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. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/174519 |
| Date | January 2011 |
| Creators | Cheung, Yu-yan, Chloe., 張語殷. |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Source | http://hub.hku.hk/bib/B47849617 |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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