Evaluation of candidate genes in a genome-wide association study of childhood asthma in Mexicans

• Published in: Journal of allergy and clinical immunology Vol. 125; no. 2; pp. 321 - 327.e13
• Main Authors: Wu, Hao, PhD, Romieu, Isabelle, MD, Shi, Min, PhD, Hancock, Dana B., PhD, Li, Huiling, MD, Sienra-Monge, Juan-Jose, MD, Chiu, Grace Y., PhD, Xu, Hong, MS, del Rio-Navarro, Blanca Estela, MD, London, Stephanie J., MD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01-02-2010; Elsevier; Elsevier Limited
• Subjects: Adolescent; Allergy; Allergy and Immunology; Asthma; Asthma - genetics; Biological and medical sciences; Child; Child, Preschool; Chromosomes; Chronic obstructive pulmonary disease, asthma; Cloning; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genes; genetic predisposition to disease; Genetic Predisposition to Disease - genetics; Genome-Wide Association Study; Genomes; Genomics; Genotype; Humans; Immunopathology; Male; Medical sciences; Methods; Mexico; Pediatrics; Pneumology; Polymorphism, Single Nucleotide; Quality control; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; single nucleotide polymorphism; Statistical analysis; Studies; Central America; Mexico; America; CYFIP2; DPP10; Allergy; Transmission disequilibrium test; GWAS; single nucleotide polymorphism; Linkage disequilibrium; Dipeptidyl-peptidase 10 gene; IL1RL1; SNP; FDR; ORMDL3; Cytoplasmic FMR1 interacting protein 2 gene; TRIad Multi-Marker test; TGFB1; TDT; asthma; IL-1 receptor–like 1 gene; ESR1; TRIMM; Estrogen receptor 1 gene; genome-wide association study; TGF-β1 gene; False discovery rate; LD; ORM1-like 3 gene; genetic predisposition to disease; IL-18 receptor 1 gene; IL18R1; Human; Lung disease; Immunopathology; Genetic variability; Respiratory disease; Genotype; Asthma; Genetic disease; Association; Immunology; Predisposition; Bronchus disease; Candidate gene; Obstructive pulmonary disease; Single nucleotide polymorphism; Genome; Child
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2009.09.007

Background More than 200 asthma candidate genes have been examined in human association studies or identified with knockout mouse approaches. However, many have not been systematically replicated in human populations, especially those containing a large number of tagging single nucleotide polymorphisms (SNPs). Objective We comprehensively evaluated the association of previously implicated asthma candidate genes with childhood asthma in a Mexico City population. Methods From the literature, we identified candidate genes with at least 1 positive report of association with asthma phenotypes in human subjects or implicated in asthma pathogenesis using knockout mouse experiments. We performed a genome-wide association study in 492 asthmatic children aged 5 to 17 years and both parents using the Illumina HumanHap 550v3 BeadChip. Separate candidate gene analyses were performed for 2933 autosomal SNPs in the 237 selected genes by using the log-linear method with a log-additive risk model. Results Sixty-one of the 237 genes had at least 1 SNP with a P  value of less than .05 for association with asthma. The 9 most significant results were observed for rs2241715 in the gene encoding TGF-β1 ( TGFB1 ; P = 3.3 × 10−5 ), rs13431828 and rs1041973 in the gene encoding IL-1 receptor–like 1 ( IL1RL1 ; P  = 2 × 10−4 and 3.5 × 10−4 ), 5 SNPs in the gene encoding dipeptidyl-peptidase 10 ( DPP10 ; P = 1.6 × 10−4 to 4.5 × 10−4 ), and rs17599222 in the gene encoding cytoplasmic FMR1 interacting protein 2 ( CYFIP2 ; P = 4.1 × 10−4 ). False discovery rates were less than 0.1 for all 9 SNPs. Multimarker analysis identified TGFB1 , IL1RL1 , the gene encoding IL-18 receptor 1 (IL18R1) , and DPP10 as the genes most significantly associated with asthma. Conclusions This comprehensive analysis of literature-based candidate genes suggests that SNPs in several candidate genes, including TGFB1 , IL1RL1 , IL18R1 , and DPP10 , might contribute to childhood asthma susceptibility in a Mexican population.