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 journalArticle

4 Citations (Scopus)

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)
JournalBMC Endocrine Disorders
DOIs
StateAccepted/In press - Jan 28 2016

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Angiopoietins
Type 2 Diabetes Mellitus
Glucose
Mutation
Fasting
Homeostasis
Sample Size
HDL Cholesterol

Keywords

  • Angiopoietin-like 8
  • Betatrophin
  • rs145464906

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism

Cite this

A null mutation in ANGPTL8 does not associate with either plasma glucose or type 2 diabetes in humans. / Clapham, Katharine R.; Chu, Audrey Y.; Wessel, Jennifer; Natarajan, Pradeep; Flannick, Jason; Rivas, Manuel A.; Sartori, Samantha; Mehran, Roxana; Baber, Usman; Fuster, Valentin; Scott, Robert A.; Rader, Daniel J.; Boehnke, Michael; McCarthy, Mark I.; Altshuler, David M.; Kathiresan, Sekar; Peloso, Gina M.

In: BMC Endocrine Disorders, 28.01.2016.

Research output: Contribution to journalArticle

Clapham, KR, Chu, AY, Wessel, J, Natarajan, P, Flannick, J, Rivas, MA, Sartori, S, Mehran, R, Baber, U, Fuster, V, Scott, RA, Rader, DJ, Boehnke, M, McCarthy, MI, Altshuler, DM, Kathiresan, S & Peloso, GM 2016, 'A null mutation in ANGPTL8 does not associate with either plasma glucose or type 2 diabetes in humans', BMC Endocrine Disorders. https://doi.org/10.1186/s12902-016-0088-8
Clapham, Katharine R. ; Chu, Audrey Y. ; Wessel, Jennifer ; Natarajan, Pradeep ; Flannick, Jason ; Rivas, Manuel A. ; Sartori, Samantha ; Mehran, Roxana ; Baber, Usman ; Fuster, Valentin ; Scott, Robert A. ; Rader, Daniel J. ; Boehnke, Michael ; McCarthy, Mark I. ; Altshuler, David M. ; Kathiresan, Sekar ; Peloso, Gina M. / A null mutation in ANGPTL8 does not associate with either plasma glucose or type 2 diabetes in humans. In: BMC Endocrine Disorders. 2016.
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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.",
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AU - Chu, Audrey Y.

AU - Wessel, Jennifer

AU - Natarajan, Pradeep

AU - Flannick, Jason

AU - Rivas, Manuel A.

AU - Sartori, Samantha

AU - Mehran, Roxana

AU - Baber, Usman

AU - Fuster, Valentin

AU - Scott, Robert A.

AU - Rader, Daniel J.

AU - Boehnke, Michael

AU - McCarthy, Mark I.

AU - Altshuler, David M.

AU - Kathiresan, Sekar

AU - Peloso, Gina M.

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N2 - 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.

AB - 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.

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