Additive genetic effect of GCKR, G6PC2, and SLC30A8 variants on fasting glucose levels and risk of type 2 diabetes.
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2022
2022
Historique:
received:
26
07
2021
accepted:
19
05
2022
entrez:
3
6
2022
pubmed:
4
6
2022
medline:
9
6
2022
Statut:
epublish
Résumé
Impaired glucose tolerance is a major risk factor for type 2 diabetes (T2D) and several cardiometabolic disorders. To identify genetic loci underlying fasting glucose levels, we conducted an analysis of 9,232 individuals of European ancestry who at enrollment were either nondiabetic or had untreated type 2 diabetes. Multivariable linear mixed models were used to test for associations between fasting glucose and 7.9 million SNPs, with adjustment for age, body mass index (BMI), sex, significant principal components of the genotypes, and cryptic relatedness. Three previously discovered loci were genome-wide significant, with the lead SNPs being rs1260326, a missense variant in GCKR (p = 1.06×10-8); rs560887, an intronic variant in G6PC2 (p = 3.39×10-11); and rs13266634, a missense variant in SLC30A8 (p = 4.28×10-10). Fine mapping, genome-wide conditional analysis, and functional annotation indicated that the three loci were independently associated with fasting glucose. Each copy of an alternate allele at any of these three SNPs was associated with a reduction of 0.012 mmol/L in fasting glucose levels (p = 8.0×10-28), and this association was replicated in trans-ethnic analysis of 14,303 individuals (p = 2.2×10-16). The three SNPs were jointly associated with significantly reduced T2D risk, with an odds ratio (95% CI) of 0.93 (0.88, 0.98) per protective allele. Our findings implicate additive effects across pathophysiological pathways involved in type 2 diabetes, including glycolysis, gluconeogenesis, and insulin secretion. Since none of the individuals homozygous for the alternate alleles at all three loci has T2D, it might be possible to use a genetic predictor of fasting glucose levels to identify individuals at low vs. high risk of developing type 2 diabetes.
Identifiants
pubmed: 35657990
doi: 10.1371/journal.pone.0269378
pii: PONE-D-21-24235
pmc: PMC9165855
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Blood Glucose
0
GCKR protein, human
0
SLC30A8 protein, human
0
Zinc Transporter 8
0
Glucose-6-Phosphatase
EC 3.1.3.9
G6PC2 protein, human
EC 3.1.3.9.
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0269378Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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