Published at www.nejm.org October 15, 2008 (10.1056/NEJMoa0806604) |
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Published at www.nejm.org October 15, 2008 (10.1056/NEJMoa0806604) |
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Background A genomewide association study has shown an association between variants at chromosome 17q21 and an increased risk of asthma. To elucidate the relationship between this locus and disease, we examined a large, family-based data set that included extensive phenotypic and environmental data from the Epidemiological Study on the Genetics and Environment of Asthma.
Methods We tested 36 single-nucleotide polymorphisms (SNPs) in the 17q21 region in 1511 subjects from 372 families for an association with asthma. We also tested for genetic heterogeneity according to the age at the onset of asthma and exposure to environmental tobacco smoke in early life.
Results Eleven SNPs were significantly associated with asthma (P<0.01), of which three (rs8069176, rs2305480, and rs4795400) were strongly associated (P<0.001). Ordered-subset regression analysis led us to select an onset at 4 years of age or younger to classify patients as having early-onset asthma. Association with early-onset asthma was highly significant (P<10–5 for four SNPs), whereas no association was found with late-onset asthma. With respect to exposure to environmental tobacco smoke in early life, we observed a significant association with early-onset asthma only in exposed subjects (P<5x10–5 for six SNPs). Under the best-fitting recessive model, homozygous status (GG) at the most strongly associated SNP (rs8069176) conferred an increase in risk by a factor of 2.9, as compared with other genotypes (AG and AA) in the group exposed to environmental tobacco smoke (P=2.8x10–6; P=0.006 for the test for heterogeneity of the SNP effect on early-onset asthma between groups with tobacco exposure and those without such exposure).
Conclusions This study shows that the increased risk of asthma conferred by 17q21 genetic variants is restricted to early-onset asthma and that the risk is further increased by early-life exposure to environmental tobacco smoke. These findings provide a greater understanding of the functional role of the 17q21 variants in the pathophysiology of asthma.
Source Information
From INSERM Unité 794, Paris (E.B., E.C., H.A., N.C., F.D.); Fondation Jean Dausset–Centre d'Etude du Polymorphisme Humain (CEPH), Paris (E.B., E.C., H.A., N.C., M.L., F.D.); Université d'Evry, Evry (E.B., H.A., N.C., F.D.); INSERM Unité 535, Villejuif (M.-H.D.); Université Paris–Sud 11, Villejuif (M.-H.D., N.L.M., F.K.); Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry (A.B., D.Z., M.L.); Hôpital Arnaud de Villeneuve, Montpellier (J.B.); Centre Hospitalier Lyon-Sud, Pierre Bénite (F.G.); Hôpital d'Enfants Armand Trousseau, Paris (J.J.); INSERM Unité 780, Villejuif (N.L.M., F.K.); Hôpital Necker, Paris (P.S.); INSERM Unité 823, Grenoble (V.S., I.P.); Hôpital Sainte-Marguerite, Marseille (D.V.); and Centre Hospitalier Universitaire de Grenoble, Grenoble (I.P.) — all in France.
This article (10.1056/NEJMoa0806604) was published at www.nejm.org on October 15, 2008. It will appear in the November 6 issue of the Journal.
Address reprint requests to Dr. Demenais at INSERM Unité 794, Fondation Jean Dausset–CEPH, 27 rue Juliette Dodu, 75010 Paris, France, or at florence.demenais{at}inserm.fr.
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