Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype

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• 作者：Manuel A.R. Ferreira ; PhD^a ; ^&lowast ; ; ^{manuel.ferreira@qimrberghofer.edu.au" class="auth_mail} ; Melanie C. Matheson ; PhD^b ; ^&lowast ; ; Clara S. Tang ; PhD^a ; ^c ; Raquel Granell ; PhD^d ; Wei Ang ; PhD^e ; Jennie Hui ; PhD^f ; ^g ; ^h ; ⁱ ; Amy K. Kiefer ; PhD^j ; David L. Duffy ; PhD^a ; Svetlana Baltic ; PhD^k ; Patrick Danoy ; PhD^l ; Minh Bui ; PhD^b ; Loren Price ; PhD^k ; Peter D. Sly ; FRACP^m ; Nicholas Eriksson ; PhD^j ; Pamela A. Madden ; PhDⁿ ; Michael J. Abramson ; PhD^o ; Patrick G. Holt ; FAA^p ; Andrew C. Heath ; DPhilⁿ ; Michael Hunter ; PhD^g ; ⁱ ; Bill Musk ; FRACP^g ; ⁱ ; ^q ; ^r ; Colin F. Robertson ; FRACP^s ; Peter Le Souë ; f ; FRACP^t ; Grant W. Montgomery ; PhD^a ; A. John Henderson ; MD^d ; Joyce Y. Tung ; PhD^j ; Shyamali C. Dharmage ; PhD^b ; Matthew A. Brown ; FRACP^l ; Alan James ; FRACPⁱ ; ^q ; ^u ; Philip J. Thompson ; FRACP^k ; Craig Pennell ; PhD^e ; Nicholas G. Martin ; PhD^a ; David M. Evans ; PhD^d ; ^v ; David A. Hinds ; PhD^j ; John L. Hopper ; PhD^b ; ^{j.hopper@unimelb.edu.au" class="auth_mail} ; ; the Australian Asthma Genetics Consortium Collaborators &Dagger
• 关键词：Rhinitis ; atopy ; selection ; genetic correlation ; bivariate ; single nucleotide polymorphism
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：June 2014
• 年：2014
• 卷：133
• 期：6
• 页码：1564-1571
• 全文大小：326 K

文摘

To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever.

Objective

We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases.

Methods

We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091).

Results

At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10⁻⁹) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10⁻⁸). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10⁻⁷) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10⁻⁶).

Conclusion

By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.