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

Citation

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]


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Copyright Statement

The Author(s) 2022 This article is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) License, (https://creativecommons.org/licenses/by/4.0/), 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: https://www.nature.com/articles/s41598-022-12866-2

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

Abstract

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
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