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

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• 作者：Eric M.  ; Schauberger BS^a ; Susan L.  ; Ewart DVM ; PhD^a ;   ; ^{ewart@cvm.msu.edu} ; Syed H.  ; Arshad DM ; FRCP^b ;   ; ^c ; Marianne  ; Huebner PhD^a ; Wilfried  ; Karmaus MD ; DrMed ; MPH^d ; John W.  ; Holloway PhD^c ; Karen H.  ; Friderici PhD^a ; Julie T.  ; Ziegler MA^e ; Hongmei  ; Zhang PhD^d ; Matthew J.  ; Rose-Zerilli BSc^c ; Sheila J.  ; Barton MSc^c ; Stephen T.  ; Holgate MD ; DSc ; FMed Sci^c ; Jeffrey R.  ; Kilpatrick BS^f ; John B.  ; Harley MD ; PhD^f ;   ; ^g ; Stephane  ; Lajoie-Kadoch PhD^h ; Isaac T.W.  ; Harley BS^h ; Qutayba  ; Hamid MD ; PhDⁱ ; Ramesh J.  ; Kurukulaaratchy DM ; MRCP^b ;   ; ^c ; Max A.  ; Seibold PhD^j ; Pedro C.  ; Avila MD^k ; William  ; Rodriguez-Cintr&oacute ; n MD^l ; Jose R.  ; Rodriguez-Santana MD^m ; Donglei  ; Hu PhDⁿ ; Christopher  ; Gignoux MSⁿ ; Isabelle  ; Romieu MD ; MPH ; ScD^o ; Stephanie J.  ; London MD ; DrPH ; MPH^p ; Esteban G.  ; Burchard MD ; MPHⁿ ; Carl D.  ; Langefeld PhD^e ; Marsha  ; Wills-Karp PhD^h
• 关键词：Asthma ; ATPAF1 ; children ; gene ; genetic ; genome-wide association ; purinergic ; respiratory ; single nucleotide polymorphism ; SNP
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2011
• 出版时间：October 2011
• 年：2011
• 卷：128
• 期：4
• 页码：753-760.e11
• 全文大小：1485 K

文摘

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 × 10^? to 2.2 × 10^?). 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.