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Open Access 01-12-2017 | Research

Genome-wide association study of subclinical interstitial lung disease in MESA

Authors: Ani Manichaikul, Xin-Qun Wang, Li Sun, Josée Dupuis, Alain C. Borczuk, Jennifer N. Nguyen, Ganesh Raghu, Eric A. Hoffman, Suna Onengut-Gumuscu, Emily A. Farber, Joel D. Kaufman, Dan Rabinowitz, Karen D. Hinckley Stukovsky, Steven M. Kawut, Gary M. Hunninghake, George R. Washko, George T. O’Connor, Stephen S. Rich, R. Graham Barr, David J. Lederer

Published in: Respiratory Research | Issue 1/2017

Abstract

Background

We conducted a genome-wide association study (GWAS) of subclinical interstitial lung disease (ILD), defined as high attenuation areas (HAA) on CT, in the population-based Multi-Ethnic Study of Atherosclerosis Study.

Methods

We measured the percentage of high attenuation areas (HAA) in the lung fields on cardiac CT scan defined as voxels with CT attenuation values between -600 and -250 HU. Genetic analyses were performed in MESA combined across race/ethnic groups: non-Hispanic White (n = 2,434), African American (n = 2,470), Hispanic (n = 2,065) and Chinese (n = 702), as well as stratified by race/ethnicity.

Results

Among 7,671 participants, regions at genome-wide significance were identified for basilar peel-core ratio of HAA in FLJ35282 downstream of ANRIL (rs7852363, P = 2.1x10⁻⁹) and within introns of SNAI3-AS1 (rs140142658, P = 9.6x10⁻⁹) and D21S2088E (rs3079677, P = 2.3x10⁻⁸). Within race/ethnic groups, 18 additional loci were identified at genome-wide significance, including genes related to development (FOXP4), cell adhesion (ALCAM) and glycosylation (GNPDA2, GYPC, GFPT1 and FUT10). Among these loci, SNP rs6844387 near GNPDA2 demonstrated nominal evidence of replication in analysis of n = 1,959 participants from the Framingham Heart Study (P = 0.029). FOXP4 region SNP rs2894439 demonstrated evidence of validation in analysis of n = 228 White ILD cases from the Columbia ILD Study compared to race/ethnicity-matched controls from MESA (one-sided P = 0.007). In lung tissue from 15 adults with idiopathic pulmonary fibrosis compared to 15 adults without lung disease. ANRIL (P = 0.001), ALCAM (P = 0.03) and FOXP4 (P = 0.046) were differentially expressed.

Conclusions

Our results suggest novel roles for protein glycosylation and cell cycle disinhibition by long non-coding RNA in the pathogenesis of ILD.

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Title: Genome-wide association study of subclinical interstitial lung disease in MESA
Authors: Ani Manichaikul
Xin-Qun Wang
Li Sun
Josée Dupuis
Alain C. Borczuk
Jennifer N. Nguyen
Ganesh Raghu
Eric A. Hoffman
Suna Onengut-Gumuscu
Emily A. Farber
Joel D. Kaufman
Dan Rabinowitz
Karen D. Hinckley Stukovsky
Steven M. Kawut
Gary M. Hunninghake
George R. Washko
George T. O’Connor
Stephen S. Rich
R. Graham Barr
David J. Lederer
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Respiratory Research / Issue 1/2017
Electronic ISSN: 1465-993X
DOI: https://doi.org/10.1186/s12931-017-0581-2

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Genome-wide association study of subclinical interstitial lung disease in MESA

Abstract

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Methods

Results

Conclusions

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Abstract

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