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Characterization of the major histocompatibility complex locus association with Behcet's disease in Iran.

ABSTRACT: The aim of this study was to characterize the association of human leukocyte antigen (HLA) B alleles and major histocompatibility complex (MHC) single nucleotide polymorphisms (SNPs) with Behçet's disease (BD) in an Iranian dataset.The association of three SNPs in the MHC region previously identified as the most associated in high-density genotyping studies was tested in a case-control study on 973 BD patients and 825 controls from Iran, and the association of HLA-B alleles was tested in a subset of 681 patients and 414 controls.We found that HLA-B*51 (P?=?4.11?×?10(-41), OR [95% CI]?=?4.63[3.66-5.85]) and B*15 confer risk for BD (P?=?2.83?×?10(-2), OR [95% CI]?=?1.75[1.08-2.84]) in Iranian, and in B*51 negative individuals, only the B*15 allele is significantly associated with BD (P?=?2.51?×?10(-3), OR [95% CI]?=?2.40[1.37-4.20]). rs76546355, formerly known as rs116799036, located between HLA-B and MICA (MHC class I polypeptide-related sequence A), demonstrated the same level of association with BD as HLA-B*51 (P adj?=?1.78?×?10(-46), OR [95% CI]?=?5.46[4.21-7.09], and P adj?=?8.34?×?10(-48), OR [95% CI]?=?5.44[4.20-7.05], respectively) in the HLA-B allelotyped subset, while rs2848713 was less associated (P adj?=?7.14?×?10(-35), OR [95% CI]?=?3.73[2.97-4.69]) and rs9260997 was not associated (P adj?=?1.00?×?10(-1)). Additionally, we found that B*51 genotype-phenotype correlations do not survive Bonferroni correction, while carriers of the rs76546355 risk allele predominate in BD cases with genital ulcers, positive pathergy test and positive BD family history (2.31?×?10(-4)???P???1.59?×?10(-3)).We found that the HLA-B*51 allele and the rs76546355/rs116799036 MHC SNP are independent genetic risk factors for BD in Iranian, and that positivity for the rs76546355/rs116799036 risk allele, but not for B*51, does correlate with specific demographic characteristics or clinical manifestations in BD patients.

SUBMITTER: Xavier JM

PROVIDER: S-EPMC4415285 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Characterization of the major histocompatibility complex locus association with Behçet's disease in Iran.

Xavier Joana M JM Davatchi Fereydoun F Abade Olga O Shahram Farhad F Francisco Vânia V Abdollahi Bahar Sadeghi BS Trindade Hélder H Nadji Abdolhadi A Shafiee Niloofar Mojarad NM Ghaderibarmi Fahmida F Ligeiro Dário D Oliveira Sofia A SA

Arthritis research & therapy 20150319

<h4>Introduction</h4>The aim of this study was to characterize the association of human leukocyte antigen (HLA) B alleles and major histocompatibility complex (MHC) single nucleotide polymorphisms (SNPs) with Behçet's disease (BD) in an Iranian dataset.<h4>Methods</h4>The association of three SNPs in the MHC region previously identified as the most associated in high-density genotyping studies was tested in a case-control study on 973 BD patients and 825 controls from Iran, and the association o ...[more]

PMID: 25889189

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Project description:BACKGROUND:Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with coronary artery disease (CAD) and/or myocardial infarction risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered. METHODS AND RESULTS:We performed a discovery meta-analysis of 5 GWAS involving 13 949 subjects (7123 cases, 6826 control subjects) imputed at approximately 5 million single nucleotide polymorphisms, using pilot 1000 Genomes-based haplotypes. Promising loci were followed up in an additional 5 studies with 11 032 subjects (5211 cases, 5821 control subjects). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome-wide significance in the combined analysis (rs3869109; p(discovery)=3.3×10(-7), p(replication)=5.3×10(-4)p(combined)=1.12×10(-9)). A subanalysis combining discovery GWAS showed an attenuation of significance when stringent corrections for European population structure were used (P=4.1×10(-10) versus 3.2×10(-7)), suggesting that the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity, and self-cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association. CONCLUSIONS:We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T-cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).

Dataset Information

Characterization of the major histocompatibility complex locus association with Behcet's disease in Iran.

Publications

Characterization of the major histocompatibility complex locus association with Behçet's disease in Iran.

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