Abstract
Gout is an inflammatory arthritis caused by NLRP3 inflammasome-mediated production of IL-1b in response to monosodium urate crystal. This disease is seen across the world but occurs in particularly high numbers in the Aotearoa New Zealand Māori and Paciܪc (Polynesian) populations. This high prevalence of gout may be due to the genomics of people with Polynesian ancestry, in particular their mitochondrial genome due to activation of the NLRP3 inflammasome by the mitochondria. Association between gout and mitochondrial DNA (mtDNA) copy number has been found in Aotearoa New Zealand Māori and Pacific (Polynesian) study cohorts but have not been investigated in non-Polynesian groups. We set out to test these previous ܪndings, as well as test a theory that this association was unique to individuals with Polynesian ancestry. To test this hypothesis, we performed a single association test between gout phenotypes and mitochondrial copy number (MCN) in a group containing 4579 genomes from individuals with European ancestry, 1340 genomes from individuals with East Polynesian ancestry (Cook Island and New Zealand Māori), and 816 from individuals with West Polynesian ancestry. MCN was negatively associated with gout in the Eastern Polynesian sample set (P = 2.9x10-6). The same negative association was also seen in the Western Polynesian cohort (P = 3.6x10-16). However, there was no association in the European sample set (P = 0.66). These results indicate that the high rates of gout among individuals with Polynesian ancestry are likely due to mitochondrial disfunction and may be linked to the unique history of Polynesia