2 research outputs found
Overlap of genetic risk between interstitial lung abnormalities and idiopathic pulmonary fibrosis
Rationale
Interstitial lung abnormalities (ILA) are associated with the highest genetic risk locus for IPF;
however, the extent to which there is additional overlap with IPF, or unique associations among
those with ILA is not known.
Objectives
To perform a genome-wide association study (GWAS) of ILA.
Methods: ILA and the subpleural-predominant subtype were assessed on chest computed
tomography (CT) scans in the AGES, COPDGene, Framingham Heart, ECLIPSE, MESA, and
SPIROMICS studies. We performed a GWAS of ILA in each cohort and combined the results
using a meta-analysis. We assessed for overlapping associations in independent GWASs of
IPF.
Measurements and Main Results
Genome-wide genotyping data were available in 1,699 ILA cases and 10,274 controls. The
MUC5B promoter variant rs35705950 was significantly associated with both ILA (p=2.6x10-27)
and subpleural ILA (p=1.6x10-29). We discovered novel genome-wide associations near IPO11
(rs6886640, p=3.8x10-8
) and FCF1P3 (rs73199442, p=4.8x10-8
) with ILA, and HTRE1
(rs7744971, p=4.2x10-8
) with subpleural-predominant ILA. These novel associations were not
associated with IPF. Of 12 previously reported IPF GWAS loci, 5 (DPP9, DSP, FAM13A, IVD,
and MUC5B) were significantly associated (p<0.05/12) with ILA.
Conclusions
In a GWAS of ILA in six studies, we confirmed the association with a MUC5B promoter variant
and found strong evidence for an effect of previously described IPF loci; however, novel ILA
associations were not associated with IPF. These findings highlight common and suggest
distinct genetically-driven biologic pathways between ILA and IPF
Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.
Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects