Replication of FTO rs9939609 variant with adiposity, insulin resistance, and insulin-resistance related malignancy in the Maltese population

Abstract

Background: Several studies have investigated the association between the common FTO variant rs9939609, insulin resistance (IR), Type 2 diabetes (T2D) and postmenopausal breast /endometrial cancer. Although studies often describe conflicting results several FTO variants, including rs9939609, have been associated with higher odds of T2D, IR and various forms of malignancy. This study aims to replicate the association between FTO rs9939609, BMI and related adiposity phenotypes in a high prevalence Mediterranean island population. The study also aims to explore the relationship between FTO genotypes and clinical outcomes related to excess adiposity. These include T2D and post-menopausal endometrial and breast cancer. Methods: This study was conducted using a total of 1106 adult Maltese individuals, all of which were genotyped for the FTO rs9939609 variant using multiplex Tetra Primer Amplification Refractory Mutation System (ARMS) PCR. The genotype-phenotype associations were than investigated using statistical modelling. Results: Several significant genotype-phenotype associations were detected. The results show an association between the A allele and waist circumference, BMI, IR, FBG and HbA1c. This study also shows that the rs9939609 variant increases odds of T2D. Individuals harbouring the AA and AT genotypes show an increased BMI of 2.7 kg/m2 and 1.1 kg/m2 respectively, when compared to the TT genotype. A 2.6 cm increase in WC amongst AA genotyped individuals can also be noted when compared to TT genotype carriers. No direct association between FTO rs9939609 and postmenopausal breast and endometrial cancer was detected. The results obtained however suggest that the rs9939609 variant may be indirectly associated with breast and endometrial carcinogenesis through BMI, since the cancer sub cohort shows a significantly higher BMI when compared to healthy individuals. Conclusions: Although further studies that take into consideration environmental and early life factors are required, our results suggest that FTO rs9939609 is directly associated with adiposity and IR.