Pacific People, Metabolic Disease and Evolutionary Processes: a mitochondrial DNA study
Data clearly indicate that there is a high burden of metabolic disease including gout, type 2 diabetes, and cardiovascular heart disease, among Polynesians. Many of the metabolic diseases have a shared aetiology and often present as comorbidities. To date, a number of studies have been undertaken, with varying success, attempting to disentangle the genetic and environmental components of these complex diseases. The high disease burden has led some to propose that Pacific populations possess a ‘Thrifty Genotype’. Here I argue that not only do the data not support this hypothesis, but that this is not in line with what is known of the evolutionary history of the region. Instead, a model for selection by a mechanism of infectious disease resistance is proposed. All of these metabolic conditions have a significant immunological component, namely the involvement of the NLRP3 inflammasome, an important component of innate immunity. A number of recent studies have indicated that mitochondria play an integral role in the activation of the NLRP3 inflammasome. Thus, a study of mitochondrial genetic variation was undertaken, exploring how genetic variation in mitochondrial DNA (mtDNA) could contribute to differences in immune response and altered metabolic efficiency. Gout was used as a proxy for altered immune response and obesity as an indicator for metabolic efficiency. Whole mitochondrial genome sequencing was undertaken on 442 Māori and Polynesian men, selected from a cohort of individuals participating in a study of gout genetics. Few genetic associations were detected between either of these proxies, however there was a statistically significant association detected between variation in the region of the poly-cytosine tracts (16179-16189) in hypervariable region 1 (HVR1) and gout status. There was some indication that sequence length heteroplasmy in this region (which coincided with individuals possessing mitochondrial genomes belonging to the B macrohaplogroup) was associated with gout. Mitochondrial DNA copy number was also examined in the context of gout. Quantitative PCR was undertaken to measure the relative amount of mtDNA in 484 Polynesians. There appeared to be a general reduction in the amount of mtDNA in participants with gout compared to healthy controls. Given the involvement of the mitochondria in the co-localisation of components of the NLRP3 inflammasome, this novel finding may explain some of what is occurring in the inflammatory processes underlying gouty disease, and possibly other metabolic diseases more generally. From this preliminary study, it appears that mitochondrial genetics may provide insights into susceptibility to metabolic conditions. This has wider implications when it comes to considering genetic ancestry and disease susceptibility, and may explain some of the high prevalence of metabolic disease among Polynesian and other Pacific populations.
Advisor: Merriman, Tony R.; Matisoo-Smith, Elizabeth A.
Degree Name: Doctor of Philosophy
Degree Discipline: Biochemistry
Publisher: University of Otago
Keywords: Gout; Polynesians; Biological Anthropology; Metabolic Disease; mtDNA; Mitochondria; Mitochondrial DNA; Copy number variation; Genetics; Anthropological Genetics; Molecular Anthropology; Pacific Island Health; Genetic variation; Maori; Hyperuricaemia; Serum urate; Pacific; Thrifty Genotype Hypothesis
Research Type: Thesis