Susceptibility loci in lung cancer and COPD: association of IREB2 and FAM13A with pulmonary diseases

Abstract

Genome-wide association studies have identified loci at 15q25 (IREB2) and 4q22 (FAM13A), associated with lung cancer (LC) and chronic obstructive pulmonary disease (COPD). The aim of our research was to determine the association of IREB2 and FAM13A SNPs with LC and severe/very severe COPD patients. We examined IREB2 variants (rs2568494, rs2656069, rs10851906, rs13180) and FAM13A (rs1903003, rs7671167, rs2869967) among 1.141 participants (468 LC, 149 COPD, 524 smoking controls). The frequency of the minor IREB2 rs2568494 AA genotype, was higher in LC vs controls (P = 0.0081, OR = 1.682). The FAM13A rs2869967 was associated with COPD (minor CC genotype: P = 0.0007, OR = 2.414). The rs1903003, rs7671167 FAM13A variants confer a protective effect on COPD (both P < 0.002, OR < 0.405). Haplotype-based tests identified an association of the IREB2 AAAT haplotype with LC (P = 0.0021, OR = 1.513) and FAM13A TTC with COPD (P = 0.0013, OR = 1.822). Cumulative genetic risk score analyses (CGRS), derived by adding risk alleles, revealed that the risk for COPD increased with the growing number of the FAM13A risk alleles. OR (95% CI) for carriers of ≥5 risk alleles reached 2.998 (1.8 to 4.97) compared to the controls. This study confirms that the IREB2 variants contribute to an increased risk of LC, whereas FAM13A predisposes to increased susceptibility to COPD.

‘WNT-er is coming’: WNT signalling in chronic lung diseases

“… 110–112 family with sequence similarity 13 member A ( FAM13A ) was identified in a GWAS as a gene that predisposes to increased susceptibility to COPD. 113 114 A subsequent study investigated the functional role of FAM13A in COPD pathogenesis and demonstrated that FAM13A induces emphysema by targeting canonical WNT signalling. 111 Increased expression of FAM13A was observed in several cell types in the lungs of patients with COPD and FAM13A-deficient mice (FAM13A −/− ) were protected against cigarette smoke-induced as well as elastase-induced emphysema development.…”

The “Iron”-y of Iron Overload and Iron Deficiency in Chronic Obstructive Pulmonary Disease

“…IRP2 is associated with COPD susceptibility (5)(6)(7)(8)(9) and with pulmonary artery enlargement in COPD (70). This association may be sex specific (8,71) and independent of smoking (72,73), and it may also associate with severe alpha-1 antitrypsin (AAT) deficiency (71) and lung cancer (74,75). IRP2 is located within a cluster of genes on chromosome 15q25, which includes several components of the nicotinic acetylcholine receptor.…”

Chronic Obstructive Pulmonary Disease and Lung Cancer: Underlying Pathophysiology and New Therapeutic Modalities

“…Single nucleotide polymorphisms of other genes such as FAM13A (at 4q24) that encode for a RhoGTPase-activating protein binding domain have been associated with both COPD and lung cancer [203]. Although their functional contribution to lung cancer and/or COPD remains yet to be elucidated, the involvement of Rho GTPases in the pulmonary endothelial barrier in lung suggests a potential mode of involvement for FAM13A [204]. Direct effects of nicotine have also been reported on endothelial and fibroblast cell populations.…”