title: Toward Precision Medicine: TBC1D4 Disruption Is Common Among the Inuit and Leads to Underdiagnosis of Type 2 Diabetes.
abstract: 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.
  
  
  
  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.
  
  
  
  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 10-6) 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).
  
  
  
  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.
authors: Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.|Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors: Despoina
authors: D
authors: Manousaki
authors: Texas Biomedical Research Institute, San Antonio, TX.
authors: Jack W
authors: JW
authors: Kent
authors: Texas Biomedical Research Institute, San Antonio, TX.
authors: Karin
authors: K
authors: Haack
authors: Department of Medicine, McGill University, Montreal, Quebec, Canada.|Department of Medicine, Université de Montréal, Montreal, Quebec, Canada.
authors: Sirui
authors: S
authors: Zhou
authors: Department of Medicine, McGill University, Montreal, Quebec, Canada.|Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada.
authors: Pingxing
authors: P
authors: Xie
authors: Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.|Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|Department of Oncology, McGill University, Montreal, Quebec, Canada.
authors: Celia M
authors: CM
authors: Greenwood
authors: Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.|Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors: Paul
authors: P
authors: Brassard
authors: Texas Biomedical Research Institute, San Antonio, TX.
authors: Deborah E
authors: DE
authors: Newman
authors: Texas Biomedical Research Institute, San Antonio, TX.
authors: Shelley
authors: S
authors: Cole
authors: MedStar Health Research Institute, Hyattsville, MD.|Georgetown-Howard Universities Center for Clinical and Translational Science, Washington.
authors: Jason G
authors: JG
authors: Umans
authors: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada.|Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
authors: Guy
authors: G
authors: Rouleau
authors: Texas Biomedical Research Institute, San Antonio, TX.
authors: Anthony G
authors: AG
authors: Comuzzie
authors: Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada brent.richards@mcgill.ca.|Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|Department of Medicine, McGill University, Montreal, Quebec, Canada.|Department of Twin Research and Genetic Epidemiology, King's College London, London, U.K.
authors: J Brent
authors: JB
authors: Richards
mesh_terms: D000413:Alaska; D001786:Blood Glucose / Q000378:metabolism; D002170:Canada; D018389:Codon, Nonsense; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics*; D005951:Glucose Tolerance Test; D006116:Greenland; D006801:Humans; D006943:Hyperglycemia / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D004930:Inuit / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D019518:Postprandial Period; D057285:Precision Medicine; D011236:Prediabetic State / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D001786:Blood Glucose; D018389:Codon, Nonsense; D020690:GTPase-Activating Proteins; D007328:Insulin; C518767:TBC1D4 protein, human