A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk.
Level 3 - non-randomized controlled study
Genome-wide association study incorporating cross-sectional, case-control, and prospective cohort components
PubMed 19060909 · doi:10.1038/ng.277
What was done
A genome-wide association study (GWAS) was conducted in 2,151 non-diabetic French individuals to identify genetic variants influencing fasting plasma glucose (FPG). The top identified variant near MTNR1B (rs1387153) was further evaluated for associations with FPG, type 2 diabetes (T2D) risk, and 9-year prospective risk of incident hyperglycemia or diabetes in European cohorts. RT-PCR was performed to assess MT2 transcript expression in neural tissues, human pancreatic islets, and beta cells.
What was found
In the discovery GWAS, rs1387153 was associated with FPG (P = 1.3 x 10^-7). In follow-up European samples, the rs1387153 T allele was associated with: - Increased FPG: beta = 0.06 mmol/l (P = 7.6 x 10^-29, N = 16,094) - Type 2 diabetes risk: OR = 1.15 (95% CI 1.08-1.22, P = 6.3 x 10^-5, cases N = 6,332) - 9-year risk of developing hyperglycemia or diabetes: HR = 1.20 (95% CI 1.06-1.36, P = 0.005, incident cases N = 515) RT-PCR confirmed MT2 expression in neural tissues, human pancreatic islets, and beta cells.
Why it matters
This study links common genetic variation near the melatonin receptor gene MTNR1B to elevated fasting glucose and type 2 diabetes risk, pointing to a role for circadian signaling pathways in pancreatic islet function and glucose regulation.
Limits
Analyses were restricted to European populations, limiting generalizability to other ancestries. The effect size on fasting plasma glucose is modest (0.06 mmol/l increase per risk allele), and functional downstream mechanisms linking receptor expression to beta-cell dysfunction were not determined in this study.
Cited by
- supports Four human genetic studies published in 2009 showed that genetic variants in the melatonin receptor gene MTNR1B are associated with elevated fasting blood glucose and increased diabetes risk.