- Title
- Genetic and non-genetic studies of type 2 diabetes in three susceptible Asian populations: Malay, Chinese and Indian
- Creator
- Abdullah, Noraidatulakma
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2018
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Both genetic and non-genetic factors have been reported to contribute to the pathogenesis of type 2 diabetes. Although numerous epidemiological studies have been conducted in various populations, the Malaysian society remains relatively understudied to date, despite having a relatively high prevalence of type 2 diabetes among Asian countries. Within Malaysia, the type 2 diabetes prevalence also differs between major ethnic groups, being highest in Indian, intermediate in Malays and lowest in Chinese. To better understand the relative contributions of genetic and non-genetic risk factors to type 2 diabetes in Malaysia, this study conducted epidemiological studies of type 2 diabetes in Malaysian participants of Malay, Chinese and Indian ethnicity from The Malaysian Cohort project. Samples from 1,604 Malays, 1,654 Chinese and 1,728 Indians were included in genetic analyses, which used genotyped data obtained from the Metabochip array. A total of 62 individual candidate single nucleotide polymorphisms (SNPs) previously associated with type 2 diabetes were assessed, individually and in the form of a genetic risk score aggregating information across all polymorphisms. Utilising the same samples, the effects of environmental (non-genetic, or lifestyle) risk factors were also assessed. Finally, we assessed the evidence for effect modification of environmental effects by genetic alleles (gene by environment). After Bonferroni correction for multiple testing, seven (7) individual SNPs showed association with type 2 diabetes in analyses of the combined Malaysian sample, adjusted for ancestry. An additional 10 SNPs showed nominal association (p<0.05 before adjustment for multiplicity). The genetic risk score showed strong association with type 2 diabetes in the individual ancestral groups (p-values ranging from 4.71x10-6 to 1.35x10-8), and the combined group (p=2.2x10-16). However, the genetic risk score explained only 1.0 to 1.7% of total risk variance. In contrast, four non-genetic risk factors, age, gender, waist-to-hip ratio and physical inactivity, accounted for about 20% of total type 2 diabetes risk variation in the Malaysian samples. The effect of increasing waist-to-hip ratio was higher in Chinese than Indian or Malay participants, suggesting anthropometric risk differences between groups. Incorporating the genetic risk score into statistical models including the environmental factors only explained an additional 1 to 2% of risk variation in each group. We found some evidence for gene by environment effect modification, with the genetic risk score showing a gradient of decreasing effect sizes across increasing strata of body mass index. While formal tests of interaction were non-significant, this is consistent with previous evidence and suggests genetic risk factors may have a larger contribution to disease pathogenesis in leaner type 2 diabetes cases. Taken together, these studies suggest that environmental, rather than genetic risk factors are the major contributors to the epidemic of type 2 diabetes in Malaysia. Our findings have some public health significance in relation to mitigating type 2 diabetes risk in Malaysia. First, these findings may inform targeted interventions focussing on abdominal obesity in the Malaysian population, especially in Chinese Malaysians. Second, these results suggest a need for the development of ethnicity-specific anthropometric cut-points, to accurately assess associations across ancestral groups with different body fat distributions. Third, these findings suggest a relatively greater contribution of genetic factors to disease among genetically predisposed lean individuals, which may have implications for personalised medicine. Future studies in larger samples could similarly investigate these findings, to further clarify the respective roles of genetic and environmental risk factors to disease, and inform personalised interventions.
- Subject
- type 2 diabetes; Malaysia; multiethnic Asian study; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1385105
- Identifier
- uon:32165
- Rights
- Copyright 2018 Noraidatulakma Abdullah
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 5 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 272 KB | Adobe Acrobat PDF | View Details Download |