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

Yue Shan, Shelley A. Cole, Karin Haack, Phillip E. Melton, Lyle G. Best, Christopher Bizon, Sayuko Kobes, Cigdem Koroglu, Leslie J. Baier, Robert L. Hanson, Serena Sanna, Yun Li, Nora Franceschini*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

68 Downloads (Pure)

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), similar to 43% were not present in publicly available repositories. We identified seven SNV-trait significant associations including a missense SNV at ABCA10 (rs779392624, p= 8 x 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 x 10(-6); TRPM3, rs760461668, p= 5 x10(-8); SPTY2D1, rs756851199, p= 1.6 x 10(-8); and TSPO, rs566547284, p= 2.4 x 10(-6)). PHIL encoded protein is involved in pancreatic beta-cell proliferation and survival, and TRPM3 protein mediates calcium signaling in pancreatic beta-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.

Original languageEnglish
Article number9317
Number of pages9
JournalScientific Reports
Volume12
Issue number1
DOIs
Publication statusPublished - 4-Jun-2022

Keywords

  • RECEPTOR POTENTIAL TRPM3
  • AMERICAN-INDIANS
  • CARDIOVASCULAR-DISEASE
  • PHIP
  • CHANNELS
  • RISK
  • IDENTIFICATION
  • ISOFORM
  • GLUCOSE
  • TIME

Fingerprint

Dive into the research topics of 'Association of protein function-altering variants with cardiometabolic traits: the strong heart study'. Together they form a unique fingerprint.

Cite this