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Meta-Analysis
. 2014 Apr;43(4):1003-17.
doi: 10.1183/09031936.00147612. Epub 2013 Jul 30.

APOM and high-density lipoprotein cholesterol are associated with lung function and per cent emphysema

Kristin M Burkart  1 , Ani Manichaikul, Jemma B Wilk, Firas S Ahmed, Gregory L Burke, Paul Enright, Nadia N Hansel, Demondes Haynes, Susan R Heckbert, Eric A Hoffman, Joel D Kaufman, Jun Kurai, Laura Loehr, Stephanie J London, Yang Meng, George T O'Connor, Elizabeth Oelsner, Marcy Petrini, Tess D Pottinger, Charles A Powell, Susan Redline, Jerome I Rotter, Lewis J Smith, María Soler Artigas, Martin D Tobin, Michael Y Tsai, Karol Watson, Wendy White, Taylor R Young, Stephen S Rich, R Graham Barr
Affiliations
Meta-Analysis

APOM and high-density lipoprotein cholesterol are associated with lung function and per cent emphysema

Kristin M Burkart et al. Eur Respir J. 2014 Apr.

Abstract

Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD. We assessed the association of lung function with 2100 genes selected for cardiovascular diseases among 20 077 European-Americans and 6900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with per cent emphysema and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio and per cent emphysema. We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10(-6)) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10(-7)). Both single-nucleotide polymorphisms (SNPs) flank the gene for apolipoprotein M (APOM), a component of high-density lipoprotein (HDL) cholesterol. Both were replicated in an independent cohort. SNPs in a second gene related to apolipoprotein M and HDL, PCSK9, were associated with FEV1/FVC ratio among African-Americans. rs707974 was associated with per cent emphysema among European-Americans and African-Americans and APOM expression was related to FEV1/FVC ratio and per cent emphysema. Higher HDL levels were associated with lower FEV1/FVC ratio and greater per cent emphysema. These findings suggest a novel role for the apolipoprotein M/HDL pathway in the pathogenesis of COPD and emphysema.

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Figures

Figure 1
Figure 1
Manhattan Plots of association results for FEV1/FVC stratified by race and combined. Manhattan Plots ordered by chromosome position of association results for FEV1/FVC. Top 3 loci are labeled with arrows. (A) Meta-analysis of 38,294 SNPs among 20,077 European-American participants. The solid black line represents 1 × 10−6. (B) Meta-analysis of 44,416 SNPs among 6,900 African-American participants. The solid black line represents 1 × 10−6. (C) Meta-analysis of SNPs among combined European-American & African-American participants. The solid black line represents 1 × 10−6. Abbreviations: FEV1/FVC = ratio of forced expiratory volume in one second over forced vital capacity.
Figure 2
Figure 2
Regional Association Plots of top SNPs flanking APOM (rs805301, rs707974) and PCSK9 SNPs for FEV1/FVC The selected SNPs with the lowest p value are illustrated by the purple diamond. The correlations (r2) of surrounding SNPs in the region are indicated by the colors shown on the graph. For the SNPs flanking APOM(rs805301 and rs707974), a 600kb flanking size was selected to include the AGER SNP on the plot whereas 500kb flanking size was selected for the PCSK9 SNP. Plots were generated using LocusZoom.[97] The Genome builds/LD populations implemented were hg 18/HapMap Phase II CEU and hg/19 1000 Genomes Nov 2010 AFR for European-American and for African-American participants, respectively. Abbreviations: SNPs = single nucleotide polymorphisms, APOM = apolipoprotein M, PCSK9 = proprotein convertase subtilisin/kexin type 9, FEV1/FVC = ratio of forced expiratory volume in one second over forced vital capacity.
Figure 3
Figure 3
Multivariate association between HDL and percent emphysema Results of multivariate analyses of the relationship between percent emphysema and plasma HDL among 8,367 MESA SHARe participants are shown. The solid line indicates smoothed regression line adjusted for age, sex, race/ethnicity, height, weight, educational attainment, scanner, tube current, total cholesterol, exercise, pack-years, cigarettes per day, alcohol use, inhaled steroids and use of statins. Figure and p value was produced using a loess smoothing function in a generalized additive model in R/GAM (R version 2.13.0).Dashed lines indicated 95% confidence intervals.
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