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Association of smoking behavior with an odorant receptor allele telomeric to the human major histocompatibility complex.

ABSTRACT: Smoking behavior has been associated in two independent European cohorts with the most common Caucasian human leukocyte antigen (HLA) haplotype (A1-B8-DR3). We aimed to test whether polymorphic members of the two odorant receptor (OR) clusters within the extended HLA complex might be responsible for the observed association, by genotyping a cohort of Hungarian women in which the mentioned association had been found. One hundred and eighty HLA haplotypes from Centre d'Etude du Polymorphisme Humain families were analyzed in silico to identify single-nucleotide polymorphisms (SNPs) within OR genes that are in linkage disequilibrium with the A1-B8-DR3 haplotype, as well as with two other haplotypes indirectly linked to smoking behavior. A nonsynonymous SNP within the OR12D3 gene (rs3749971(T)) was found to be linked to the A1-B8-DR3 haplotype. This polymorphism leads to a (97)Thr --> Ile exchange that affects a putative ligand binding region of the OR12D3 protein. Smoking was found to be associated in the Hungarian cohort with the rs3749971(T) allele (p = 1.05 x 10(-2)), with higher significance than with A1-B8-DR3 (p = 2.38 x 10(-2)). Our results link smoking to a distinct OR allele, and demonstrate that the rs3749971(T) polymorphism is associated with the HLA haplotype-dependent differential recognition of cigarette smoke components, at least among Caucasian women.

SUBMITTER: Santos PS

PROVIDER: S-EPMC2635552 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Association of smoking behavior with an odorant receptor allele telomeric to the human major histocompatibility complex.

Santos Pablo Sandro Carvalho PS Füst George G Prohászka Zoltán Z Volz Armin A Horton Roger R Miretti Marcos M Yu Chack-Yung CY Beck Stephan S Uchanska-Ziegler Barbara B Ziegler Andreas A

Genetic testing 20081201 4

Smoking behavior has been associated in two independent European cohorts with the most common Caucasian human leukocyte antigen (HLA) haplotype (A1-B8-DR3). We aimed to test whether polymorphic members of the two odorant receptor (OR) clusters within the extended HLA complex might be responsible for the observed association, by genotyping a cohort of Hungarian women in which the mentioned association had been found. One hundred and eighty HLA haplotypes from Centre d'Etude du Polymorphisme Humai ...[more]

PMID: 18939942

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Project description:ImportanceUnderstanding the genetic contribution of the major histocompatibility complex (MHC) region to the risk of cervical cancer (CC) will help understand how immune responses to infection with human papillomaviruses are associated with CC.ObjectiveTo determine whether the HLA-B*52:01 allele is associated with CC in Japanese women.Design, setting, and participantsThis was a multicenter genetic association study. Genotype and phenotype data were obtained from BioBank Japan Project. Additional patients with CC were enrolled from the Aichi Cancer Center Research Institute. An MHC fine-mapping study was conducted on CC risk in the Japanese population by applying a human leukocyte antigen (HLA) imputation method to the large-scale CC genome-wide association study data of using the Japanese population-specific HLA reference panel. Participants included 540 women in BioBank Japan Project with CC or 39 829 women without gynecologic diseases, malignant neoplasms, and MHC-related diseases as controls. An additional 168 patients with CC were recruited from Aichi Cancer Center Research Institute. Histopathological subtypes and clinical stages were not considered. Participants with low genotype call rate, closely related participants, and outliers in the principal component analysis were excluded. Data analysis was performed from August 2018 to January 2020.Main outcomes and measuresLoci within the MHC region associated with CC risk, and the direction and size of association.ResultsA total of 704 CC cases and 39 556 controls were analyzed. All participants were Japanese women with a median (range) age of 67 (18 to 100) years. One of the class I HLA alleles of HLA-B*52:01 was significantly associated with CC risk (odds ratio, 1.60; 95% CI, 1.38-1.86; P = 7.4 × 10-10). Allele frequency spectra of HLA-B*52:01 are heterogeneous among worldwide populations with high frequency in Japanese populations (0.109 in controls), suggesting its population-specific risk associated with CC. The conditional analysis suggested that HLA-B*52:01 could explain most of the MHC risk associated with CC because no other HLA alleles remained significant after conditioning on the HLA-B*52:01. The HLA amino acid residue-based analysis suggested that HLA-B p.Tyr171His located in the peptide-binding groove was associated with the most significant CC risk (odds ratio, 1.47; 95% CI, 1.30-1.66; P = 1.2 × 10-9).Conclusions and relevanceThe results of this study contribute to understanding of the genetic background of CC. The results suggest that immune responses mediated by class I HLA molecules are associated with susceptibility to CC.

Dataset Information

Association of smoking behavior with an odorant receptor allele telomeric to the human major histocompatibility complex.

Publications

Association of smoking behavior with an odorant receptor allele telomeric to the human major histocompatibility complex.

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