Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controls

Abstract

Recent evidence suggests that inflammation plays a pivotal role in the development of lung cancer. In this study, we used a two-stage approach to investigate associations between genetic variants in inflammation pathways and lung cancer risk based on genome-wide association study (GWAS) data. A total of 7,650 sequence variants from 720 genes relevant to inflammation pathways were identified using keyword and pathway searches from Gene Cards and Gene Ontology databases. In Stage 1, six GWAS datasets from the International Lung Cancer Consortium were pooled (4,441 cases and 5,094 controls of European ancestry), and a hierarchical modeling (HM) approach was used to incorporate prior information for each of the variants into the analysis. The prior matrix was constructed using (1) role of genes in the inflammation and immune pathways; (2) physical properties of the variants including the location of the variants, their conservation scores and amino acid coding; (3) LD with other functional variants and (4) measures of heterogeneity across the studies. HM affected the priority ranking of variants particularly among those having low prior weights, imprecise estimates and/or heterogeneity across studies. In Stage 2, we used an independent NCI lung cancer GWAS study (5,699 cases and 5,818 controls) for in silico replication. We identified one novel variant at the level corrected for multiple comparisons (rs2741354 in EPHX2 at 8q21.1 with p value = 7.4 × 10−6), and confirmed the associations between TERT (rs2736100) and the HLA region and lung cancer risk. HM allows for prior knowledge such as from bioinformatic sources to be incorporated into the analysis systematically, and it represents a complementary analytical approach to the conventional GWAS analysis.

TERT Genetic Polymorphism rs2736100 Was Associated with Lung Cancer: A Meta-Analysis Based on 14,492 Subjects

“…This polymorphism has also been linked to idiopathic pulmonary fibrosis, a disease associated with increased risk of developing lung cancer (Wang et al, 2009). It is also the most studied polymorphism of the TERT gene, as it was described in several previous studies (Chen et al, 2010(Chen et al, , 2012Miki et al, 2010;Wang et al, 2010;Bae et al, 2012;Brenner et al, 2013;Myneni et al, 2103). This polymorphism was reported associated not only with lung cancer (Chen et al, 2010(Chen et al, , 2012Miki et al, 2010;Wang et al, 2010;Bae et al, 2012;Brenner et al, 2013;Myneni et al, 2103), but also with other types of cancer (Wang et al, 2003;Carpentier et al, 2007;Hunter et al, 2007;Sagoo et al, 2009;Savage et al, 2007;Yeager et al, 2007).…”

“…Recently, a number of case-control studies have suggested that rs2736100 in the TERK gene is associated with the risk of lung cancer (Chen et al, 2010(Chen et al, , 2012Miki et al, 2010;Wang et al, 2010;Bae et al, 2012;Brenner et al, 2013;Myneni et al, 2103). The telomerase reverse transcriptase (TERT) gene is located on chromosome 5 (locus 5p15.33) and synthesizes the TTAGGG DNA sequences onto the ends of chromosomes in cooperation with other proteins of the core telomerase complex (e.g., telomerase RNA component [TERC] and dyskerin [DKC1]).…”

Co-occurrence of Myeloproliferative Neoplasms and Solid Tumors Is Attributed to a Synergism Between Cytoreductive Therapy and the Common TERT Polymorphism rs2736100

“…Associations with cancers affecting skin (20), lung (21)(22)(23), colon (24), prostate (25), breast (26), testicle (27), bladder (28), and brain (29) were reported. Predisposition to hematologic malignancies such as acute lymphoid leukemia (18), and chronic lymphoid leukemia (30,31), and recently MPN (4-6) were also linked to the TERT locus.…”

A hierarchical modeling approach for assessing the safety of exposure to complex antiretroviral drug regimens during pregnancy

“…15–17 It has been used in areas such as nutrition, occupational health, and genetics. 15,17–26 Hierarchical models have also previously been used in evaluating outcomes among HIV-infected adults, but have not been utilized in the context of addressing safety of ARV use during pregnancy. 27–29 …”