The genetics of HLA-associated disease

Larsen, Charles E.; Alper, Chester A.

doi:10.1016/j.coi.2004.07.014

Cited by 92 publications

(67 citation statements)

References 53 publications

(70 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Finally, this exceptional conservation, together with the enhanced diabetogenicity of the Basque haplotype, also supports the hypothesis that, apart from disease-predisposing (HLA-DRB1*0301-DQB1*0201), these chromosomes carry another etiological gene elsewhere, whose susceptibility allele is fixed in certain CEHs but may not be present in other non-predisposing DR3 chromosomes. 21 We and others have very recently shown that the diabetogenic DR3-B8 CEH is conserved throughout approximately 3.6 Mb, between HLA-A and HLA-DQ, 23,24 and those findings, together with our results, might help to define more precisely the susceptibility region. As the risk allele will invariantly be present in the CEH, comparison with other, less conserved, predisposing haplotypes (e.g.…”

Section: Resultssupporting

confidence: 79%

“…20 Other possible candidate genes include HLA class I genes and complement proteins, and again, alleles that seem to modulate the risk to the disease (including HLA-A*30, HLA-B*18, F1C30), although not always in an HLA-class II-independent manner, are part of the complete DR3-B18 CEH. 9,14,15,21 The analysis of 2322 SNPs showed that identity between HLA-haploidentical siblings was above 99% and transmission from homozygous parents to their offspring was consistent with Mendelian inheritance. No evidence suggestive of recombination was observed between disease-discordant, HLA-haploidentical siblings.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease

et al. 2006

View full text Add to dashboard Cite

The major susceptibility locus for type 1 diabetes mellitus (T1D) maps to the human lymphocyte antigen (HLA) class II region in the major histocompatibility complex on chromosome 6p21. In southern European populations, like the Basques, the greatest risk to T1D is associated with DR3 homo-and heterozygosity and is comparable to that of DR3/DR4, the highest risk genotype in northern European populations. Celiac disease (CD) is another DR3-associated autoimmune disorder showing certain overlap with T1D that has been explained by the involvement of common genetic determinants, a situation more frequent in DR3-rich populations, like the Basques. As both T1D-and CD-associated HLA alleles are part of conserved extended haplotypes (CEH), we compared DR3-homozygous T1D and CD patients to determine whether CEHs were equally distributed between both disorders or there was a differential contribution of different haplotypes. We observed a very pronounced distribution bias (Po10 À5 ) of the two major DR3 CEHs, with DR3-B18 predominating in T1D and DR3-B8 in CD. Additionally, high-density single nucleotide polymorphism (SNP) analysis of the complete CEH [A*30-B*18-MICA*4-F1C30-DRB1*0301-DQB1*0201-DPB1*0202] revealed extraordinary conservation throughout the 4.9 Mbp analyzed supporting the existence of additional diabetogenic variants (other than HLA-DRB1*0301-DQB1*0201), conserved within the DR3-B18 CEH (but not in other DR3 haplotypes) that could explain its enhanced diabetogenicity.

show abstract

Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease

et al. 2006

View full text Add to dashboard Cite

show abstract

“…[14][15][16][17] However, there is limited genetic evidence to support this view because of the strong linkage disequilibrium across the MHC. 16,18,19 DR3-DQ2 is of special interest, in part because of its association with multiple immunopathologies and in part because of the extended conservation of this haplotype. 20 Unlike DR4 and DQ8, which occur on several DR-DQ haplotypes, DR3 occurs almost exclusively on haplotypes also carrying DQ2, and conversely, DQ2 occurs almost exclusively on haplotypes also carrying DR3.…”

Section: Introductionmentioning

confidence: 99%

Differential effects of DRB10301 and DQA10501-DQB1*0201 on the activation and progression of islet cell autoimmunity

et al. 2007

View full text Add to dashboard Cite

Autoimmune diabetes shows extreme variation in age of onset and clinical presentation, although most studies have been done in children with the most severe subtype. Disease risk is strongly associated with HLA-DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2), but it has not been possible to separate the effects of the DR and DQ alleles. We have identified a large Bedouin kindred in which a high prevalence of islet autoimmunity is associated with two different DR3 haplotypes, one carrying the usual DQ2 and the other carrying DQA1*0102-DQB1*0502 (DQ5). Results of prospective follow-up studies indicate that DR3 is associated with the initial activation of islet autoimmunity whereas DQ2 is associated with early-onset and severe clinical disease. The association signals map to a 350-kb interval, thus implicating primary effects for DR3 and DQ2. Overall, our results emphasize the importance of prospective genetic studies that examine the full range of variation in the initiation, progression and expression of autoimmune disease.

show abstract

“…Because C2 and BF reside in the MHC locus with many other genes involved in inflammation, it is possible that the associations observed in this study are due to LD with adjacent loci 23 . Five lines of evidence, however, suggest that the C2/BF locus is the main contributor to the observed association.…”

mentioning

confidence: 96%

Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration

et al. 2006

View full text Add to dashboard Cite

Age-related macular degeneration (AMD) is the most common form of irreversible blindness in developed countries 1,2 . Variants in the factor H gene (CFH, also known as HF1), which encodes a major inhibitor of the alternative complement pathway, are associated with the risk for developing AMD [3][4][5][6][7][8] . Here we test the hypothesis that variation in genes encoding other regulatory proteins of the same pathway is associated with AMD. We screened factor B (BF) and complement component 2 (C2) genes, located in the major histo-compatibility complex class III region, for genetic variation in two independent cohorts comprising ~900 individuals with AMD and ~400 matched controls. Haplotype analyses identify a statistically significant common risk haplotype (H1) and two protective haplotypes. The L9H variant of BF and the E318D variant of C2 (H10), as well as a variant in intron 10 of C2 and the R32Q variant of BF (H7), confer a significantly reduced risk of AMD (odds ratio = 0. 45 and 0.36, respectively). Combined analysis of the C2 and BF haplotypes and CFH variants shows that variation in the two loci can predict the clinical outcome in 74% of the affected individuals and 56% of the controls. These data expand and refine our understanding of the genetic risk for AMD.Correspondence should be addressed to R.A. (rla22@columbia.edu) or M.D. (dean@ncifcrf.gov). Note: Supplementary information is available on the Nature Genetics website. AUTHOR CONTRIBUTION STATEMENTThe AMD Genetics Clinical Study Group includes Stanley Chang, Lawrence A. Yannuzzi, John C. Merriam and Irene Barbazetto (Department of Ophthalmology, Columbia University, New York); Leonid E. Lerner (F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia) and Stephen Russell, Jamal Hoballah, Jill Hageman and Heather Stockman (Department of Ophthalmology and Visual Sciences, Center for Macular Degeneration, University of Iowa, Iowa City, Iowa, USA). COMPETING INTERESTS STATEMENTThe authors declare competing financial interests (see the Nature Genetics website for details).Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/ NIH Public Access Inflammation has a central role in the pathobiology of AMD 9-14 . Dysfunction of the complement pathway is proposed to induce significant damage to macular cells, leading to atrophy, degeneration and the elaboration of choroidal neovascular membranes 3,[15][16][17] . Activation of the alternative pathway is initiated by cleavage of C3b-bound factor B (BF), resulting in the formation of the C3Bb complex (C3 convertase). This complex is stabilized by properdin, whereas its dissociation is accelerated by regulatory proteins, including complement factor H (CFH), the major inhibitor of the alternative complement pathway. As CFH haplotypes are associated with AMD 3 , we hypothesized that the same may be true for activators of the same pathway, such as complement factor B (BF). BF and compl...

show abstract

The genetics of HLA-associated disease

Cited by 92 publications

References 53 publications

Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease

Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease

Differential effects of DRB10301 and DQA10501-DQB1*0201 on the activation and progression of islet cell autoimmunity

Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration

Contact Info

Product

Resources

About

The genetics of HLA-associated disease

Cited by 92 publications

References 53 publications

Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease

Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease

Differential effects of DRB1*0301 and DQA1*0501-DQB1*0201 on the activation and progression of islet cell autoimmunity

Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration

Contact Info

Product

Resources

About

Differential effects of DRB10301 and DQA10501-DQB1*0201 on the activation and progression of islet cell autoimmunity