Genetic susceptibility to type 2 diabetes/obesity, and the role of UCP2, UCP3 and CAPN10
The global prevalence of type 2 diabetes (T2DM) and obesity is increasing, with obesity the
most important predisposing factor contributing to the development of T2DM.
Epidemiological and genetic evidence supports a major genetic component in both
multifactorial and heterogeneous disorders. The identification of disease susceptibility genes
in humans could greatly assist in the elucidation of underlying pathophysiological
mechanisms and allow the development of more effective preventative and therapeutic
strategies for these conditions.
Three candidate genes, uncoupling proteins 2 and 3 (UCP2; UCP3) and calpain 10
(CAPN10), are proposed and the rationale for their selection discussed. Gene variants were
identified in UCP2 and UCP3. These variants were tested for association with T2DM,
obesity and intermediate quantitative traits in a South Indian population and family
collection, and also a cohort of British obese case/control subjects. No variant was
associated with T2DM. However, investigations revealed positive associations with a UCP2
3'UTR 45bp Ins/Del and a novel UCP3 promoter variant (-55C/T) with variation in body
mass (BMI) and fat distribution (WHR) respectively. The results support the view that
uncoupling proteins may influence weight gain and hence progression to obesity/T2DM. A
significant correlation with plasma leptin levels and the UCP2 Ins/Del variant might indicate
one potential mechanism whereby weight could be modulated by uncoupling proteins.
A linkage study in affected sibling pairs of North European descent, was negative for the
putative T2DM susceptibility gene region, NIDDMI. In contrast, haplotypes of four
sequence variants of a T2DM susceptibility gene (CAPN10) identified in this region
positively associated with T2DM in a South Indian population.
In conclusion, these investigations provide evidence that the three genes studied may
contribute to susceptibility for development of T2DM or obesity. However, the findings are
in agreement with the most likely genetic model for non-Mendelian complex diseases, that
many genes are involved in determining susceptibility to disease with no single gene
capable of determining the overall disease phenotype.