A null mutation in ANGPTL8 does not associate with either plasma glucose or type 2 diabetes in humans

Katharine R. Clapham, Audrey Y. Chu, Jennifer Wessel, Pradeep Natarajan, Jason Flannick, Manuel A. Rivas, Samantha Sartori, Roxana Mehran, Usman Baber, Valentin Fuster, Robert A. Scott, Daniel J. Rader, Michael Boehnke, Mark I. McCarthy, David M. Altshuler, Sekar Kathiresan, Gina M. Peloso

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Background: Experiments in mice initially suggested a role for the protein angiopoietin-like 8 (ANGPTL8) in glucose homeostasis. However, subsequent experiments in model systems have challenged this proposed role. We sought to better understand the importance of ANGPTL8 in human glucose homeostasis by examining the association of a null mutation in ANGPTL8 with fasting glucose levels and risk for type 2 diabetes. Methods: A naturally-occurring null mutation in human ANGPTL8 (rs145464906; c.361C > T; p.Q121X) is carried by ~1 in 1000 individuals of European ancestry and is associated with higher levels of plasma high-density lipoprotein cholesterol, suggesting that this mutation has functional significance. We examined the association of p.Q121X with fasting glucose levels and risk for type 2 diabetes in up to 95,558 individuals (14,824 type 2 diabetics and 80,734 controls). Results: We found no significant association of p.Q121X with either fasting glucose or type 2 diabetes (p-value=0.90 and 0.65, respectively). Given our sample sizes, we had >98 % power to detect at least a 0.23 mmol/L effect on plasma glucose and >95 % power to detect a 70 % increase in risk for type 2 diabetes. Conclusion: Disruption of ANGPTL8 function in humans does not seem to have a large effect on measures of glucose tolerance.

Original languageEnglish (US)
Article number7
JournalBMC Endocrine Disorders
Volume16
Issue number1
DOIs
StatePublished - Jan 28 2016

Keywords

  • Angiopoietin-like 8
  • Betatrophin
  • Rs145464906

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism

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