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TBC1D4 Disruption Is Common Among the Inuit

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TBC1D4 Disruption Is Common Among the Inuit Diabetes Care Volume 39, November 2016 1889 PRECISION MEDICINE Despoina Manousaki,1,2 Jack W. Kent Jr.,3 Toward Precision Medicine: Karin Haack,3 Sirui Zhou,4,5 Pingxing Xie,4,6 Celia M. Greenwood,1,2,7 Paul Brassard,1,4 TBC1D4 Disruption Is Common Deborah E. Newman,3 Shelley Cole,3 Jason G. Umans,8,9 Guy Rouleau,2,6,10 Among the Inuit and Leads to Anthony G. Comuzzie,3 and Underdiagnosis of Type 2 Diabetes J. Brent Richards1,2,4,11 Diabetes Care 2016;39:1889–1895 | DOI: 10.2337/dc16-0769 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 1Centre for Clinical Epidemiology, Department of postprandial glucose. We investigated the frequency and effect of the TBC1D4 mu- Epidemiology, Lady Davis Institute for Medical tation on glucose metabolism and type 2 diabetes diagnosis among Canadian and Research, Jewish General Hospital, McGill Uni- versity, Montreal, Quebec, Canada Alaskan Inuit. 2Department of Human Genetics, McGill Univer- sity, Montreal, Quebec, Canada RESEARCH DESIGN AND METHODS 3Texas Biomedical Research Institute, San Anto- Exome sequencing of the TBC1D4 variant was performed in 114 Inuit from Nunavik, nio, TX 4 Canada, and Sanger sequencing was undertaken in 1,027 Alaskan Inuit from the Department of Medicine, McGill University, Montreal, Quebec, Canada Genetics of Coronary Artery Disease in Alaskan Natives (GOCADAN) Study. Associa- 5Department of Medicine, UniversitedeMon-´ tion testing evaluated the effect of the TBC1D4 variant on diabetes-related metabolic treal,´ Montreal, Quebec, Canada traits and diagnosis. 6Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada 7 RESULTS Department of Oncology, McGill University, Montreal, Quebec, Canada The TBC1D4 mutation was present in 27% of Canadian and Alaskan Inuit. It was 8MedStar Health Research Institute, Hyattsville, 2 strongly associated with higher glucose (effect size +3.3 mmol/L; P =2.5x10 6) MD and insulin (effect size +175 pmol/L; P = 0.04) 2 h after an oral glucose load in 9Georgetown-Howard Universities Center for homozygote carriers. TBC1D4 carriers with prediabetes and type 2 diabetes had an Clinical and Translational Science, Washington, DC increased risk of remaining undiagnosed unless postprandial glucose values were 10Department of Neurology and Neurosurgery, tested (odds ratio 5.4 [95% CI 2.5–12]) compared with noncarriers. Of carriers with McGill University, Montreal, Quebec, Canada 11 prediabetes or type 2 diabetes, 32% would remain undiagnosed without an oral Department of Twin Research and Genetic Ep- idemiology, King’s College London, London, U.K. glucose tolerance test (OGTT). Corresponding author: J. Brent Richards, brent. CONCLUSIONS [email protected]. Disruption of TBC1D4 is common among North American Inuit, resulting in exclu- Received 7 April 2016 and accepted 9 August 2016. sively elevated postprandial glucose. This leads to underdiagnosis of type 2 di- This article contains Supplementary Data online abetes, unless an OGTT is performed. Accounting for genetic factors in the care of at http://care.diabetesjournals.org/lookup/ Inuit with diabetes provides an opportunity to implement precision medicine in suppl/doi:10.2337/dc16-0769/-/DC1. this population. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not Precision medicine, as defined by the National Institutes of Health’s Precision Medicine for profit, and the work is not altered. More infor- Initiative Working Group, aims to tailor health care to individual variability in genes, mation is available at http://www.diabetesjournals environment, and lifestyles (1). While oncology has demonstrated some tangible suc- .org/content/license. cess with precision medicine, few examples exist in other domains of health care (2). See accompanying articles, pp. 1854, Genetic predisposition to disease may vary not only by individual but also by ancestry, 1858, 1870, 1874, 1879, 1896, 1902, and harnessing this information may help health care providers to better understand 1909, and 1915. 1890 Inuit TBC1D4 Variant and Type 2 Diabetes Diabetes Care Volume 39, November 2016 how to approach disease among different Alaskan Natives (GOCADAN) study (6) (the different ancestral populations with ethnicities. This may be particularly rele- Western North American Arctic). available data in phase 3 of the 1000 Ge- vant in specific populations, such as the Inuit from Nunavik were recruited nomes Project (8). Inuit, that have had different natural se- originally for the purposes of a research Next, we conducted a genetic associ- lection pressures leading to different fre- project assessing genetic determinants ation study of the GOCADAN cohort, ap- quencies of genetic variants. of fatty acid metabolism (7). While that plying both additive and recessive genetic Moltke et al. (3) recently identified a study did not include type 2 diabetes models to test for associations between population-specific nonsense variant in status or metabolic traits, it was used the TBC1D4 variant and reported type 2 TBC1D4 which was both common (minor to quantify the prevalence of the diabetes status, as well as 14 traits related allele frequency [MAF] 17%) and had a TBC1D4 variant in Nunavik. to type 2 diabetes (fasting and 2-h plasma large effect on type 2 diabetes risk among Informed consent for the current study glucose concentrations at OGTT, fasting the Greenlandic population (homozygote was obtained from all participants. The and 2-h serum insulin concentrations odds ratio [OR] 10.3; P =1.63 10224 in a TBC1D4 variant (rs61736969, a nonsense at OGTT, Gutt insulin sensitivity index recessive model). Specifically, compared polymorphism in TBC1D4 that is also [ISI0,120] (9), serum HbA1c, triglycerides, with noncarriers, homozygous carriers of called p.Arg684Ter or c.2050C.T) was total serum cholesterol, LDL cholesterol, the TBC1D4 p.Arg684.Ter variant had assayed using exome sequencing (see HDL cholesterol, albuminuria, BMI, percent- markedly higher concentrations of 2-h the Supplementary Data for a detailed age fat mass, and waist circumference). plasma glucose (3.8 mmol/L [68 mg/dL]; description of the exome sequencing). For these quantitative traits, the associa- P =2.53 10235) and serum insulin We next tested the effect of this variant tion testing was done only in participants (165 pmol/L [24 uIU/mL]; P =1.53 on glucose metabolism in the GOCADAN without diabetes. To evaluate the associa- 10220) after an oral glucose tolerance study (6). This longitudinal, population- tion between the TBC1D4 variant and test (OGTT). Conversely, this variant de- based study, conducted between October type 2 diabetes status, we used the full creased fasting glucose and had little effect 2000 and April 2004, aimed to investigate data set (both patients with diabetes and on HbA1c.Thesameeffectsdalthough of the genetic determinants of cardiovascu- those without diabetes). Because of skewed smaller magnitudedwere also observed lar disease among 1,214 Inuit from several values for some traits, we performed addi- in heterozygote carriers. coastal villages in the Norton Sound re- tional association tests after a rank-based What is not known is whether this var- gion of Western Alaska. All individuals inverse normal transformation (10) of the iant is present in other Inuit and whether older than 18 years residing in this re- values to ensure normality. The measured it may, given the exclusive effect on post- gion were invited to participate. Testing genotype association method used for the prandial glucose, influence diagnostic included a physical examination, labora- association testing was implemented in the strategies for type 2 diabetes. Such infor- tory determinations, and measures of Sequential Oligogenic Linkage Analysis Rou- mation may have clinical utility given that subclinical disease (described in detail tines software program (available from the prevalence of type 2 diabetes has elsewhere [6]). Specifically, type 2 diabe- https://www.nitrc.org/projects/se_linux; been increasing dramatically among the tes status was determined by self-report, described in detail elsewhere [11]). Finally, Inuit over the past 25 years (4). medication use, and fasting glucose we accounted for multiple testing by Interestingly, the ancestors of the Inuit screening (Accu-Chek Advantage). A urine applying a Bonferroni correction (12), divid- in Greenland are thought to have mi- sample was collected and blood samples ing the a level (0.05) by the number of traits grated from Siberia, across the Central were taken when fasted and 2 h after a tested (n = 14). We recognize that this cor- and Eastern Canadian Arctic (5). If the standard 75-g OGTT (Glutol; Paddock Lab- rection is overly conservative because many TBC1D4 nonsense mutation arose earlier oratory Inc., Minneapolis, MN). Partici- of the traits are highly correlated. along migration routes out of Siberia, this pants were excluded from the OGTT if To compare the risk of underdiagno- mutation would also be present in North they were already considered as having sis of prediabetes and type 2 diabetes American Inuit. Therefore, in this study type 2 diabetes according to the following among TBC1D4 carriers and noncarriers, we assessed the prevalence of the criteria: having known type 2 diabetes we applied the 2010 American Diabetes TBC1D4 mutation and its effect on diag- and requiring insulin,
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