eCite Digital Repository

Association of protein function-altering variants with cardiometabolic traits: the strong heart study


Shan, Y and Cole, SA and Haack, K and Melton, PE and Best, LG and Bizon, C and Kobes, S and Koroglu, C and Baier, LJ and Hanson, RL and Sanna, S and Li, Y and Franceschini, N, Association of protein function-altering variants with cardiometabolic traits: the strong heart study, Scientific reports, 12, (1) Article 9317. ISSN 2045-2322 (2022) [Refereed Article]

PDF (Published version)

Copyright Statement

The Author(s) 2022 This article is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) License, (, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

Official URL:

DOI: doi:10.1038/s41598-022-12866-2


Clinical and biomarker phenotypic associations for carriers of protein function-altering variants may help to elucidate gene function and health effects in populations. We genotyped 1127 Strong Heart Family Study participants for protein function-altering single nucleotide variants (SNV) and indels selected from a low coverage whole exome sequencing of American Indians. We tested the association of each SNV/indel with 35 cardiometabolic traits. Among 1206 variants (average minor allele count = 20, range of 1 to 1064), ~ 43% were not present in publicly available repositories. We identified seven SNV-trait significant associations including a missense SNV at ABCA10 (rs779392624, p = 8 10-9) associated with fasting triglycerides, which gene product is involved in macrophage lipid homeostasis. Among non-diabetic individuals, missense SNVs at four genes were associated with fasting insulin adjusted for BMI (PHIL, chr6:79,650,711, p = 2.1 10-6; TRPM3, rs760461668, p = 5 10-8; SPTY2D1, rs756851199, p = 1.6 10-8; and TSPO, rs566547284, p = 2.4 10-6). PHIL encoded protein is involved in pancreatic β-cell proliferation and survival, and TRPM3 protein mediates calcium signaling in pancreatic β-cells in response to glucose. A genetic risk score combining increasing insulin risk alleles of these four genes was associated with 53% (95% confidence interval 1.09, 2.15) increased odds of incident diabetes and 83% (95% confidence interval 1.35, 2.48) increased odds of impaired fasting glucose at follow-up. Our study uncovered novel gene-trait associations through the study of protein-coding variants and demonstrates the advantages of association screenings targeting diverse and high-risk populations to study variants absent in publicly available repositories.

Item Details

Item Type:Refereed Article
Keywords:Amerindian, exome sequencign, cardiometabolic.
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Gene mapping
Objective Division:Health
Objective Group:Evaluation of health and support services
Objective Field:Health inequalities
UTAS Author:Melton, PE (Dr Phillip Melton)
ID Code:153566
Year Published:2022
Deposited By:Menzies Institute for Medical Research
Deposited On:2022-09-26
Last Modified:2022-10-12
Downloads:1 View Download Statistics

Repository Staff Only: item control page