title: A genome-wide association study of pulmonary function measures in the Framingham Heart Study.
abstract: The ratio of forced expiratory volume in one second to forced vital capacity (FEV(1)/FVC) is a measure used to diagnose airflow obstruction and is highly heritable. We performed a genome-wide association study in 7,691 Framingham Heart Study participants to identify single-nucleotide polymorphisms (SNPs) associated with the FEV(1)/FVC ratio, analyzed as a percent of the predicted value. Identified SNPs were examined in an independent set of 835 Family Heart Study participants enriched for airflow obstruction. Four SNPs in tight linkage disequilibrium on chromosome 4q31 were associated with the percent predicted FEV(1)/FVC ratio with p-values of genome-wide significance in the Framingham sample (best p-value = 3.6e-09). One of the four chromosome 4q31 SNPs (rs13147758; p-value 2.3e-08 in Framingham) was genotyped in the Family Heart Study and produced evidence of association with the same phenotype, percent predicted FEV(1)/FVC (p-value = 2.0e-04). The effect estimates for association in the Framingham and Family Heart studies were in the same direction, with the minor allele (G) associated with higher FEV(1)/FVC ratio levels. Results from the Family Heart Study demonstrated that the association extended to FEV(1) and dichotomous airflow obstruction phenotypes, particularly among smokers. The SNP rs13147758 was associated with the percent predicted FEV(1)/FVC ratio in independent samples from the Framingham and Family Heart Studies producing a combined p-value of 8.3e-11, and this region of chromosome 4 around 145.68 megabases was associated with COPD in three additional populations reported in the accompanying manuscript. The associated SNPs do not lie within a gene transcript but are near the hedgehog-interacting protein (HHIP) gene and several expressed sequence tags cloned from fetal lung. Though it is unclear what gene or regulatory effect explains the association, the region warrants further investigation.
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, USA. jwilk@bu.edu
authors.forename: Jemma B
authors.initials: JB
authors.lastname: Wilk
authors.forename: Ting-Hsu
authors.initials: TH
authors.lastname: Chen
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Gottlieb
authors.forename: Robert E
authors.initials: RE
authors.lastname: Walter
authors.forename: Michael W
authors.initials: MW
authors.lastname: Nagle
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Brandler
authors.forename: Richard H
authors.initials: RH
authors.lastname: Myers
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.forename: George T
authors.initials: GT
authors.lastname: O'Connor
mesh_terms: D002352:Carrier Proteins / Q000235:genetics; D002894:Chromosomes, Human, Pair 4; D005541:Forced Expiratory Volume; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D015894:Genome, Human; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods; D006801:Humans; D015810:Linkage Disequilibrium; D008168:Lung / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D012129:Respiratory Function Tests; D014797:Vital Capacity
chemical_list: D002352:Carrier Proteins; C117596:HHIP protein, human; D008562:Membrane Glycoproteins