Association of the rs4567312 variant in the leptin receptor gene with plasma leptin concentrations and lung cancer incidence in the PREDIMED study

Abstract

Background: Many studies have found leptin related genes involved in tumorigenesis and have suggested it may play a role in the pathogenesis of lung cancer. Leptin Receptor (LEPR) is expressed in many tissues and cells, including lung mucosal cells. LEPR was reported to be associated with tumor cell proliferation and angiogenesis. Our objective has been to estimate the association between the rs4567312‐LEPR gene and lung cancer incidence in a Mediterranean population. Methods: We analyzed 1094 participants (398 men, 696 women) recruited in the PREDIMED‐Valencia Study. Participants were high cardiovascular risk subjects aged 67±6 years at baseline. PREDIMED is a multicenter randomized, controlled trial aimed at assessing the effect of theMediterranean diet (MedDiet) on cardiovascular prevention (primary outcome). Cancer incidence was a secondary outcome in this trial. Demographic, clinical, life‐style, biochemical, and genetic variables were obtained. Subjects were followed‐up prospectively from2003 to 2014 (in the extended‐follow‐up). Results: We detected 12 new cases of lung cancer from 2003 to 2014 (1.1% cumulative incidence). Tobacco smoking was strongly associated with lung cancer incidence (91.7% of current or former smokers in lung cancer subjects vs 41.5% in the noncancer participants (p=0.001). In the whole population, prevalence of the rs4567312 polymorphism was: 95.5% CC, 4.4% CT and 0.1% TT. We also detected in the whole population an association between this polymorphism and plasma leptin concentrations, 26.9±22.9 ng/mL in CC vs 18.4±16.7 ng/mL in T carriers (p=0.013). We found a strong association between the rs4567312‐LEPR polymorphism and lung cancer risk, being higher in carriers of the T‐allele. This association remained statistically significant (OR=7.61; 95% CI: 1.74‐33.37 for T‐carriers vs CC) even after adjustment for gender, age, tobacco smoking, dietary intervention group (MedDiet vs control diet) and leptin levels. Conclusions: T‐carriers allele in the rs4567312‐LEPR polymorphism presented a higher incidence of lung cancer in this Mediterranean population even after adjustment for tobacco smoking and dietary intervention.