Genetic Variations in Type 2 Diabetes and Cardiovascular Disease: A Focus on Gene-Lifestyle Interactions and Mendelian Randomization

Sammanfattning: Type 2 diabetes (T2D) and cardiovascular disease (CVD) are highly prevalent complex diseases that result from lifestyle and genetic factors. Gene-lifestyle interactions are also believed to contribute to the etiology of these diseases. The aim of this thesis was to investigate gene-lifestyle interactions using the strongest T2D and CVD susceptibility genetic loci and to understand the causal nature of the associations of common cardio-metabolic biomarkers with T2D and coronary heart disease (CHD). The Malmö Diet and Cancer Study (MDCS), a population-based prospective study, was used and included around 30,000 individuals with comprehensive baseline dietary and lifestyle assessment between the years 1991-1996. The TCF7L2 genotype modified the association between fiber intake and the risk of T2D. The lower risk of T2D by higher fiber intake was restricted to individuals carrying the CC non-risk genotype (Pinteraction = 0.049). Similar interaction was observed with baseline levels of HbA1C (Pinteraction = 0.02). Other T2D associated genes were then investigated for links to WNT signaling pathway where TCF7L2 acts as a transcription factor. Of the 51 T2D associated gene loci 7 genes were annotated to the WNT pathway. Interaction analyses between single nucleotide polymorphisms (SNPs) in these loci and dietary fiber intake were significant for the TCF7L2, NOTCH2 and ZBED3 SNPs. Higher fiber intake associated with lower risk of T2D only among risk allele carriers of the NOTCH2 SNP (Pinteraction = 0.01) and only among homozygotes for the risk allele of the ZBED3 SNP (Pinteraction = 0.003). The interaction between TCF7L2 and fiber intake was further explored in relation to the metabolic syndrome in 4,606 individuals. Higher fiber intake was observed to be associated with lower prevalence of the metabolic syndrome only among non-risk CC genotype carriers (Pinteraction = 0.02) and similar interactions were observed on baseline levels of several traits related to the metabolic syndrome. The chromosome 9p21 genotype modified the association of vegetable and wine intake with the risk of CVD. Lower risk of CVD by higher vegetable intake was restricted to non-carriers of the 9p21 risk G allele (Pinteraction = 0.043), while wine consumption appeared to lower the risk of CVD only among carriers of the risk allele (Pinteraction = 0.029). Instrumental variable analyses using cardio-metabolic genetic risk scores have indicated an inverse causal association between LDLC and T2D. Similar results were obtained in multivariable Mendelian randomization analyses using MDCS (P = 0.008) and genome-wide association studies data (P = 5×10-7). Using similar analyses, a direct causal association was observed between LDLC and CHD. In conclusion, this thesis provides important evidence for gene-lifestyle interactions in the development of T2D and CVD. It also provides evidence for an inverse causal relationship between LDLC and T2D indicating that LDLC has opposite roles in the causality of T2D and CHD.