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Nat Genet. 2017 Sep;49(9):1398-1402. doi: 10.1038/ng.3928. Epub 2017 Aug 7.

Effect of sequence variants on variance in glucose levels predicts type 2 diabetes risk and accounts for heritability.

Author information

1
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
2
School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
3
Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
4
Department of Endocrinology and Metabolic Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.
5
Children's Medical Center, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.
6
Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
7
Laboratory in Mjodd, RAM, Reykjavik, Iceland.
8
Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, Iceland.
9
Department of Clinical Biochemistry, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.
10
Iranian Molecular Medicine Network, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
11
Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Abstract

Sequence variants that affect mean fasting glucose levels do not necessarily affect risk for type 2 diabetes (T2D). We assessed the effects of 36 reported glucose-associated sequence variants on between- and within-subject variance in fasting glucose levels in 69,142 Icelanders. The variant in TCF7L2 that increases fasting glucose levels increases between-subject variance (5.7% per allele, P = 4.2 × 10-10), whereas variants in GCK and G6PC2 that increase fasting glucose levels decrease between-subject variance (7.5% per allele, P = 4.9 × 10-11 and 7.3% per allele, P = 7.5 × 10-18, respectively). Variants that increase mean and between-subject variance in fasting glucose levels tend to increase T2D risk, whereas those that increase the mean but reduce variance do not (r2 = 0.61). The variants that increase between-subject variance increase fasting glucose heritability estimates. Intuitively, our results show that increasing the mean and variance of glucose levels is more likely to cause pathologically high glucose levels than increase in the mean offset by a decrease in variance.

PMID:
28783164
DOI:
10.1038/ng.3928
[Indexed for MEDLINE]

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