Genome-wide Association Study of Subclinical Interstitial Lung Disease in MESA

Overview

Journal Respir Res

Specialty Pulmonary Medicine

Date 2017 May 20

PMID 28521775

Citations 18

Authors

Ani Manichaikul

Xin-Qun Wang

Li Sun

Josee 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 OConnor

Stephen S Rich

R Graham Barr

David J Lederer

Affiliations

Soon will be listed here.

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) and within introns of SNAI3-AS1 (rs140142658, P = 9.6x10) and D21S2088E (rs3079677, P = 2.3x10). 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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