Studies using genetic isolates with limited genetic variation may be useful in chronic obstructive pulmonary disease (COPD) genetics, but are thus far lacking. The associations between single nucleotide polymorphisms (SNPs) in candidate genes and lung function in COPD were studied in a genetic isolate. In 91 subjects with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage ≥1 COPD, who were members of an extended pedigree including 6,175 people from the Genetic Research in Isolated Populations study, 32 SNPs were analysed in 13 candidate genes: a disintegrin and metalloprotease domain 33 gene (ADAM33), transforming growth factor-β1 gene (TGFB1), matrix metalloprotease-1 gene (MMP1), MMP2, MMP9, MMP12, tissue inhibitor of metalloprotease-1 gene (TIMP1), surfactant protein A1 gene (SFTPA1), SFTPA2, SFTPB, SFTPD, glutathione S-transferase P1 gene (GSTP1), and haem oxygenase 1 gene (HMOX1). Their relation to forced expiratory volume in 1 s (FEV1), inspiratory vital capacity (IVC) and FEV1/IVC were studied using restricted maximum likelihood linear mixed modelling, accounting for pedigree structure. Significant associations were replicated in the general Vlagtwedde/Vlaardingen study. Six SNPs in TGFB1, SFTPA1, SFTPA2 and SFTPD were significantly associated with FEV1/IVC in subjects with GOLD stage ≥1 COPD. Two SNPs in TGFB1 (C to T substitution at nucleotide -509 and substitution of leucine 10 with proline (Leu10Pro)), Leu50Val in SFTPA1 and Ala160Thr in SFTPD showed evidence suggestive of association with FEV1/IVC in subjects with GOLD stage ≥2 COPD. The TGFB1 associations were replicated in GOLD stage o2 patients from the Vlagtwedde/ Vlaardingen population, with similar effect sizes. It was shown that a genetic isolate can be used to determine the genetics of lung function, which can be replicated in COPD patients from an independent population. Copyright

Chronic obstructive pulmonary disease, Genetically isolated population, Lung function, Single nucleotide polymorphism,
The European Respiratory Journal
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Erasmus MC: University Medical Center Rotterdam

van Diemen, C.C, Postma, D.S, Aulchenko, Y.S, Snijders, P.J, Oostra, B.A, Tikka-Kleemola, P, & Boezen, H.M. (2010). Novel strategy to identify genetic risk factors for COPD severity: A genetic isolate. The European Respiratory Journal, 35(4), 768–775. doi:10.1183/09031936.00054408