Abstract
Pacific Islanders, including Micronesians, are disproportionately affected by cardiometabolic diseases like gout and hyperuricemia. While these populations share a similar disease burden, Micronesians are often underrepresented in research on these conditions. Key challenges include limited resources, research capacity, and the need for culturally appropriate approaches to engage Indigenous island communities. As genetic variation is increasingly recognized as a significant factor in gout risk, it is crucial to include Micronesians in these studies. The genetic differences between Micronesians and other Pacific Islanders, such as Polynesians and Melanesians, are shaped by distinct population histories, which may contextualize and provide valuable insights into the genetic factors influencing gout risk across the Pacific Islander population. This thesis aims to: 1) apply Indigenous research frameworks to engage Micronesian communities; 2) use whole-genome sequencing to explore genetic variation that informs their population history; and 3) examine how this genetic variation impacts gout risk in Micronesians, while also analyzing shared genetic variation across Pacific Islander communities on gout risk.
Whole-genome sequencing was conducted on 359 individuals from CHamoru, Micronesian (Chuukese, Yapese, Kosraean, Pohnpean), and Filipino communities in Guam. Phenotypic and health history data were collected, with a subset sequenced at high coverage (~30X). Regression modeling was used to assess the effects of known gout-related variants on gout risk in Micronesians. The Genome Aggregation Database (GnomAD) helped identify potential Pacific-amplified genetic variants, and functional databases like GeneCards were used to assess their impact on gout risk and serum urate levels.
The study found rare mitochondrial DNA (mtDNA) haplogroups, such as B4a1a1x in Micronesians and E1a1b1 in CHamoru populations, reflecting shared ancestry and historical migrations across the Pacific. Y-chromosome analysis revealed European and East Asian haplogroups, reflecting the effects of colonialism on Micronesian genetics. Whole-genome data also revealed genetic similarities between Eastern Micronesians and Western Polynesians, indicating historical interactions between these groups. Regarding gout, common variants like ABCG2 (rs2231142) and GCKR (rs780094) had marginal effects on gout risk in Micronesians, with no impact on serum urate levels. Preliminary analyses of population amplified variants show that they may have some influence on gout and serum urate.
This thesis also discusses initiatives like the Summer Internship for Indigenous Peoples in Genomics (SING Micronesia), which aims to build genomic research capacity in Micronesian communities. Understanding genetic variation in Micronesians provides important insights into both their population history and the genetic factors contributing to gout disease risk.