Rationale: Previously reported linkage to FEV 1 (LOD score ϭ 5.0) on 6q27 in the Framingham Heart Study (FHS) led us to explore a candidate gene, SMOC2, at 168.6 Mb. Objectives: We tested association between SMOC2 polymorphisms and FEV 1 and FVC in unrelated FHS participants. Methods: Twenty single-nucleotide polymorphisms (SNPs) around SMOC2 were genotyped in 1,734 subjects. Measurements and Main Results: SNP data were analyzed using multiple linear regression models incorporating sex, age, body mass index, height, and smoking history as covariates, and analyses were repeated within strata of ever-and never-smokers. The minor allele of SNP rs1402 was associated with higher mean FEV 1 (p ϭ 0.003) and FVC (p ϭ 0.02) measures. In never-smoking subjects, association with higher measures was observed with the minor allele of rs747995 (FEV 1 , p ϭ 0.0006; FVC, p ϭ 0.0008). These two SNPs lie in different haplotype blocks and reside in intron 4 of SMOC2. Haplotype analysis revealed a common G-T haplotype (rs747995-rs1402) with 77% frequency in never-smoking FHS subjects. The G-T haplotype was associated with reduction of 126 ml for FEV 1 (p ϭ 0.0002) and 157 ml for FVC (p ϭ 0.0002). The G-T haplotype was similarly associated in a set of never-smoking subjects from the Family Heart Study (FEV 1 , p ϭ 0.03; FVC, p ϭ 0.03).
Conclusions:The replication of the association in two populations supports the possibility that SMOC2 might play an important role in the determination of FEV 1 and FVC.Keywords: FEV 1 ; FVC; genetics; single-nucleotide polymorphismThe observation that pulmonary diseases cluster in families (1, 2) and the substantial heritability of spirometric pulmonary function measures demonstrated in population-based samples (3-10) support the hypothesis that genetic factors influence both variability in pulmonary function and risk of chronic obstructive pulmonary disease (COPD). The spirometric measurements of FEV 1 , FVC, and FEV 1 /FVC are estimated to be between 15 and 60% heritable in population-based samples (8, 10). Familial factors may influence lung size during development, as well as affect the response to environmental toxins such as cigarette smoke.Today, ␣ 1 -antitrypsin deficiency is the only proven genetic determinant of COPD (11-16). The homozygous deficiency of the serine protease inhibitor ␣ 1 -antitrypsin is associated with early-onset emphysema in smokers in their fourth decade of life and nonsmokers in their fifth decade (17) and accounts for less
What This Study Adds to the FieldThe study provides evidence for the implication of yet another gene, SMOC2, in lung function. SMOC2 was found to affect FEV 1 and FVC in two different populations, the NHLBI Framingham Heart Study and the NHLBI Family Heart Study.than 2% of all COPD (18). The heterozygous form of the mutation has been inconsistently associated with an increased risk of COPD. Mutations in alleles of ␣ 1 -antichymotrypsin, a highly homologous protease inhibitor (19), have also been associated with obstructive lung disease in case-contr...