Identification of ATPAF1 as a novel candidate gene for asthma in children

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:128

Article

Ewart, Susan L.¹  Arshad, Syed H.^2,3  Karmaus, Wilfried⁴  Holloway, John W.³  Ziegler, Julie T.⁵  Zhang, Hongmei⁴  Rose-Zerilli, Matthew J.³  Barton, Sheila J.³  Holgate, Stephen T.³  Kilpatrick, Jeffrey R.⁶  Harley, John B.^6,7  Lajoie-Kadoch, Stephane⁸  Harley, Isaac T. W.⁸  Hamid, Qutayba⁹  Kurukulaaratchy, Ramesh J.^2,3  Seibold, Max A.¹⁰  Avila, Pedro C.¹¹  Rodriguez-Cintron, William¹²  Rodriguez-Santana, Jose R.¹³  Hu, Donglei¹⁴  Gignoux, Christopher¹⁴  Romieu, Isabelle¹⁵  London, Stephanie J.¹⁶  Burchard, Esteban G.¹⁴  Langefeld, Carl D.⁵  Wills-Karp, Marsha⁸ 

[1] Michigan State Univ, Vet Med Ctr G100, E Lansing, MI 48824 USA

[2] David Hide Asthma & Allergy Res Ctr, Isle Of Wight, England

[3] Univ Southampton, Sch Med, Southampton SO9 5NH, Hants, England

[4] Univ S Carolina, Columbia, SC 29208 USA

[5] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA

[6] JKA Genom, Oklahoma City, OK USA

[7] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA

[8] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA

[9] McGill Univ, Meakins Christie Lab, Montreal, PQ, Canada

[10] Natl Jewish Hlth, Denver, CO USA

[11] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA

[12] Vet Affairs Med Ctr, San Juan, PR USA

[13] CSP, Ctr Neumol Pediatr, San Juan, PR USA

[14] Univ Calif San Francisco, San Francisco, CA 94143 USA

[15] Natl Inst Publ Hlth, Cuernevaca, Mexico

[16] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA

关键词: Asthma;    ATPAF1;    children;    gene;    genetic;    genome-wide association;    purinergic;    respiratory;    single nucleotide polymorphism;    SNP;   

DOI  :  10.1016/j.jaci.2011.04.058

来源: Elsevier

【 摘 要 】

Background: Asthma is a common disease of children with a complex genetic origin. Understanding the genetic basis of asthma susceptibility will allow disease prediction and risk stratification. Objective: We sought to identify asthma susceptibility genes in children. Methods: A nested case-control genetic association study of children of Caucasian European ancestry from a birth cohort was conducted. Single nucleotide polymorphisms (SNPs, n = 116,024) were genotyped in pools of DNA samples from cohort children with physician-diagnosed asthma (n = 112) and normal controls (n = 165). A genomic region containing the ATPAF1 gene was found to be significantly associated with asthma. Additional SNPs within this region were genotyped in individual samples from the same children and in 8 independent study populations of Caucasian, African American, Hispanic, or other ancestries. SNPs were also genotyped or imputed in 2 consortia control populations. ATPAF1 expression was measured in bronchial biopsies from asthmatic patients and controls. Results: Asthma was found to be associated with a cluster of SNPs and SNP haplotypes containing the ATPAF1 gene, with 2 SNPs achieving significance at a genome-wide level (P = 2.26 x 10(-5) to 2.2 x 10(-8)). Asthma severity was also found to be associated with SNPs and SNP haplotypes in the primary population. SNP and/or gene-level associations were confirmed in the 4 non-Hispanic populations. Haplotype associations were also confirmed in the non-Hispanic populations (P = .045-.0009). ATPAF1 total RNA expression was significantly (P < .01) higher in bronchial biopsies from asthmatic patients than from controls. Conclusion: Genetic variation in the ATPAF1 gene predisposes children of different ancestries to asthma. (J Allergy Clin Immunol 2011;128:753-60.)

【 授权许可】

Free