Genome-wide association study of bronchial asthma in the Volga-Urals region of Russia

Bronchial asthma is a chronic inflammatory respiratory disease caused by a complex interaction of environmental influences and genetic susceptibility. The first genome-wide association study of bronchial asthma discovered a significant association between single nucleotide polymorphisms (SNPs) located within the genomic region 17q12-q21 and childhood bronchial asthma in individuals of European descent. This result was later replicated in a number of independent population samples of European and Asian origin. Here we report the results of the first genome-wide association study of bronchial asthma in the Volga-Urals region of Russia. The study involved 358 unrelated patients with physician-diagnosed bronchial asthma and 369 disease-free control subjects of different ethnicity (Russians, Tatars, and Bashkirs). DNA specimens were genotyped using an Illumina Human610 quad array as a part of the GABRIEL project (EC contract no. LSHB-CT-2006-018996). After QC filtering procedures, a final set of 550 915 SNPs genotyped in 330 patients and 348 controls was tested for association with bronchial asthma. Five markers on chromosome 17q12-21 showed significant association with bronchial asthma (p ≤ 4.79 × 10−7). The rs7216389 SNP located in GSDMB intron 1 showed the strongest evidence for association (p = 1.01 × 10−7). Association with childhood asthma (p = 1.97 × 10−6 for rs7216389) was stronger than with late-onset asthma (p = 1.8 × 10−4 for rs7216389). A replication study of three SNPs located within GSDMB confirmed association only with childhood asthma. In sum, these results suggest that genetic variants of 17q12–q21 play an important role in susceptibility to bronchial asthma in the Volga-Urals region of Russia.

[1]  S Rozen,et al.  Primer3 on the WWW for general users and for biologist programmers. , 2000, Methods in molecular biology.

[2]  James J Schlesselman.  Case-Control Studies: Design, Conduct, Analysis , 1982 .

[3]  S. Holgate,et al.  Genetics of allergic disease. , 2010, The Journal of allergy and clinical immunology.

[4]  J. Bousquet,et al.  Effect of 17q21 variants and smoking exposure in early-onset asthma. , 2008, The New England journal of medicine.

[5]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[6]  K. Dewar,et al.  Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease. , 2009, American journal of human genetics.

[7]  W. Cookson,et al.  Chromosome 17q21 SNP and Severe Asthma , 2010, Journal of Human Genetics.

[8]  Christer S. Ejsing,et al.  Orm family proteins mediate sphingolipid homeostasis , 2010, Nature.

[9]  Florence Demenais,et al.  A large-scale, consortium-based genomewide association study of asthma. , 2010, The New England journal of medicine.

[10]  D. Clayton,et al.  Genome-wide association study and meta-analysis finds over 40 loci affect risk of type 1 diabetes , 2009, Nature Genetics.

[11]  C. Mathew,et al.  The isolation of high molecular weight eukaryotic DNA. , 1985, Methods in molecular biology.

[12]  M. Katoh,et al.  Identification and characterization of human ZPBP-like gene in silico. , 2003, International journal of molecular medicine.

[13]  D. Postma,et al.  A sequence variant on 17q21 is associated with age at onset and severity of asthma , 2010, European Journal of Human Genetics.

[14]  K. Siminovitch,et al.  Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. , 2009, The New England journal of medicine.

[15]  R. Schneider-Stock,et al.  Differential expression and localisation of gasdermin‐like (GSDML), a novel member of the cancer‐associated GSDMDC protein family, in neoplastic and non‐neoplastic gastric, hepatic, and colon tissues , 2008, Pathology.

[16]  L. G. Davis,et al.  Basic methods in molecular biology , 1986 .

[17]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[18]  M. Ng,et al.  Asthma and atopy are associated with chromosome 17q21 markers in Chinese children , 2009, Allergy.

[19]  Yusuke Nakamura,et al.  Genetic polymorphism regulating ORM1-like 3 (Saccharomyces cerevisiae) expression is associated with childhood atopic asthma in a Japanese population. , 2008, The Journal of allergy and clinical immunology.

[20]  Judy H. Cho,et al.  Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease , 2008, Nature Genetics.

[21]  Ryan M. Smith,et al.  ORMDL3 variants associated with asthma susceptibility in North Americans of European ancestry. , 2008, The Journal of allergy and clinical immunology.

[22]  Jinho Yu,et al.  Polymorphisms in GSDMA and GSDMB are associated with asthma susceptibility, atopy and BHR , 2011, Pediatric pulmonology.

[23]  Joseph T. Glessner,et al.  17q12-21 variants interact with smoke exposure as a risk factor for pediatric asthma but are equally associated with early-onset versus late-onset asthma in North Americans of European ancestry. , 2009, The Journal of allergy and clinical immunology.

[24]  R. Pauwels,et al.  GLOBAL STRATEGY FOR ASTHMA MANAGEMENT AND PREVENTION , 1996 .

[25]  S. London,et al.  Genetic variation in ORM1‐like 3 (ORMDL3) and gasdermin‐like (GSDML) and childhood asthma , 2009, Allergy.

[26]  L. Liang,et al.  Mapping complex disease traits with global gene expression , 2009, Nature Reviews Genetics.

[27]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[28]  E. Burchard,et al.  ORMDL3 gene is associated with asthma in three ethnically diverse populations. , 2008, American journal of respiratory and critical care medicine.

[29]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[30]  P. Debré,et al.  Aiolos and Ikaros: Regulators of lymphocyte development, homeostasis and lymphoproliferation , 2002, Apoptosis.

[31]  K. Sumiyama,et al.  Members of a novel gene family, Gsdm, are expressed exclusively in the epithelium of the skin and gastrointestinal tract in a highly tissue-specific manner. , 2007, Genomics.

[32]  Manuel A. R. Ferreira,et al.  Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia , 2011, European Journal of Human Genetics.

[33]  Gonçalo R. Abecasis,et al.  Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma , 2007, Nature.

[34]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[35]  M. Freidin,et al.  Genome-wide association study of allergic diseases in Russians of West Siberia , 2011, Molecular Biology.

[36]  C. Palmer,et al.  A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications. , 2008, The Journal of allergy and clinical immunology.

[37]  Cecilia Kim,et al.  Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood. , 2009, American journal of respiratory and critical care medicine.

[38]  Teri A Manolio,et al.  Genomewide association studies and assessment of the risk of disease. , 2010, The New England journal of medicine.

[39]  T. Hudson,et al.  Replication of an association between 17q21 SNPs and asthma in a French-Canadian familial collection , 2008, Human Genetics.

[40]  F Kauffmann,et al.  17q21 variants modify the association between early respiratory infections and asthma , 2009, European Respiratory Journal.