The multi-ethnic study of atherosclerosis lung/snp health association resource study

Ani Manichaiku, 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. BrantlyRhea 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, R. Graham Barr

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


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 than2950 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 = 2.2×10-8) and PPT2 (rs10947233; P = 3.2 × 10-8), both of which replicated in an additional 6,023 individuals of European ancestry. Both singlenucleotide 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 a-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 × 10210; MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 × 10-8; MAF, 2.6%), which acts on a-linked mannose. Among African Americans, a locus near a third a-mannosidase-related gene, MAN1C1 (rs12130495; P = 9.9 × 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.

Original languageEnglish
Pages (from-to)408-418
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number4
StatePublished - 15 Feb 2014


  • Cohort study
  • Computed tomography
  • Emphysema
  • Genetic association
  • Multiethnic


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