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A Genetic Isolate Eur Respir J 2010; 35: 768–775 DOI: 10.1183/09031936.00054408 CopyrightßERS Journals Ltd 2010 Novel strategy to identify genetic risk factors for COPD severity: a genetic isolate C.C. van Diemen*, D.S. Postma#, Y.S. Aulchenko", P.J.L.M. Snijders", B.A. Oostra", C.M. van Duijn" and H.M. Boezen* ABSTRACT: Studies using genetic isolates with limited genetic variation may be useful in chronic AFFILIATIONS obstructive pulmonary disease (COPD) genetics, but are thus far lacking. The associations Depts of *Epidemiology and #Pulmonology, University Medical between single nucleotide polymorphisms (SNPs) in candidate genes and lung function in COPD Center Groningen, University of were studied in a genetic isolate. Groningen, Groningen, and " In 91 subjects with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage o1 Epidemiology and Biostatistics, COPD, who were members of an extended pedigree including 6,175 people from the Genetic Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands. Research in Isolated Populations study, 32 SNPs were analysed in 13 candidate genes: a disintegrin and metalloprotease domain 33 gene (ADAM33), transforming growth factor-b1 gene CORRESPONDENCE (TGFB1), matrix metalloprotease-1 gene (MMP1), MMP2, MMP9, MMP12, tissue inhibitor of H.M. Boezen metalloprotease-1 gene (TIMP1), surfactant protein A1 gene (SFTPA1), SFTPA2, SFTPB, SFTPD, Dept of Epidemiology, E3.29 University Medical Center Groningen glutathione S-transferase P1 gene (GSTP1), and haem oxygenase 1 gene (HMOX1). Their relation P.O. Box 30.001 to forced expiratory volume in 1 s (FEV1), inspiratory vital capacity (IVC) and FEV1/IVC were 9700 RD Groningen studied using restricted maximum likelihood linear mixed modelling, accounting for pedigree The Netherlands structure. Significant associations were replicated in the general Vlagtwedde/Vlaardingen study. E-mail: [email protected] 1 Six SNPs in TGFB1, SFTPA1, SFTPA2 and SFTPD were significantly associated with FEV /IVC in Received: subjects with GOLD stage o1 COPD. Two SNPs in TGFB1 (C to T substitution at nucleotide -509 April 09 2008 and substitution of leucine 10 with proline (Leu10Pro)), Leu50Val in SFTPA1 and Ala160Thr in Accepted after revision: Aug 28 2009 SFTPD showed evidence suggestive of association with FEV1/IVC in subjects with GOLD stage o2 First published online: COPD. The TGFB1 associations were replicated in GOLD stage o2 patients from the Vlagtwedde/ Sept 24 2009 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. KEYWORDS: Chronic obstructive pulmonary disease, genetically isolated population, lung function, single nucleotide polymorphism hronic obstructive pulmonary disease use various definitions of disease status, which (COPD) is the third leading cause of makes it difficult to compare their results. C death worldwide, and is expected to Therefore, it makes sense to choose a robust increase in prevalence until 2030 [1, 2]. The phenotype for definition of COPD, such as the disease has a large personal, societal, and level of lung function, which can be more easily economic impact. COPD is characterised by compared between studies. Moreover, a low level chronic airway inflammation, airway remodel- of lung function is a predictor of mortality due to ling and airflow limitation that is not fully COPD [3–5]. reversible. Since not all smokers develop COPD, genetic susceptibility must play a role in the Another complicating factor in studies on the development of this disease, in addition to genetics of COPD is that COPD is considered a environmental factors. The genetic determinants complex genetic trait, i.e. multiple, possibly for COPD are difficult to study, since COPD is a interacting, genetic and environmental factors disease that becomes clinically manifest only at are involved. Therefore, there are advantages to later ages, when parents of COPD patients have attempting to identify risk genes in populations already died and their children are probably too that are relatively genetically and environmen- young to manifest airway obstruction. This limits tally homogeneous, such as genetically isolated European Respiratory Journal the option of performing family-based genetic populations, in which genetic variation is Print ISSN 0903-1936 research. Moreover, published studies frequently reduced owing to the small number of founders Online ISSN 1399-3003 768 VOLUME 35 NUMBER 4 EUROPEAN RESPIRATORY JOURNAL C.C. VAN DIEMEN ET AL. COPD and drift [6]. However, these processes raise the question of significant SNPs in previous studies, tagging SNPs for the whether findings can be extrapolated to the general popula- gene, or SNPs with a known functional effect on gene tion. Previous simulation studies suggest that this is the case expression or function. Genotyping was performed using for common variants with a frequency of .1% [6], but no Applied Biosystems TaqMan1 SNP Genotyping Assays empirical evidence is available. (Applied Biosystems, Nieuwerkerk aan de IJssel, the Netherlands). Sequences of primers and probes are available A candidate gene study was conducted for level of airflow on request. limitation in patients with COPD who were ascertained as part of the Genetic Research in Isolated Populations (GRIP) study Statistical analysis that is being conducted in a young genetically isolated In order to analyse pedigree data, use was made of the population from the south-western part of the Netherlands. measured genotype (MG) approach [33], which models All patients were genotyped using 32 single nucleotide quantitative traits as polymorphisms (SNPs) in 13 candidate genes for COPD, X chosen based on their previously published association with y ~mzkg z b c zG ze either COPD, level of lung function or lung function decline, as i i j ji i i j reported in the general population. Extensive genealogical information was collected, resulting in an extremely large and where yi is the phenotype of the ith individual, g the vector of complex pedigree of 6,175 members. Finally, 1,390 Caucasians genotypes at the marker under study, k the marker genotype from the general Dutch population were studied, including 351 effect, cij the value of the jth covariate or fixed effect for the patients with COPD, in order to establish whether or not the individual i, bj an estimate of the jth fixed effect or covariate present findings could be replicated in the general population. and Gi and ei random additive polygenic and residual effects, In both studies, it was investigated whether the severity of the respectively. The random effects are assumed to follow disease, as reflected by lung function reduction, is genetically multivariate normal distribution with a mean of zero. The 2 influenced in established COPD. variance for the polygenic effects is defined as WsG , where W 2 is the relationship matrix and sG the additive genetic variance METHODS due to polygenes. For the residual random effects, the variance 2 2 Study populations is defined as Ise , where I is the identity matrix and se the The present study forms part of the GRIP programme [7, 8]. residual variance. The GRIP programme is based in a recently genetically isolated Since the pedigree under analysis was very large, fast genome- population from the south-western part of the Netherlands, wide rapid association using mixed model and regression which was founded in the middle of the eighteenth century by (GRAMMAR) approximation to the full MG approach was , 150 individuals and was genetically isolated until the middle used [34]. The GRAMMAR consists of a fast though con- , of the twentieth century. The population now includes 20,000 servative test at the screening stage, followed up with full MG inhabitants in eight adjacent communities. GRIP programme analysis of polymorphisms that pass the relaxed screening participants are generally related via multiple lines of descent significance threshold (p,0.1). All analyses involving pedigree and are inbred via multiple consanguineous loops [9, 10]. were performed using ASReml v2.0 [35], a package for linear Subjects with general-practitioner-diagnosed COPD were mixed model analysis using restricted maximum likelihood. invited to the research centre to undergo spirometry and This is a joint venture between the biometrics programme of complete a questionnaire [11]. Spirometry was performed by the New South Wales Department of Primary Industries trained pulmonary research technicians using a pneumotacho- (Orange, Australia) and the Biomathematics University of graph (Viasys, Houten, the Netherlands; formerly Jaeger Rothamsted Research (Harpenden, UK). Statisticians in the UK spirometry system). Predicted values for forced expiratory and Australia have collaborated in its development. volume in 1 s (FEV1) were calculated using adjusted QUANJER Significant associations were tested using linear regression et al. [12] equations for Caucasian subjects. DNA was isolated analyses in the Vlagtwedde/Vlaardingen population. All 1 from blood using Puregene DNA Purification Kits (Gentra, analyses were adjusted for age, height and sex. Inc., Minneapolis, MN, USA). All participants gave written informed consent. RESULTS In order to verify the findings from the GRIP study in the GRIP study population general population, cross-sectional data from the general- A total of 157 individuals who were diagnosed with COPD by population-based
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