Toward Precision Medicine: TBC1D4 Disruption Is Common Among the Inuit and Leads to Underdiagnosis of Type 2 Diabetes.

MedStar author(s):
Citation: Diabetes Care. 39(11):1889-1895, 2016 NovPMID: 27561922Institution: MedStar Health Research InstituteForm of publication: Journal ArticleMedline article type(s): Journal ArticleSubject headings: *Diabetes Mellitus, Type 2/ge [Genetics] | *GTPase-Activating Proteins/ge [Genetics] | *Hyperglycemia/ge [Genetics] | *Inuits/ge [Genetics] | *Prediabetic State/ge [Genetics] | Alaska | Blood Glucose/me [Metabolism] | Canada | Codon, Nonsense | Diabetes Mellitus, Type 2/di [Diagnosis] | Diabetes Mellitus, Type 2/me [Metabolism] | Female | Glucose Tolerance Test | Greenland | Humans | Hyperglycemia/di [Diagnosis] | Hyperglycemia/me [Metabolism] | Insulin/me [Metabolism] | Male | Middle Aged | Postprandial Period | Precision Medicine | Prediabetic State/di [Diagnosis] | Prediabetic State/me [Metabolism] | Sequence Analysis, DNAYear: 2016Local holdings: Available online from MWHC library: 1995 - present, Available in print through MWHC library: 1999 - 2006ISSN:
  • 0149-5992
Name of journal: Diabetes careAbstract: CONCLUSIONS: Disruption of TBC1D4 is common among North American Inuit, resulting in exclusively elevated postprandial glucose. This leads to underdiagnosis of type 2 diabetes, unless an OGTT is performed. Accounting for genetic factors in the care of Inuit with diabetes provides an opportunity to implement precision medicine in this population.Copyright � 2016 by the American Diabetes Association.OBJECTIVE: A common nonsense mutation in TBC1D4 was recently found to substantially increase the odds of type 2 diabetes in Greenlandic Inuit, leading to exclusively increased postprandial glucose. We investigated the frequency and effect of the TBC1D4 mutation on glucose metabolism and type 2 diabetes diagnosis among Canadian and Alaskan Inuit.RESEARCH DESIGN AND METHODS: Exome sequencing of the TBC1D4 variant was performed in 114 Inuit from Nunavik, Canada, and Sanger sequencing was undertaken in 1,027 Alaskan Inuit from the Genetics of Coronary Artery Disease in Alaskan Natives (GOCADAN) Study. Association testing evaluated the effect of the TBC1D4 variant on diabetes-related metabolic traits and diagnosis.RESULTS: The TBC1D4 mutation was present in 27% of Canadian and Alaskan Inuit. It was strongly associated with higher glucose (effect size +3.3 mmol/L; P = 2.5 x 10<sup>-6</sup>) and insulin (effect size +175 pmol/L; P = 0.04) 2 h after an oral glucose load in homozygote carriers. TBC1D4 carriers with prediabetes and type 2 diabetes had an increased risk of remaining undiagnosed unless postprandial glucose values were tested (odds ratio 5.4 [95% CI 2.5-12]) compared with noncarriers. Of carriers with prediabetes or type 2 diabetes, 32% would remain undiagnosed without an oral glucose tolerance test (OGTT).All authors: Brassard P, Cole S, Comuzzie AG, Greenwood CM, Haack K, Kent JW Jr, Manousaki D, Newman DE, Richards JB, Rouleau G, Umans JG, Xie P, Zhou SFiscal year: FY2016Digital Object Identifier: Date added to catalog: 2017-05-24
Holdings
Item type Current library Collection Call number Status Date due Barcode
Journal Article MedStar Authors Catalog Article 27561922 Available 27561922

Available online from MWHC library: 1995 - present, Available in print through MWHC library: 1999 - 2006

CONCLUSIONS: Disruption of TBC1D4 is common among North American Inuit, resulting in exclusively elevated postprandial glucose. This leads to underdiagnosis of type 2 diabetes, unless an OGTT is performed. Accounting for genetic factors in the care of Inuit with diabetes provides an opportunity to implement precision medicine in this population.

Copyright � 2016 by the American Diabetes Association.

OBJECTIVE: A common nonsense mutation in TBC1D4 was recently found to substantially increase the odds of type 2 diabetes in Greenlandic Inuit, leading to exclusively increased postprandial glucose. We investigated the frequency and effect of the TBC1D4 mutation on glucose metabolism and type 2 diabetes diagnosis among Canadian and Alaskan Inuit.

RESEARCH DESIGN AND METHODS: Exome sequencing of the TBC1D4 variant was performed in 114 Inuit from Nunavik, Canada, and Sanger sequencing was undertaken in 1,027 Alaskan Inuit from the Genetics of Coronary Artery Disease in Alaskan Natives (GOCADAN) Study. Association testing evaluated the effect of the TBC1D4 variant on diabetes-related metabolic traits and diagnosis.

RESULTS: The TBC1D4 mutation was present in 27% of Canadian and Alaskan Inuit. It was strongly associated with higher glucose (effect size +3.3 mmol/L; P = 2.5 x 10<sup>-6</sup>) and insulin (effect size +175 pmol/L; P = 0.04) 2 h after an oral glucose load in homozygote carriers. TBC1D4 carriers with prediabetes and type 2 diabetes had an increased risk of remaining undiagnosed unless postprandial glucose values were tested (odds ratio 5.4 [95% CI 2.5-12]) compared with noncarriers. Of carriers with prediabetes or type 2 diabetes, 32% would remain undiagnosed without an oral glucose tolerance test (OGTT).

English

Powered by Koha