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Genetic predisposition to long-term non-diabetic deteriorations in glucose homeostasis: ten-year follow-up of the GLACIER Study.

Renström, F; Shungin, Dmitry LU ; Johansson, I; Florez, JC; Hallmans, G; Hu, FB and Franks, Paul LU (2011) In Diabetes 60(1). p.54-345
Abstract
To assess whether recently discovered genetic loci associated with hyperglycemia also predict long-term changes in glycemic traits. Methods: Sixteen fasting glucose-raising loci were genotyped in middle-aged adults from the GLACIER Study, a population-based prospective cohort study from Northern Sweden. Genotypes were tested for association with baseline fasting and 2-hr post-challenge glycemia (N=16,398), and with change in glycemic traits during a 10 year follow-up period (N=4,059). Results: Cross-sectional directionally consistent replication with fasting glucose concentrations was achieved for 12/16 variants; nine variants also associated with impaired fasting glucose (IFG) and seven were independently associated with 2-hr... (More)
To assess whether recently discovered genetic loci associated with hyperglycemia also predict long-term changes in glycemic traits. Methods: Sixteen fasting glucose-raising loci were genotyped in middle-aged adults from the GLACIER Study, a population-based prospective cohort study from Northern Sweden. Genotypes were tested for association with baseline fasting and 2-hr post-challenge glycemia (N=16,398), and with change in glycemic traits during a 10 year follow-up period (N=4,059). Results: Cross-sectional directionally consistent replication with fasting glucose concentrations was achieved for 12/16 variants; nine variants also associated with impaired fasting glucose (IFG) and seven were independently associated with 2-hr post-challenge glucose concentrations. In prospective analyses corrected for multiple testing, the effect alleles at four loci (GCK rs4607517, ADRA2A rs10885122, DGKB-TMEM195 rs2191349, G6PC2 rs560887) were statistically associated with worsening fasting glucose concentrations during 10-years follow-up. MTNR1B rs10830963, which was predictive of elevated fasting glucose concentrations in cross-sectional analyses, was associated with a protective effect on post-challenge glucose concentrations during follow-up; however, this was only when baseline fasting and 2-hr glucoses were adjusted for. An additive effect of multiple risk alleles on glycemic traits was observed: a weighted genetic risk score (80(th) vs. 20(th) centiles) was associated with a 0.16mmol/l (P=2.4×10(-6)) greater elevation in fasting glucose and a 64% (95% CI:33-201%) higher risk of developing IFG during 10-years follow-up. Conclusions: Our findings imply that genetic profiling might facilitate the early detection of persons who are genetically susceptible to deteriorating glucose control; studies of incident type 2 diabetes and discrete cardiovascular endpoints will help establish whether the magnitude of these changes is clinically relevant. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
60
issue
1
pages
54 - 345
publisher
American Diabetes Association Inc.
external identifiers
  • wos:000286017300042
  • scopus:78751535877
ISSN
1939-327X
DOI
10.2337/db10-0933
language
English
LU publication?
yes
id
4d338a7c-d461-4883-b0cc-164635a7edae (old id 1715808)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20870969
date added to LUP
2010-11-11 11:48:41
date last changed
2017-10-22 04:20:29
@article{4d338a7c-d461-4883-b0cc-164635a7edae,
  abstract     = {To assess whether recently discovered genetic loci associated with hyperglycemia also predict long-term changes in glycemic traits. Methods: Sixteen fasting glucose-raising loci were genotyped in middle-aged adults from the GLACIER Study, a population-based prospective cohort study from Northern Sweden. Genotypes were tested for association with baseline fasting and 2-hr post-challenge glycemia (N=16,398), and with change in glycemic traits during a 10 year follow-up period (N=4,059). Results: Cross-sectional directionally consistent replication with fasting glucose concentrations was achieved for 12/16 variants; nine variants also associated with impaired fasting glucose (IFG) and seven were independently associated with 2-hr post-challenge glucose concentrations. In prospective analyses corrected for multiple testing, the effect alleles at four loci (GCK rs4607517, ADRA2A rs10885122, DGKB-TMEM195 rs2191349, G6PC2 rs560887) were statistically associated with worsening fasting glucose concentrations during 10-years follow-up. MTNR1B rs10830963, which was predictive of elevated fasting glucose concentrations in cross-sectional analyses, was associated with a protective effect on post-challenge glucose concentrations during follow-up; however, this was only when baseline fasting and 2-hr glucoses were adjusted for. An additive effect of multiple risk alleles on glycemic traits was observed: a weighted genetic risk score (80(th) vs. 20(th) centiles) was associated with a 0.16mmol/l (P=2.4×10(-6)) greater elevation in fasting glucose and a 64% (95% CI:33-201%) higher risk of developing IFG during 10-years follow-up. Conclusions: Our findings imply that genetic profiling might facilitate the early detection of persons who are genetically susceptible to deteriorating glucose control; studies of incident type 2 diabetes and discrete cardiovascular endpoints will help establish whether the magnitude of these changes is clinically relevant.},
  author       = {Renström, F and Shungin, Dmitry and Johansson, I and Florez, JC and Hallmans, G and Hu, FB and Franks, Paul},
  issn         = {1939-327X},
  language     = {eng},
  number       = {1},
  pages        = {54--345},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Genetic predisposition to long-term non-diabetic deteriorations in glucose homeostasis: ten-year follow-up of the GLACIER Study.},
  url          = {http://dx.doi.org/10.2337/db10-0933},
  volume       = {60},
  year         = {2011},
}