Obesity and type 2 diabetes susceptibility genes identified from recent genome-wide association studies: impact on Southern Chinese

Abstract

Background and objectives:

Recent genome-wide association (GWA) studies conducted in Caucasian

populations have significantly expanded the list of confirmed and potential

susceptibility genes for obesity and type 2 diabetes.

The major objective of this thesis was to establish the role of the previously

identified obesity- and T2DM-susceptibility genes in the Hong Kong Southern Chinese

population.

Major findings:

In a cross-sectional case-control study of Southern Chinese which involved 470

obese cases and 700 normal-weight controls, significant associations with obesity were

demonstrated in 7 of 13 single nucleotide polymorphisms (SNPs) that have shown

significant associations with obesity and/or body mass index (BMI) in previous

Caucasian GWA studies. These SNPs are located within or near the GNPDA2, FTO,

MC4R, KCTD15, SFRS10-ETV5-DGKG, SEC16B-RASAL2 and NEGR1 loci. The

combined genetic risk score (GRS) of the 13 studied SNPs was associated with an

increased risk for obesity.

The GNPDA2 rs10938397, FTO rs8050136, and MC4R rs17782313, which showed

the most significant associations with obesity, were further examined for their

associations with persistent central obesity and the metabolic syndrome (MetS). Both

rs8050136 and rs10938397 were significantly associated with persistent central obesity.

rs10938397 was also associated with the MetS. The combined GRS of these 3 SNPs

showed significant associations with both persistent central obesity and persistent MetS.

Nineteen multimarker-tagging SNPs that span a well-defined LD block of the FTO

gene were evaluated for their associations with obesity in a case-control study which

involved 249 cases and 400 controls. rs16952522 was found to be significantly

associated with obesity, in addition to the well-known SNP rs8050136. These 2 SNPs

were nominally associated with T2DM, although the associations were abolished after

adjustment for age, sex and BMI. However, the GA haplotype composed of the risk

alleles of these 2 SNPs was significantly associated with T2DM, independent of BMI.

Seventeen previously identified T2DM-associated SNPs were investigated for the

associations with glycaemic progression in an 8-year follow-up study which involved

518 cases and 998 controls. Their combined GRS was associated with an increased risk

for glycaemic progression. A significant association with glycaemic progression was

found with CDKN2A/B rs10811661. Moreover, KCNJ11 rs5219 and IGF2BP2

rs11711477 also showed potential associations with glycaemic progression. In the

subsequent 12-year follow-up study, which involved 200 cases and 903 controls, the

CDKN2A/B rs10811661 showed a significant independent association with incident

T2DM.

The KCNJ11 E23K (rs5219) variant was examined for its association with diabetes

development in a 12-year prospective study. It was found to be significantly associated

with the development of prediabetes but not with the development of T2DM. However,

in a meta-analysis which involved 15680 subjects across different populations, this

variant could indeed predict T2DM.

Conclusions:

The findings of this thesis have provided novel evidence supporting the role of the

GWA studies-identified obesity- and T2DM-associated genetic variants as genetic

markers of obesity and T2DM among Southern Chinese in Hong Kong, and suggest that

the GNPDA2, FTO and MC4R genes confer susceptibility to obesity and that the

CDKN2A/B and KCNJ11 genes may play a role in diabetes development.