FAM13A locus in COPD is independently associated with lung cancer – evidence of a molecular genetic link between COPD and lung cancer

Abstract

Recent genome-wide association studies have reported a FAM13A variant on chromosome 4q22.1 is associated with lung function and COPD. We examined this variant in a case-control study of current or former smokers with chronic obstructive pulmonary disease (COPD, n = 458), lung cancer (n = 454), or normal lung function (n = 488). Sex, age, and smoking history were comparable between groups. We confirmed the FAM13A variant (rs7671167) confers a protective effect on smoking-related COPD alone (C allele odds ratio [OR] = 0.79, P = 0.013, and CC genotype OR = 0.71, P = 0.024) and those with COPD, both with and without lung cancer (C allele OR = 0.80, P = 0.008, and CC genotype OR = 0.70, P = 0.007). The FAM13A variant also confers a protective effect on lung cancer overall (C allele OR = 0.75, P = 0.002, and CC genotype OR = 0.64, P = 0.003) even after excluding those with co-existing COPD (C allele OR = 0.67, P = 0.0007, and CC genotype OR = 0.58, P = 0.006). This was independent of age, sex, height, lung function, and smoking history. This protective effect was confined to those with nonsmall cell lung cancer (C allele OR = 0.72, P = 0.0009, and CC genotype OR = 0.61, P = 0.003). This study suggests that genetic predisposition to COPD is shared with lung cancer through shared pathogenetic factors such as the 4q22.1 locus implicating the Rho-kinase pathway.

Genetic Predisposition to Chronic Obstructive Pulmonary Disease and/or Lung Cancer: Important Considerations When Evaluating Risk

“…A variant in the FAM13A gene on 4q22 (associated with lung function; ref. 25) is similarly linked to a reduced risk of COPD and lung cancer (35). It is interesting that extending the lung cancer risk models by addition of the top single-nucleotide polymorphism (SNP; P < 10 À7 ) identified through GWAS has not necessarily further improved the discriminatory power of models compared with their epidemiology-based counterparts because these top SNPs confer only small to modest degrees of risk for disease, even though each individual SNP has genomewide significance (36).…”

“…Similarly, healthy or resistant smokers (controls) for COPD studies can only be reliably identified by spirometry. Comparing COPD smokers with healthy/ resistant control smokers is critical for identifying protective genetic effects (34,35).…”

Role of mtDNA haplogroups in COPD susceptibility in a southwestern Han Chinese population

“…Cigarette smoking, air pollution, and environmental and occupational toxins are the most common environmental risk factors for the development of lung cancer and COPD. Epidemiological findings demonstrated that the presence of COPD and airflow obstruction increases the risk of developing lung cancer, even in individuals who have never smoked [55][56][57][58][59][60]. COPD-induced Del, deletion.…”

Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects

“…In addition, the effect of several recognized risk alleles on lung function or risk of COPD, particularly in cohorts of severely affected subjects, has not been well studied. Meta-analysis of genetic associations across multiple cohorts has the advantage of improving power to detect additional susceptibility risk variants by combining information across studies, which may add to our understanding of disease mechanisms (14), as well as providing potential new targets for COPD therapy development (15,16).…”