ABSTRACT
Asthma is a heterogeneous multifactorial disease that is characterized in most cases by chronic respiratory tract inflammation. We carried out a GWAS in order to identify susceptibility genes for asthma in individuals of different ethnic backgrounds. The study sample consisted of 358 unrelated patients with asthma (160 Russians, 125 Tatars, and 73 Bashkirs) and 369 individuals of a control group (152 Russians, 117 Tatars, and 100 Bashkirs). DNA samples were genotyped with an Illumina human610 quad array (Illumina) as part of the project GABRIEL. Replication of the results of genome-wide analysis was carried out on an additional independent sample of 310 asthma patients (132 Russians, 105 Tatars, and 73 Bashkirs) and 310 individuals in a control group (131 Russians, 106 Tatars, and Bashkirs 77). Genome-wide analysis showed an association of asthma in Russians with the polymorphic loci of gene MUC19 (12q12) encoding gel-forming mucin 19. The highest level of association with asthma was found in rs2933346, which is located in intron 52 of this gene (p = 2.59 x 10(-6)). Seven polymorphic loci of gene MUC19 (rs1492313, rs2588401, rs2588402, rs2638863, rs2638864, rs1352940, and rs2933373), which are in close linkage disequilibrium among themselves and rs2933346, are associated with asthma with the same p-value (p = 4.96 x 10(-6)). The replicative study of rs1492313 in the independent sample of individuals confirmed the presence of the association of the polymorphic loci of this gene with the development of asthma in Russians. According to our data, the association of polymorphic variants of gene MUC19 with asthma has not been previously identified in any study. Our results indicate the important role of polymorphic variants of gene MUC19 in the formation of a predisposition to the development of asthma in individuals of Russian ethnicity.
Subject(s)
Asthma/ethnology , Asthma/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Mucins/genetics , Polymorphism, Genetic , Adolescent , Adult , Aged , Child , Child, Preschool , Female , Genetic Loci , Humans , Linkage Disequilibrium , Male , Middle Aged , Russia/ethnologyABSTRACT
Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disease developing as a result of the interaction between genetic predisposition and environmental factors. Considerable role in allergic diseases development is played by polymorphisms of genes of pattern-recognition receptors (PRR) which are capable of recognizing conservative standard molecular structures (patterns) unique for large pathogen groups. In this study polymorphic variants of PRR genes--Toll-like receptors (TLR1, TLR2, TLR4, TLR5, TLR6, TLR9, TLR10), NOD-like receptors (NOD1, NOD2), lipopolysaccharide receptor CD14 gene, and C11orf30 and LRRC32 genes, located in 11q13.5 region, have been investigated in AD patients and control subjects from the Republic of Bashkortostan. An association of TLR1 (rs5743571 and rs5743604), TLR6 (rs5743794) and TLR10 (rs11466617) with AD was found. Our results confirm an important role of the innate immune system in the pathogenesis of AD and the significance of polymorphisms within the Toll-like receptor 2 subfamily genes in AD development.
Subject(s)
Dermatitis, Atopic/genetics , Genetic Predisposition to Disease , Polymorphism, Genetic , Toll-Like Receptors/genetics , Adolescent , Adult , Alleles , Bashkiria , Case-Control Studies , Child , Child, Preschool , Chromosomes, Human, Pair 11 , Dermatitis, Atopic/immunology , Dermatitis, Atopic/pathology , Female , Gene Expression , Gene Frequency , Gene-Environment Interaction , Genetic Loci , Humans , Lipopolysaccharide Receptors/genetics , Lipopolysaccharide Receptors/immunology , Male , Membrane Proteins/genetics , Membrane Proteins/immunology , Middle Aged , Neoplasm Proteins/genetics , Neoplasm Proteins/immunology , Nod1 Signaling Adaptor Protein/genetics , Nod1 Signaling Adaptor Protein/immunology , Nod2 Signaling Adaptor Protein/genetics , Nod2 Signaling Adaptor Protein/immunology , Nuclear Proteins/genetics , Nuclear Proteins/immunology , Repressor Proteins/genetics , Repressor Proteins/immunology , Toll-Like Receptors/immunologyABSTRACT
Bronchial asthma is a chronic inflammatory respiratory disease that is caused by the complex interaction of environmental influences and genetic susceptibility. The first genome-wide association study of bronchial asthma discovered a significant association between SNPs within 17q12-21 genomic region and childhood bronchial asthma in individuals of European descent. Association with this genomic region was then replicated in a number of independent samples of European and Asian descent. Here we report results of the first genome-wide association study of bronchial asthma in the Volga-Ural region of Russia. The present study includes 358 unrelated patients with physician-diagnosed bronchial asthma and 369 disease-free control subjects of different ethnic origin (Russians, Tatars and Bashkirs). Genotyping of DNA samples was carried out using the Illumina Human610 quad array as a part of GABRIEL project (contract from the EC No LSHB-CT-2006-018996). After QC filtering procedures, a final set of 550915 SNPs genotyped in 330 cases and 348 controls was tested for association with bronchial asthma. Five markers on chromosome 17q12-21 showed statistically significant association with bronchial asthma (p < or = 4.79 x 10(-7)). SNP rs7216389 with the strongest evidence for association (p = 1.01 x 10(-7)) is located within the first intron of the GSDMB gene. Evidence for association was stronger with childhood-onset asthma (p = 1.97 x 10(-6) for SNP rs7216389) compared to late-onset asthma (p = 1.8 x 10(-4) for SNP rs7216389). Our replication study using three SNPs within GSDMB gene confirmed association with only childhood-onset asthma. In summary, these results suggest an important role for genetic variants within 17q12-q21 region in the development of bronchial asthma in the Volga-Ural region of Russia.