Abstract
We previously showed that a common genetic variant leads to a remarkably increased risk of type 2 diabetes (T2D) in the small and historically isolated Greenlandic population. Motivated by this, we aimed at discovering novel genetic determinants for glycated hemoglobin (HbA1C) and at estimating the effect of known HbA1C-associated loci in the Greenlandic population. We analyzed genotype data from 4049 Greenlanders generated using the Illumina Cardio-Metabochip. We performed the discovery association analysis by an additive linear mixed model. To estimate the effect of known HbA1C-associated loci, we modeled the effect in the European and Inuit ancestry proportions of the Greenlandic genome (EAPGG and IAPGG, respectively). After correcting for multiple testing, we found no novel significant associations. When we investigated loci known to associate with HbA1C levels, we found that the lead variant in the GCK locus associated significantly with HbA1C levels in the IAPGG (\(P_{IAPGG} = 4.8 \times 10^{ - 6},\,\beta _{IAPGG} = 0.13\,{\mathrm{SD}}\)). Furthermore, for 10 of 15 known HbA1C loci, the effects in IAPGG were similar to the previously reported effects. Interestingly, the ANK1 locus showed a statistically significant ancestral population differential effect, with opposing directions of effect in the two ancestral populations. In conclusion, we found only 1 of the 15 known HbA1C loci to be significantly associated with HbA1C levels in the IAPGG and that two-thirds of the loci showed similar effects in Inuit as previously found in European and East Asian populations. Our results shed light on the genetic effects across ethnicities.
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References
Moltke I, Fumagalli M, Korneliussen TS, et al. Uncovering the genetic history of the present-day Greenlandic population. Am J Hum Genet. 2015;96:54–69.
Sturtevant WC, Damas D. Handbook of North American Indians vol 5. The Arctic. In: Sturtevant WC, Damas D, editors. Handbook of North American Indians vol 5. The Arctic. Washington, D.C.: Smithsonian Institution; 1984. p. 845.
Jørgensen ME, Borch-Johnsen K, Stolk R, Bjerregaard P. Fat distribution and glucose intolerance among Greenland Inuit. Diabetes Care. 2013;36:2988–94.
Jørgensen ME, Bjeregaard P, Borch-Johnsen K, et al. Diabetes and impaired glucose tolerance among the Inuit population of Greenland. Diabetes Care. 2002;25:1766–71.
Jørgensen ME, Borch-Johnsen K, Witte DR, Bjerregaard P. Diabetes in Greenland and its relationship with urbanization. Diabet Med. 2012;29:755–60.
Moltke I, Grarup N, Jørgensen ME, et al. A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes. Nature. 2014;512:190–3.
Report A, Consultation WHO. Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitus. Diabetes Res Clin Pract. 2011;93:299–309.
Nathan DM, Turgeon H, Regan S. Relationship between glycated haemoglobin levels and mean glucose levels over time. Diabetologia. 2007;50:2239–44.
Selvin E, Steffes MW, Zhu H, et al. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med. 2010;362:800–11.
Chen P, Takeuchi F, Lee J-Y, et al. Multiple nonglycemic genomic loci are newly associated with blood level of glycated hemoglobin in East Asians. Diabetes. 2014;63:2551–62.
Soranzo N, Sanna S, Wheeler E, et al. Common variants at 10 genomic loci influence hemoglobin A1C levels via glycemic and nonglycemic pathways. Diabetes. 2010;59:3229–39.
Dupuis J, Langenberg C, Prokopenko I, et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet. 2010;42:105–16.
Scott Ra, Lagou V, Welch RP, et al. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nat Genet. 2012;44:991–1005.
Steinthorsdottir V, Thorleifsson G, Reynisdottir I, et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet. 2007;39:770–5.
Bjerregaard P, Curtis T, Borch-Johnsen K, et al. Inuit health in Greenland: a population survey of life style and disease in Greenland and among Inuit living in Denmark. Int J Circumpolar Health. 2003;62:3–79.
Tosoh method sheet for Hemoglobin A1c.
BioRad variant hemoglobin A1c program. Instruction manual.
Jeppsson JO, Kobold U, Barr J, et al. Approved IFCC reference method for the measurement of HbA1c in human blood. Clin Chem Lab Med. 2002;40:78–89.
Jørgensen T, Borch-Johnsen K, Thomsen TF, Ibsen H, Glumer C, Pisinger C. A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: baseline results Inter99 (1). Eur J Cardiovasc Prev Rehabil. 2003;10:377–86.
Voight BF, Kang HM, Ding J, et al. The metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits. PLoS Genet. 2012;8:e1002793.
Zhou X, Stephens M. Genome-wide efficient mixed-model analysis for association studies. Nat Genet. 2012;44:821–4.
Skotte L, Korneliussen TSS, Moltke I, Albrechtsen A. Ancestry specific association mapping in admixed populations. 2015. https://doi.org/10.1101/014001.
Alexander DH, Novembre J, Lange K. Fast model-based estimation of ancestry in unrelated individuals. Genome Res. 2009;19:1655–64.
Fumagalli M, Moltke I, Grarup N, et al. Greenlandic Inuit show genetic signatures of diet and climate adaptation. Science (80-). 2015;349:1343–7.
Hussain S, Richardson E, Ma Y, et al. Glucokinase activity in the arcuate nucleus regulates glucose intake. J Clin Invest. 2015;125:337–49.
Jørgensen ME, Bjerregaard P, Borch-Johnsen K, Witte D. New diagnostic criteria for diabetes: is the change from glucose to HbA1c possible in all populations? J Clin Endocrinol Metab. 2010;95:E333–6.
Scott LJ, Erdos MR, Huyghe JR, et al. The genetic regulatory signature of type 2 diabetes in human skeletal muscle. Nat Commun. 2016;7:11764.
Machiela MJ, Chanock SJ. LD link: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics. 2014;31:3555–7.
Caruso M, Ma D, Msallaty Z, et al. Increased interaction with insulin receptor substrate 1, a novel abnormality in insulin resistance and type 2 diabetes. Diabetes. 2014;63:1933–47.
Wang H, Liu L, Zhao J, et al. Large scale meta-analyses of fasting plasma glucose raising variants in GCK, GCKR, MTNR1B and G6PC2 and their impacts on type 2 diabetes mellitus risk. PLoS ONE. 2013;8:e67665.
Grarup N, Moltke I, Albrechtsen A, Hansen T. Diabetes in population isolates: lessons from Greenland. Rev Diabet Stud. 2015;12:320–9.
Acknowledgements
The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). The B99 and IHIT study was supported by Karen Elise Jensen’s Foundation, NunaFonden, the Medical Research Council of Denmark, the Medical Research Council of Greenland, and the Commission for Scientific Research in Greenland. The study was partially funded by the Novo Nordisk Foundation (grants NNF15OC0017918 and NNF16OC0019986). None of the funding agencies had any role in the study design or in the collection or interpretation of the data.
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Appel, E.V., Moltke, I., Jørgensen, M.E. et al. Genetic determinants of glycated hemoglobin levels in the Greenlandic Inuit population. Eur J Hum Genet 26, 868–875 (2018). https://doi.org/10.1038/s41431-018-0109-3
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DOI: https://doi.org/10.1038/s41431-018-0109-3
