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Title: The interplay between genes and dietary factors in the aetiology of Type 2 Diabetes Mellitus
Author: Li, Sherly (Xueyi)
ISNI:       0000 0004 7228 7354
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2018
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To help mitigate the escalating prevalence of Type 2 Diabetes (T2D) and alleviate society of its associated morbidity and economic burden on health care, it is crucial to understand its aetiology. Both genetic and the environmental risk factors are known to be involved. Healthy diets have been proven to reduce the risk of T2D in primary prevention trials, however, which components and exact mechanisms are involved is not fully understood, in particular, the role of macronutrient intake. Body weight, glycaemic markers and T2D are all to some extent genetically regulated. There may also be genetic influences on how people digest, absorb or metabolise macronutrients. This poses the possibility that the interplay between genes and our diet may help us unravel T2D’s aetiology. The aim of this PhD was to investigate gene-diet interactions on the risk of incident T2D, focusing primarily on macronutrient intake as the dietary factor. First, I systematically evaluated the current evidence before taking a step-wise approach (hypothesis driven to hypothesis-free) to interrogate gene-macronutrient interactions. This identified 13 publications, with 8 unique interactions reported between macronutrients (carbohydrate, fat, saturated fat, dietary fibre, and glycaemic load derived from self-report of dietary intake and circulating n-3 polyunsaturated fatty acids) and genetic variants in or near TCF7L2, GIPR, CAV2 and PEPD (p < 0.05) on T2D. All studies were observational with moderate to serious risk of bias and limitations that included lack of adequate adjustment for confounders, lack of reported replication and insufficient correction for multiple testing. Second, these reported interactions did not replicate in a large European multi-centre prospective T2D case-cohort study called EPIC-InterAct. We concluded that the heterogeneity between our results and those published could be explained by methodological differences in dietary measurement, population under study, study design and analysis but also by the possibility of spurious interactions. Third, given the paucity of gene-macronutrient interaction research using genetic risk scores (GRS), we examined the interaction between three GRS (for BMI (97 SNPs), insulin resistance (53 SNPs) and T2D (48 SNPs)) and macronutrient intake (quantity and quality indicators) in EPIC-InterAct. We did not identify any statistically significant interactions that passed multiple testing corrections (p≥0.20, with a p value threshold for rejecting the null hypothesis of 0.0015 (based on 0.05/33 tests)). We also examined 15 foods and beverages identified as being associated with T2D, and no significant interactions were detected. Lastly, we applied a hypothesis-free method to examine gene-macronutrient interactions and T2D risk by using a genome-environment-wide-interaction-study. Preliminary findings showed no significant interactions for total carbohydrate, protein, saturated fat, polyunsaturated fat and cereal fibre intake on T2D. In conclusion, the consistently null findings in this thesis using a range of statistical approaches to examine interactions between genetic variants and macronutrient intake on the risk of developing T2D have two key implications. One, based on the specific interactions examined, this research does not confirm evidence for gene-diet interactions in the aetiology of T2D and two, this research suggests that the association between macronutrient intake and the risk of developing T2D does not differ by genotype.
Supervisor: Forouhi, Nita ; Wareham, Nick ; Scott, Robert Sponsor: Commonwealth Scholarship Commission ; Cambridge Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: genes ; nutrition ; diabetes ; interaction ; effect modification ; macronutrient intake ; personalised nutrition ; precision nutrition ; nutritional genomics ; nutrigenetics