, especially for TG (4.4% for haplotype vs. 2.4% for -1131T>C max based on R-square) and HDL-C (5.1% for haplotype vs. 0.9% for c.553G>T based on R-square). Serum lipid parameters were also correlated with genotypes and several environment factors.Several common SNPs and their haplotypes in the ApoA1/C3/A5 gene cluster are closely associated with modifications of serum lipid parameters in the general Chinese population.

Dataset Information

The frequent and conserved DR3-B8-A1 extended haplotype confers less diabetes risk than other DR3 haplotypes.

Publications

The frequent and conserved DR3-B8-A1 extended haplotype confers less diabetes risk than other DR3 haplotypes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets