Background: Asthma is a complex disease characterized by sex-specific differences in incidence, prevalence, and severity, but little is known about the molecular basis of these sex-based differences. Objective: To investigate the genetic architecture of sex differences in asthma risk, we evaluated (1) associations between polymorphisms in the IFNG gene and childhood-onset asthma in combined and sex-specific samples and (2) interactions between polymorphisms and sex on asthma risk. Methods: Main and sex-interaction effects of IFNG genetic diversity on asthma risk and IFN-γ levels were examined in a birth cohort of children at high risk for asthma and allergic diseases. Replication of the genetic association was assessed in an independent sample of asthma cases. Results: Significant genotype-sex interactions on asthma were observed for 2 IFNG single nucleotide polymorphisms, rs2069727 and rs2430561, which were in strong linkage disequilibrium with each other. In contrast, none of the 10 IFNG single nucleotide polymorphisms showed significant main effects on asthma. The observed genotype-sex interaction on asthma was characterized by nonadditivity; that is, heterozygous boys had the highest risk for asthma, and heterozygous girls had the lowest risk. The interaction effect was robust to other asthma risk factors but was limited to children who experienced wheezing illnesses with viral infections during the first 3 years of life. Genotype-sex interactions were also observed in the IFN-γ response to LPS in the first year of life. Finally, the sex-interaction effect was replicated in an independent population of childhood asthma cases. Conclusions: These results provide insight into the genetic basis of sex differences in asthma and highlight the potential importance of interactions among sex, genotype, and environmental factors in asthma pathogenesis.
Bibliographical noteFunding Information:
Supported by National Institutes of Health grants R01 HL61879, P01 HL70831, M01 RR03186, R01 HL085197, and M01 RR00055 . D.A.L. was supported by National Institutes of Health grants F32 HL095268 and T32 HL007605 .
Disclosure of potential conflict of interest: D. J. Jackson has received research support from Pharmaxis, the National Institutes of Health, and the American Academy of Allergy, Asthma & Immunology/GlaxoSmithKline . J. E. Gern is on the scientific advisory board of and holds stock options for 3V Biosciences; has consulted and holds stock options for EraGen Biosciences; has consulted for Synairgen, Boehringer Inhgelheim, Pulmatrix, GlaxoSmithKline, and Biota; and has received research support from AstraZeneca and Merck. R. F. Lemanske, Jr, is a speaker for Merck, Doembecher Children’s Hospital, Washington University, the Medicus Group, the Park Nicolet Institute, the ACAAI, the LA Allergy Society, the Michigan Allergy/Asthma Society, the Medical College of Wisconsin, the Fund for Medical Research and Education (Detroit), the Children’s Hospital of Minnesota, the Toronto Allergy Society, the AAAAI, Beaumont Hospital, the University of Illinois, the Canadian Society of Allergy and Clinical Immunology, New York Presbyterian, the Med Media Educational Group, Onpointe Medical Communication, the Medical University of South Carolina, Health Matters Communication, Bishop McCann, Donohue Purohit Miller, the Center for Health Care Education, the University of California San Francisco, the American Thoracic Society, the University of Iowa, Indiana University, the American Lung Association of the Upper Midwest, Vanderbilt University, and Rochester Children’s Hospital; is a consultant and speaker for AstraZeneca; is a consultant for Map Pharmaceuticals, Gray Consulting, Smith Research, the Merck Childhood Asthma Network, Novartis, Quintiles/Innovax, RC Horowitz & Co, International Meetings and Science, Scienomics, Scientific Therapeutics, Gray Consulting, and Cognimed Inc; is an author of Up-to-Date; and is a textbook Editor for Elsevier. C. Ober receives research support from the National Institutes of Health. The rest of the authors have declared that they have no conflict of interest.
- association study
- sex differences
- single nucleotide polymorphism