Genome-wide study of percent emphysema on computed tomography in the general population: The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study

Rationale: Pulmonary emphysema overlaps partially with spirometrically defined chronic obstructive pulmonary disease and is heritable, with moderately high familial clustering.

Objectives: To complete a genome-wide association study (GWAS) for the percentage of emphysema-like lung on computed tomography in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung/SNP Health Association Resource (SHARe) Study, a large, population-based cohort in the United States.

Methods: We determined percent emphysema and upper-lower lobe ratio in emphysema defined by lung regions less than -950 HU on cardiac scans. Genetic analyses were reported combined across four race/ethnic groups: non-Hispanic white (n = 2,587), African American (n = 2,510), Hispanic (n = 2,113), and Chinese (n = 704) and stratified by race and ethnicity.

Measurements and Main Results: Among 7,914 participants, we identified regions at genome-wide significance for percent emphysema in or near SNRPF (rs7957346; P = 2.2 x 10(-8)) and PPT2 (rs10947233; P = 3.2 x 10(-8)), both of which replicated in an additional 6,023 individuals of European ancestry. Both single-nucleotide polymorphisms were previously implicated as genes influencing lung function, and analyses including lung function revealed independent associations for percent emphysema. Among Hispanics, we identified a genetic locus for upper-lower lobe ratio near the alpha-mannosidase-related gene MAN2B1 (rs10411619; P = 1.1 x 10(-9); minor allele frequency [MAF], 4.4%). Among Chinese, we identified single-nucleotide polymorphisms associated with upper-lower lobe ratio near DHX15 (rs7698250; P = 1.8 x 10(-10); MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 x 10(-8); MAF, 2.6%), which acts a third alpha-mannosidase-related gene, MAN1C1 (rs12130495; P = 9.9 x 10(-6); MAF, 13.3%) was associated with percent emphysema.

Conclusions: Our results suggest that some genes previously identified as influencing lung function are independently associated with emphysema rather than lung function, and that genes related to a-mannosidase may influence risk of emphysema.