Genetics of gout - Progression from hyperuricaemia to gout
Gout is an inflammatory arthritis that is prevalent in New Zealand (NZ) populations, with a higher frequency in Māori (6.06%) and Pacific Islanders (7.60%) in comparison to NZ Europeans (3.24%). This inflammatory arthritis arises from an innate immune response to monosodium urate (MSU) crystals that accumulate in joints and surrounded tissues. MSU crystals are formed in the presence of hyperuricaemia (elevated serum urate levels). Hyperuricaemia (HU) is a prerequisite for gout, but not sufficient. Therefore, it suggests the contribution of other factors that are causal to gout. Genome-wide association studies, an indispensable approach in population genetics, have reported dozens of loci associated with serum urate levels and confirm the importance of urate excretion in controlling urate levels and gout. However, genetic contribution to the progression from hyperuricaemia to gout is poorly understood. Some candidate gene studies have identified genes encoding proteins that are involved in the NLRP3 (NOD-LRR and pyrin domain-containing 3) inflammasome activation that is a key regulator in gout pathogenesis. Thereby, the current research project aims to investigate causal association between non-urate, inflammatory loci and gout. The current study provides evidence of association between non-urate transporters CNIH2, CUX2, FAM35A and NIPAL1 and inflammatory loci PPARGC1B, IL37 and IL23R with gout in NZ Polynesian and European populations. Recent studies reported association of some of these loci with gout in the Japanese population such as CUX2 (rs4766566), CNIH2 (rs4073582), NIPAL1 (rs11733284), FAM35A (rs7903456), PPARGC1B (rs45520937) and IL23R (rs7517847). The causal role that these variants have in gout pathogenesis in NZ populations has not been reported before and is important for understanding disease mechanisms and developing effective therapeutic stratigies to cure gout. Population-specific genetic effects on gout are also evident but are not being explored as much as in other complex phenotypes. With the help of an in-silico resequencing approach applied to whole genome sequencing (WGS) gout data, several novel population-specific association signals were found and among these CACNA1S (rs13374149), TAP2 (rs2071) and IL37 (rs17521135) were successfully validated for their association with gout in the New Zealand Polynesian cohort. They were identified with a high prevalence and increasing risk of gout only in a Polynesian sample set. Notably the IL37 (rs17521135) G-allele increased the risk of gout using hyperuricaemic controls compared to gout cases (OR= 1.81, P = 0.031), indicating that this locus is involved in the progression from hyperuricaemia to gout in a population-dependent manner. Lastly, the current study attempted to evaluate the cause-effect relationship between mitochondria and gout susceptibility through influencing mitochondrial copy number. The hypothesis was generated based on a recent report of identification of low mitochondrial DNA (mtDNA) copy number in Polynesian (Māori and Pacific) gout individuals (Gosling et al. 2018). My study replicated the Gosling et al. (2018) association but did not find association of mtDNA copy number with gout in European. My study evidenced the association of nuclear genome encoded variant rs149132393 (in a FCRL6 gene) with increased mtDNA copy number (in the Eastern Polynesian group) and protected from risk of gout in the Polynesian (Western Polynesian group) population using HU controls versus gout cases. In addition, a previously identified mitochondrial variant 16189C in Polynesian gout patients (Gosling et al. 2018) was associated with gout risk (OR = 0.45, P = 0.045) through mitochondrial-wide association analysis among this NZ Polynesian cohort. Collectively my study indicates a potential contribution of mitochondrial genome variation in gout pathophysiology by affecting mitochondrial copy number.
Advisor: Merriman, Tony
Degree Name: Doctor of Philosophy
Degree Discipline: Biochemistry
Publisher: University of Otago
Research Type: Thesis