• Ani Manichaikul, Eric A Hoffman, Joanna Smolonska, Wei Gao, Michael H Cho, Heather Baumhauer, Matthew Budoff, John H M Austin, George R Washko, J Jeffrey Carr, Joel D Kaufman, Tess Pottinger, Charles A Powell, Cisca Wijmenga, Pieter Zanen, Harry J M Groen, Dirkje S Postma, Adam Wanner, Farshid N Rouhani, Mark L Brantly, Rhea Powell, Benjamin M Smith, Dan Rabinowitz, Leslie J Raffel, Karen D Hinckley Stukovsky, James D Crapo, Terri H Beaty, John E Hokanson, Edwin K Silverman, Josée Dupuis, George T O'Connor, H Marike Boezen, Stephen S Rich, and R Graham Barr.
• 1 Center for Public Health Genomics, and.
• Am. J. Respir. Crit. Care Med. 2014 Feb 15; 189 (4): 408418408-18.

RationalePulmonary emphysema overlaps partially with spirometrically defined chronic obstructive pulmonary disease and is heritable, with moderately high familial clustering.ObjectivesTo 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.MethodsWe 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 ResultsAmong 7,914 participants, we identified regions at genome-wide significance for percent emphysema in or near SNRPF (rs7957346; P = 2.2 × 10(-8)) and PPT2 (rs10947233; P = 3.2 × 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 α-mannosidase-related gene MAN2B1 (rs10411619; P = 1.1 × 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 × 10(-10); MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 × 10(-8); MAF, 2.6%), which acts on α-linked mannose. Among African Americans, a locus near a third α-mannosidase-related gene, MAN1C1 (rs12130495; P = 9.9 × 10(-6); MAF, 13.3%) was associated with percent emphysema.ConclusionsOur 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 α-mannosidase may influence risk of emphysema.

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