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Marzi, Carola (2014): Is acute-phase serum amyloid a protein a risk factor for type 2 diabetes: epidemiologic perspective including a genetic approach. Dissertation, LMU München: Medizinische Fakultät



Type 2 diabetes is a metabolic disorder with globally increasing prevalence. Therefore, the identification of etiological factors is of ascending relevance for the understanding, treatment, and prevention of the disease. Levels of the acute-phase serum amyloid A (A-SAA) protein have been found to be elevated in type 2 diabetic subjects, but little is known about their causal implication in the development of type 2 diabetes so far. This doctoral thesis presents an epidemiological perspective on the association between circulating levels of A-SAA and risk of type 2 diabetes and assesses a possible causality in this association using a genetic approach. Three studies were conducted. In a prospective cohort study, A-SAA levels were measured in 836 initially non-diabetic, elderly, Western European subjects without clinically overt inflammation who participated in a seven-year follow-up examination. Results of this study provided first evidence that levels of A-SAA are elevated years before the manifestation of type 2 diabetes independent of other type 2 diabetes risk factors. However, adjustment for parameters related to glucose metabolism, particularly levels of 2h-glucose, attenuated the association suggesting a potential link via post-challenge hyperglycemia in the association between elevated levels of A-SAA and type 2 diabetes or, alternatively, a possible reverse causality between levels of A-SAA and 2h-glucose. In a meta-analysis of genome-wide association studies (GWAS) on levels of A-SAA conducted in three population-based studies and one prospective case-cohort study including a total of 4,212 participants of European descent two biologically highly plausible genetic susceptibility loci for A-SAA proteins at chromosome 11p15.5-p13 and chromosome 1p31 were identified. One of these loci represented a suitable candidate for a Mendelian Randomization study. In Mendelian Randomization studies, genetic variants are used as proxies for a biomarker. These studies benefit from the fact that genotypes are randomly assorted at meiosis and are largely independent of non-genetic confounding and disease processes. Thus, they constitute a genetic approach to assess whether the association between a biomarker and a disease is causal. The associations between genetic variants of the candidate locus and type 2 diabetes were extracted from the results of a meta-analysis of eight GWAS (8,130 cases, 38,987 controls) published by DIAGRAM, a large diabetes and genetic consortium. In spite of sufficient power, the above mentioned associations were not significant suggesting that there are genetic mechanisms that raise plasma levels of A-SAA without translating into an increase in type 2 diabetes risk. In conclusion, results of this doctoral thesis indicated that levels of A-SAA are elevated years before the manifestation of type 2 diabetes but could not provide evidence that the association is truly causal using a genetic approach. Rather it seems likely that the association between levels of A-SAA and risk of type 2 diabetes is substantially influenced by post-challenge hyperglycemia. Time-series studies are warranted to elucidate the role of post-challenge hyperglycemia in this association.