The Haplotype Structure of the Human Major Histocompatibility Complex

Alper, Chester A.; Larsen, Charles E.; Dubey, Devendra P.; Awdeh, Zuheir L.; Fici, D; Yunis, Edmond J.

doi:10.1016/j.humimm.2005.11.006

Cited by 97 publications

(117 citation statements)

References 81 publications

(99 reference statements)

Supporting

Mentioning

111

Contrasting

Unclassified

Order By: Relevance

“…This level of complexity is not surprising in the MHC, which is known to contain frequent ancestral haplotypes with variable conservation between distant markers, [15][16][17][18] and LD patterns that show great variation depending on the particular DRB1-DQA1-DQB1 haplotype. [19][20][21] Therefore, it seems clear that only analyses involving haplotypes will give the necessary depth in the results to establish true independence.…”

Section: Discussionmentioning

confidence: 99%

“…It is well-known that both the LD and allelic content vary on different HLA haplotypes. [19][20][21]46 Population stratification and results in European subpopulations Although the T1DGC MHC dataset consists mostly of samples of Caucasian ancestry (only approximately 2% of the samples have known non-Caucasian ancestry), population stratification is still a possible confounding factor. However, there are several reasons why this is not likely to have had a large impact on our results: Firstly, the logistic regression approach used in the first step to identify candidate markers for further analyses is, unlike the haplotype estimations, not sensitive to population stratification.…”

Section: Strong Evidence For a Primary Role Of Hla-b In Regionmentioning

confidence: 99%

See 1 more Smart Citation

Conditional analyses on the T1DGC MHC dataset: novel associations with type 1 diabetes around HLA-G and confirmation of HLA-B

et al. 2008

View full text Add to dashboard Cite

The major histocompatibility complex (MHC) is known to harbour genetic risk factors for type 1 diabetes (T1D) additional to the class II determinants HLA-DRB1, -DQA1 and -DQB1, but strong linkage disequilibrium (LD) has made efforts to establish their location difficult. This study utilizes a dataset generated by the T1D genetics consortium (T1DGC), with genotypes for 2965 markers across the MHC in 2321 T1D families of multiple (mostly Caucasian) ethnicities. Using a comprehensive approach consisting of complementary conditional methods and LD analyses, we identified three regions with T1D association, independent both of the known class II determinants and of each other. A subset of polymorphisms that could explain most of the association in each region included single nucleotide polymorphisms (SNPs) in the vicinity of HLA-G, particular HLA-B and HLA-DPB1 alleles, and SNPs close to the COL11A2 and RING1 genes. Apart from HLA-B and HLA-DPB1, all of these represent novel associations, and subpopulation analyses did not indicate large population-specific differences among Caucasians for our findings. On account of the unusual genetic complexity of the MHC, further fine mapping is demanded, with the possible exception of HLA-B. However, our results mean that these efforts can be focused on narrow, defined regions of the MHC.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Strong Evidence For a Primary Role Of Hla-b In Regionmentioning

confidence: 99%

Conditional analyses on the T1DGC MHC dataset: novel associations with type 1 diabetes around HLA-G and confirmation of HLA-B

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Cw*05 is a marker of three ancestral or conserved extended HLA haplotypes, [14][15][16] As stated above, the A*02-Cw*05 combination is carried by two HLA ancestral haplotypes (44.1 and 18.3). However, as the individuals included in this study were not typed for HLA-B and other HLA markers, from our data it is not possible to conclude whether the enhanced MS-protective effect of the A*02-Cw*05 combination is due to an haplotype effect (that is the presence of a primarily associated protective factor carried by the extended haplotype marked by A*02 and Cw*05) or to a direct interactive role of the two markers.…”

Section: Hla-class I Markers Involved In Ms Susceptibility L Bergamasmentioning

confidence: 99%

HLA-class I markers and multiple sclerosis susceptibility in the Italian population

et al. 2009

View full text Add to dashboard Cite

Previous studies reported an association with multiple sclerosis (MS) of distinct HLA-class I markers, namely HLA-A*02, HLA-Cw*05 and MOG-142L. In this work, we tested the association with MS of A*02 and Cw*05 in 1273 Italian MS patients and 1075 matched controls, which were previously analyzed for MOG-142, and explored the relationship among these three markers in modulating MS risk. HLA-A*02 conferred a statistically robust MS protection (odds ratio, OR ¼ 0.61; 95% confidence intervals, CI ¼ 0.51-0.72, Po10 À9 ), which was independent of DRB1*15 and of any other DRB1* allele and remained similar after accounting for the other two analyzed class I markers. Conversely, the protective effect we previously observed for MOG-142L was secondary to its linkage disequilibrium with A*02. Cw*05 was not associated considering the whole sample, but its presence significantly enhanced the protection in the HLA-A*02-positive group, independently of DRB1: the OR conferred by A*02 in Cw*05-positive individuals (0.22, 95% CI ¼ 0.13-0.38) was significantly lower than in Cw*05-negative individuals (0.69, 95% CI ¼ 0.58-0.83) with a significant (P ¼ 4.94 Â 10 À5 ) multiplicative interaction between the two markers. In the absence of A*02, Cw*05 behaved as a risk factor, particularly in combination with DRB1*03 (OR ¼ 3.89, P ¼ 0.0006), indicating that Cw*05 might be a marker of protective or risk haplotypes, respectively.

show abstract

“…There is a classic body of work documenting existence of what have been termed "extended" or "ancestral" MHC haplotypes on which a series of polymorphisms extending over ϳ1 million nucleotides are in almost total linkage disequilibrium (14 -16 (16). We report here strong evidence for an association between type 1A diabetes and a locus in the UBD/MAS1L region that is apparently independent of HLA class II and I alleles and also independent of linkage disequilibrium with the common MHC 8.1 haplotype.…”

mentioning

confidence: 99%

Analysis of Single Nucleotide Polymorphisms Identifies Major Type 1A Diabetes Locus Telomeric of the Major Histocompatibility Complex

et al. 2008

View full text Add to dashboard Cite

(DR3/4-DQ8) siblings who share both major histocompatibility complex (MHC) haplotypes identical-by-descent with their proband siblings have a higher risk for type 1A diabetes than DR3/4-DQ8 siblings who do not share both MHC haplotypes identical-bydescent. Our goal was to search for non-DR/DQ MHC genetic determinants that cause the additional risk in the DR3/4-DQ8 siblings who share both MHC haplotypes. RESEARCH DESIGN AND METHODS-We completed an extensive single nucleotide polymorphism (SNP) analysis of the extended MHC in 237 families with type 1A diabetes from the U.S. and 1,240 families from the Type 1 Diabetes Genetics Consortium.RESULTS-We found evidence for an association with type 1A diabetes (rs1233478, P ϭ 1.6 ϫ 10 Ϫ23 , allelic odds ratio 2.0) in the UBD/MAS1L region, telomeric of the classic MHC. We also observed over 99% conservation for up to 9 million nucleotides between chromosomes containing a common haplotype with the HLA-DRB1*03, HLA-B*08, and HLA-A*01 alleles, termed the "8.1 haplotype." The diabetes association in the UBD/MAS1L region remained significant both after chromosomes with the 8.1 haplotype were removed (rs1233478, P ϭ 1.4 ϫ 10 Ϫ12 ) and after adjustment for known HLA risk factors HLA-DRB1, HLA-DQB1, HLA-B, and HLA-A (P ϭ 0.01). CONCLUSIONS-Polymorphisms

show abstract

The Haplotype Structure of the Human Major Histocompatibility Complex

Cited by 97 publications

References 81 publications

Conditional analyses on the T1DGC MHC dataset: novel associations with type 1 diabetes around HLA-G and confirmation of HLA-B

Conditional analyses on the T1DGC MHC dataset: novel associations with type 1 diabetes around HLA-G and confirmation of HLA-B

HLA-class I markers and multiple sclerosis susceptibility in the Italian population

Analysis of Single Nucleotide Polymorphisms Identifies Major Type 1A Diabetes Locus Telomeric of the Major Histocompatibility Complex

Contact Info

Product

Resources

About