Native Hawaiians and Pacific Islanders (NHPIs) have among the world's highest burden of metabolic disease, including obesity and diabetes, and are at increased risk for other associated comorbidities, including kidney disease and cardiovascular disease. While NHPIs are among the most affected populations with metabolic disease, they have been vastly underrepresented in studies aimed at identifying the underlying factors that contribute to their increased risk. To begin investigating genetic factors that might contribute to the increased risk of disease in NHPIs, we performed Blended Genome-Exome Sequencing in 69 participants of the Utah Pacific Islander Diabetes Study (UPIDS), including 26 individuals of Tongan ancestry, 25 individuals of Samoan ancestry, and 18 individuals of other Pacific Islander ancestry. Among more than 18,000 genes sequenced at a mean depth of >30X coverage, we identified 95,238 variants, including 9,679 novel variants not observed in available population-based genetic variation databases. Interestingly, we identified 91 novel population-specific putative loss-of-function (pLOF) variants (i.e., stop-gain, stop-loss, frameshift insertion/deletion, and splice variants) with allele count >2 in participants of the UPIDS, including novel stop-gain variants in 20 genes. Further investigation of the association of these pLOF variants with health and disease among participants of the UPIDS and other NHPI populations is ongoing. Importantly, the identification and investigation of these and other population-specific variants may help to identify genetic factors that contribute to disease risk in NHPI populations and lead to improved risk stratification, treatment, and health equity in these populations.