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

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.

• Authors: Yue Shan, Shelley A Cole, Karin Haack, Phillip E Melton, Lyle G Best, Christopher Bizon, Sayuko Kobes, Çiğdem Köroğlu, Leslie J Baier, Robert L Hanson, Serena Sanna, Yun Li, Nora Franceschini
• Journal: Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 9317 (06 04 2022) ISSN: 2045-2322 [Electronic] England
• PMID: 35665752 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2022. The Author(s).

Chemical References

• Insulin
• Receptors, GABA
• TSPO protein, human
• Glucose

Topics

• Cardiovascular Diseases
• Diabetes Mellitus, Type 2 (metabolism)
• Fasting
• Genetic Predisposition to Disease
• Glucose (metabolism)
• Humans
• Insulin (genetics)
• Polymorphism, Single Nucleotide
• Receptors, GABA (genetics)