Uncoupling the Roles of HLA-DRB1 and HLA-DRB5 Genes in Multiple Sclerosis
Stacy J. CaillierFarren BriggsBruce CreeSergio E. BaranziniMarcelo Fernández-ViñaPatricia P. RamsayOmar KhanWalter RoyalStephen L. HauserLisa F. BarcellosJorge R. Oksenberg
119
Citation
54
Reference
10
Related Paper
Citation Trend
Abstract:
Abstract Genetic susceptibility to multiple sclerosis (MS) is associated with the MHC located on chromosome 6p21. This signal maps primarily to a 1-Mb region encompassing the HLA class II loci, and it segregates often with the HLA-DQB1*0602, -DQA1*0102, -DRB1*1501, -DRB5*0101 haplotype. However, the identification of the true predisposing gene or genes within the susceptibility haplotype has been handicapped by the strong linkage disequilibrium across the locus. African Americans have greater MHC haplotypic diversity and distinct patterns of linkage disequilibrium, which make this population particularly informative for fine mapping efforts. The purpose of this study was to establish the telomeric boundary of the HLA class II region affecting susceptibility to MS by assessing genetic association with the neighboring HLA-DRB5 gene as well as seven telomeric single nucleotide polymorphisms in a large, well-characterized African American dataset. Rare DRB5*null individuals were previously described in African populations. Although significant associations with both HLA-DRB1 and HLA-DRB5 loci were present, HLA-DRB1*1503 was associated with MS in the absence of HLA-DRB5, providing evidence for HLA-DRB1 as the primary susceptibility gene. Interestingly, the HLA-DRB5*null subjects appear to be at increased risk for developing secondary progressive MS. Thus, HLA-DRB5 attenuates MS severity, a finding consistent with HLA-DRB5’s proposed role as a modifier in experimental autoimmune encephalomyelitis. Additionally, conditional haplotype analysis revealed a susceptibility signal at the class III AGER locus independent of DRB1. The data underscore the power of the African American MS dataset to identify disease genes by association in a region of high linkage disequilibrium.Keywords:
Linkage Disequilibrium
Linkage Disequilibrium
SNP
Genetic Association
Cite
Citations (23)
Linkage Disequilibrium
Disequilibrium
Cite
Citations (4)
HLA haplotype frequency was studied by typing 201 members of 32 unrelated families. Linkage disequilibrium was determined by observed and expected haplotype frequencies. The two-locus haplotype frequencies with most significant linkage disequilibrium were A30-B13, Aw33-B17, Bw46-Cw11, B12-Cw8, A1-Cw6 and A33-Cw3. No locus recombination was noted among 137 children.
Linkage Disequilibrium
HLA-A
Disequilibrium
Cite
Citations (0)
Abstract: Juvenile idiopathic arthritis (JIA) is an HLA‐associated rheumatic disease with onset in childhood. We recently reported that allele 5 at microsatellite D6S265 in the HLA class I region is associated with JIA, independent of linkage disequilibrium with the high risk DR8‐DQ4 haplotype. In the present study, we investigated whether alleles at D6S265, or other markers in this region, also modify the risk for JIA on other haplotypes, i.e., DRB1*1301‐DQB1*0603 or DRB1*1101/4‐DQB1*0301. We observed a significant association with allele 6 at D6S265 on the DRB1*1301‐DQB1*0603 haplotype. We also noted an association with allele 3 at D6S265, when carried on the DRB1*1101/4‐DQB1*0301 haplotype. Our results further support an additional JIA susceptibility gene in the HLA class I region in linkage disequilibrium with alleles at D6S265.
Linkage Disequilibrium
Genetic Association
Cite
Citations (8)
Present studies examined the DNA polymorphisms in the AGT genes in a Chinese population in Henan province of central China. By using PCR-RFLP and maximum likelihood estimation (MLE), we estimated the pattern of intragenic linkage disequilibrium and the haplotype structure and explored the possible association between the polymorphisms of AGT gene and essential hypertension in a case-control study. Seven polymorphic sites (SNPs) and seven major haplotypes of AGT gene were analyzed. Among the individual SNP pairs examined, the A-6G, C+31T and M235T are nearly completely disequilibrium. All those single polymorphism loci were individually not associated with hypertension. But we found the frequency of haplotype H2 (-217: G, -152: G, -20: A, -6: G, +31: T, 174: T, 235: M) was significantly higher in controls than patients (P=0.010). Our study suggested that few haplotypes derived seven polymorphism loci could account for the most of the variation in AGT gene in Chinese Hans. The haplotype H2 of AGT gene might represent or be in disequilibrium with a genetic protective factor against EH.
Linkage Disequilibrium
Disequilibrium
SNP
Tag SNP
Genetic Association
Cite
Citations (6)
Abstract A haplotype block is a DNA sequence containing polymorphisms in strong linkage disequilibrium (LD) and with low haplotype diversity, separated from other blocks by steps of low LD with high haplotype diversity. Haplotype blocks may be as short as 2 kb or more than 150 kb, depending both on block definition and the spacing of LD cold spots, which tend to be shorter than blocks. Haplotype diversity measured by the effective number of haplotypes is said to be low if smaller than the number of polymorphisms defining the haplotype. To be useful in genetic analysis, the haplotype should be shorter than a typical block.
Linkage Disequilibrium
Haplotype estimation
Disequilibrium
Sequence (biology)
Cite
Citations (9)
Associations between major histocompatibility complex (MHC) ancestral haplotypes (AHs) and immunopathological diseases are traditionally ascribed to human leukocyte antigen (HLA) class I or class II alleles. However, polymorphisms in TNF and nearby genes in the central MHC can influence risk. We have defined TNF block haplotypes in Asian, European and Australian Aboriginal donors and shown conservation of TNF block haplotypes in geographically distinct populations, consistent with a common evolutionary origin. Here we show that most TNF block haplotypes do not align with a single MHC AH and associations often vary with ethnicity. This suggests more recent recombination events between the TNF block and the HLA alleles.
Cite
Citations (20)
Linkage Disequilibrium
Linkage (software)
Genetic Association
Disequilibrium
Cite
Citations (6)
It is well known that certain alleles from different loci within the Human Leucocyte Antigen (HLA) complex are in linkage disequilibrium. This linkage phenomenon is relatively well characterized for haplotypes that include specific class I and class II alleles such as HLA‐B8 and HLA‐DR3. However, the HLA‐DP genes are located at the centromeric end of the HLA complex and are less well characterized with regard to linkage disequilibrium. The availability of a large population of healthy subjects and sequence‐specific oligonucleotide (SSO) typing enabled us to assess the degree of linkage between HLA‐DPBl and HLA‐DQBl genes. Using the polymerase chain reaction and a series of oligonucleotide probes which define seven DQβ alleles and twenty DPβ alleles, we studied 180 unrelated, normal Caucasian individuals and found only weak or negative associations between HLA‐DPBl and HLA‐DQBl. These data demonstrate that the association between HLA‐DQ and DP is weak and also imply that DP extended haplotypes related to particular diseases may not reflect normal associations. Implications of these results might impact on the concept of linkage disequilibrium in general as well as the evolution of the HLA complex. In addition, extensions of this work may have clinical ramifications with regard to bone marrow transplantation and founder effects in certain diseases.
Linkage Disequilibrium
Disequilibrium
Cite
Citations (23)
有主要 histocompatibility 的多态的算术逻辑单元插入(POALIN ) 的协会建筑群(MHC ) 一级基因使我们能更好在不同人口识别 MHC 一级区域 haplotypes 的起源和进化。为进一步在云南省在汉和 Jinuo 人口学习 MHC 一级区域 haplotypes 的起源和进化，我们调查了五 POALIN 的频率，他们有 HLA 的协会-- A 和-B,在高山以内的 three-loci POALIN haplotype 频率和 HLA/POALIN four-loci haplotype 频率哈一些 MHC 一级区域。我们发现那在 AluHG 和 HLA 之间的一个强壮的积极协会 --*02 在 Jinuo，然而并非在云南汉。这些结果建议学习人口可能从不同祖先 haplotypes 和 MHC I-POALINs 导出的二的那 MHC 一级区域 haplotypes 是为在不同人口调查 MHC 一级区域 haplotypes 的起源和进化的增进知识的基因标记。
Cite
Citations (0)