We performed a genome-wide association study in non-Hispanic white subjects with

We performed a genome-wide association study in non-Hispanic white subjects with fibrotic idiopathic interstitial pneumonias (N=1616) and controls (N=4683); replication was assessed in 876 cases and 1890 controls. defense cell-cell adhesion and DNA repair contribute to the risk of fibrotic IIP. Rabbit Polyclonal to SLC25A12. The idiopathic interstitial pneumonias (IIPs) represent a group of lung diseases commonly characterized by pulmonary fibrosis or progressive scarring of the alveolar interstitium which can lead to significant morbidity and mortality due to hypoxemic respiratory insufficiency NVP-LAQ824 1. While some forms of pulmonary fibrosis are associated with known environmental exposures (e.g. asbestos) drug toxicity 2 radiation exposure or collagen vascular diseases (e.g. scleroderma) the IIPs have no known etiology. The most common and severe IIP is NVP-LAQ824 usually idiopathic pulmonary fibrosis (IPF) 1 which has a median survival of 2-3 years after diagnosis. There are no IPF pharmacologic therapies approved for use in the United States and lung transplantation is the only intervention known to prolong life 3. Although all IIPs have a variable clinical course they often progress to end-stage lung disease and death. While it appears that risk of IIP is likely determined by multiple genetic variants and environmental toxins the specific causes of IIP are only beginning to emerge. The evidence for a genetic component to the risk of NVP-LAQ824 IIP is usually substantial and includes familial clustering of disease the occurrence of pulmonary fibrosis as part of systemic genetic syndromes considerable variability in the risk of pulmonary fibrosis among those with comparable exposures to known environmental brokers such as asbestos and identification of genetic risk loci in IIP. Rare mutations in the genes have been associated with familial interstitial pneumonia (FIP; defined as 2 or more family members with IIP) and IPF 4-9 and a common polymorphism in has been associated with IPF 10. Recently we have identified a promoter variant in the gene (rs35705950) that is present in approximately 50-60% of individuals with FIP or IPF and is estimated to increase risk 6-fold for heterozygotes and 20-fold for homozygotes 11. The identification of as a common risk factor has altered our view of the pathogenesis of pulmonary fibrosis from focusing primarily on alveolar epithelial cells and lung matrix to inclusion of mucus-producing cells in the distal airways of the lung 11 12 However the variant is usually observed in ~19% of unaffected individuals and approximately one third of individuals with IIP do not have any identifiable genetic risk factors for this disease suggesting that other genetic variants contribute to disease risk NVP-LAQ824 alone or in combination with the variant. With the goal of identifying additional genetic risk factors that collectively further our understanding of IIP we have completed a case-control genome-wide association study (GWAS; 1616 cases and 4683 controls) and replication study (876 cases and 1890 controls) of IIP. We included all types of fibrotic IIP in our case group since: a) distinguishing among the IIP diagnoses is NVP-LAQ824 usually often problematic due to substantial clinical pathological and radiological overlap; and b) there is strong evidence for shared genetic susceptibility; over 40% of families with FIP have more than one type of IIP among the affected family members 13. We also included both familial and sporadic IIPs since the variants provide suggestive evidence that sporadic IIP is usually genetically similar to the familial form of this disease. We hypothesized that IIPs are caused by multiple genetic variants acting independently or in combination and that the same genetic variants can lead to different histologic types of IIP. Results Genome-wide Discovery We genotyped 1914 self-reported non-Hispanic white fibrotic IIP cases around the Illumina 660 Quad beadchip. Of those 298 were excluded based on being a genetic outlier (N=14) evidence for being a first degree relative of another case (N=126) high heterozygosity (N=8) or missing >2% of genotypes across all SNPs (N=150 see Statistical Methods); 1616 cases were included in analyses (Supplementary Tables 1-3). Among 15 352 out-of study controls without phenotypic information also genotyped around the Illumina 660 Quad beadchip in the same laboratory we selected 4 683 controls most genetically comparable to our cases based on genome-wide identity-by-state comparisons who met the same quality control criteria as cases (see Online Methods and Supplementary Table.