Association of Smoking Behavior with an Odorant Receptor Allele Telomeric to the Human Major Histocompatibility Complex

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 ⁹⁷Thr → 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 × 10⁻²), with higher significance than with A1-B8-DR3 (p = 2.38 × 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.