Toward precision medicine: TBC1D4 disruption is common among the inuit and leads to underdiagnosis of type 2 diabetes

Despoina Manousaki, Jack W. Kent, Karin Haack, Sirui Zhou, Pingxing Xie, Celia M. Greenwood, Paul Brassard, Deborah E. Newman, Shelley Cole, Jason G. Umans, Guy Rouleau, Anthony G. Comuzzie, J. Brent Richards

    Research output: Contribution to journalArticle

    16 Scopus citations

    Abstract

    OBJECTIVE Acommon nonsensemutation in TBC1D4was 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-relatedmetabolic 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 1026) and insulin (effect size +175 pmol/L; P = 0.04) 2 h after an oral glucose load in homozygote carriers. TBC1D4 carrierswith 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). 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.

    Original languageEnglish (US)
    Pages (from-to)1889-1895
    Number of pages7
    JournalDiabetes care
    Volume39
    Issue number11
    DOIs
    StatePublished - Nov 1 2016

    ASJC Scopus subject areas

    • Internal Medicine
    • Endocrinology, Diabetes and Metabolism
    • Advanced and Specialized Nursing

    Fingerprint Dive into the research topics of 'Toward precision medicine: TBC1D4 disruption is common among the inuit and leads to underdiagnosis of type 2 diabetes'. Together they form a unique fingerprint.

  • Cite this

    Manousaki, D., Kent, J. W., Haack, K., Zhou, S., Xie, P., Greenwood, C. M., Brassard, P., Newman, D. E., Cole, S., Umans, J. G., Rouleau, G., Comuzzie, A. G., & Richards, J. B. (2016). Toward precision medicine: TBC1D4 disruption is common among the inuit and leads to underdiagnosis of type 2 diabetes. Diabetes care, 39(11), 1889-1895. https://doi.org/10.2337/dc16-0769