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Secreted Modular Calcium-binding Protein 2 Haplotypes Are Associated with Pulmonary Function

¹ Departments of Neurology and Medicine, ² Department of Genetics and Genomics, ³ Framingham Heart Study Genetics Laboratory, Department of Neurology, and ⁴ Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts; and ⁵ Department of Human Genetics, University of Chicago, Chicago, Illinois

Correspondence and requests for reprints should be addressed to Samer Karamohamed, Ph.D., The University of Chicago, Department of Human Genetics, 920 East 58th Street, Room 515, Chicago, IL 60611. E-mail: samer{at}uchicago.edu

Rationale: Previously reported linkage to FEV₁ (LOD score = 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 FEV₁ 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 FEV₁ (p = 0.003) and FVC (p = 0.02) measures. In never-smoking subjects, association with higher measures was observed with the minor allele of rs747995 (FEV₁, p = 0.0006; FVC, p = 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 FEV₁ (p = 0.0002) and 157 ml for FVC (p = 0.0002). The G-T haplotype was similarly associated in a set of never-smoking subjects from the Family Heart Study (FEV₁, p = 0.03; FVC, p = 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 FEV₁ and FVC.

Key Words: FEV₁ • FVC • genetics • single-nucleotide polymorphism

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject 1-Antitrypsin deficiency is the only proven genetic determinant of chronic obstructive pulmonary disease. What This Study Adds to the Field The study provides evidence for the implication of yet another gene, SMOC2, in lung function. SMOC2 was found to affect FEV1 and FVC in two different populations, the NHLBI Framingham Heart Study and the NHLBI Family Heart Study.

 

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