Genetic determinants of glycated hemoglobin levels in the Greenlandic Inuit population

• Published in: European Journal of Human Genetics
• Main Authors: Appel, Emil V.R., Moltke, Ida, Jørgensen, Marit E., Bjerregaard, Peter, Linneberg, Allan, Pedersen, Oluf, Albrechtsen, Anders, Hansen, Torben, Grarup, Niels
• Format: Article in Journal/Newspaper
• Language: English
• Published: 2018
• Subjects: Ankyrins/genetics; Asian Continental Ancestry Group/genetics; Blood Glucose/genetics; Diabetes Mellitus; Type 2/blood; Ethnic Groups/genetics; European Continental Ancestry Group; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Genotype; Glycated Hemoglobin A/genetics; Greenland; Humans; Inuits/genetics; Male; Middle Aged; Protein-Serine-Threonine Kinases/genetics; greenlander*; greenlandic; inuit; inuits
• Online Access: https://portal.findresearcher.sdu.dk/da/publications/3c4858f2-8fcd-4fcc-907b-95ed153add3e; https://doi.org/10.1038/s41431-018-0109-3; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974304/pdf/41431_2018_Article_109.pdf

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 (HbA 1C) and at estimating the effect of known HbA 1C-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 HbA 1C-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 HbA 1C levels, we found that the lead variant in the GCK locus associated significantly with HbA 1C levels in the IAPGG ([Formula: see text]). Furthermore, for 10 of 15 known HbA 1C 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 HbA 1C loci to be significantly associated with HbA 1C 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.