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Year of Publication
Association of Smoking Behavior with an Odorant Receptor Allele Telomeric to the Human Major Histocompatibility Complex
Santos, Pablo Sandro Carvalho
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 (rs3749971T) 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 rs3749971T 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 rs3749971T polymorphism is associated with the HLA haplotype-dependent differential recognition of cigarette smoke components, at least among Caucasian women.
The Leukocyte Receptor Complex in Chicken Is Characterized by Massive Expansion and Diversification of Immunoglobulin-Like Loci
The innate and adaptive immune systems of vertebrates possess complementary, but intertwined functions within immune responses. Receptors of the mammalian innate immune system play an essential role in the detection of infected or transformed cells and are vital for the initiation and regulation of a full adaptive immune response. The genes for several of these receptors are clustered within the leukocyte receptor complex (LRC). The purpose of this study was to carry out a detailed analysis of the chicken (Gallus gallus domesticus) LRC. Bacterial artificial chromosomes containing genes related to mammalian leukocyte immunoglobulin-like receptors were identified in a chicken genomic library and shown to map to a single microchromosome. Sequencing revealed 103 chicken immunoglobulin-like receptor (CHIR) loci (22 inhibitory, 25 activating, 15 bifunctional, and 41 pseudogenes). A very complex splicing pattern was found using transcript analyses and seven hypervariable regions were detected in the external CHIR domains. Phylogenetic and genomic analysis showed that CHIR genes evolved mainly by block duplications from an ancestral inhibitory receptor locus, with transformation into activating receptors occurring more than once. Evolutionary selection pressure has led not only to an exceptional expansion of the CHIR cluster but also to a dramatic diversification of CHIR loci and haplotypes. This indicates that CHIRs have the potential to complement the adaptive immune system in fighting pathogens.
The immune system developed to cope with a diverse array of pathogens, including infectious organisms. The detection of these pathogens by cells of the immune system is mediated by a large set of specific receptor proteins. Here the authors seek to understand how a particular subset of cell surface receptors of the domestic chicken, the chicken Ig-like receptors (CHIR), has evolved. They demonstrate that at least 103 such receptor loci are clustered on a single microchromosome and provide the first detailed analysis of this region. The sequences of the CHIR genes suggest the presence of inhibitory, activating, and bifunctional receptors, as well as numerous incomplete loci (pseudogenes) that appear to have evolved by duplications of an ancestral inhibitory receptor gene. Multiple regions of very high sequence variability were also identified within CHIR loci which, together with considerable expansion of the number of these genes, suggest that CHIR polypeptides are involved in critical functions in the immune system of the chicken.
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