G-allele of Intronic rs10830963 in MTNR1B Confers Increased Risk of Impaired Fasting Glycemia and Type 2 Diabetes Through an Impaired Glucose-Stimulated Insulin Release

Steno Diabetes Center, Gentofte, Denmark. .
Diabetes (Impact Factor: 8.1). 04/2009; 58(6):1450-6. DOI: 10.2337/db08-1660
Source: PubMed


Genome-wide association studies have identified several variants within the MTNR1B locus that are associated with fasting plasma glucose (FPG) and type 2 diabetes. We refined the association signal by direct genotyping and examined for associations of the variant displaying the most independent effect on FPG with isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), type 2 diabetes, and measures of insulin release and peripheral and hepatic insulin sensitivity.
We examined European-descent participants in the Inter99 study (n = 5,553), in a sample of young healthy Danes (n = 372), in Danish twins (n = 77 elderly and n = 97 young), in additional Danish type 2 diabetic patients (n = 1,626) and control subjects (n = 505), in the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study (n = 4,656), in the North Finland Birth Cohort 86 (n = 5,258), and in the Haguenau study (n = 1,461).
The MTNR1B intronic variant, rs10830963, carried most of the effect on FPG and showed the strongest association with FPG (combined P = 5.3 x 10(-31)) and type 2 diabetes. The rs10830963 G-allele increased the risk of i-IFG (odds ratio [OR] 1.64, P = 5.5 x 10(-11)) but not i-IGT. The G-allele was associated with a decreased insulin release after oral and intravenous glucose challenges (P < 0.01) but not after injection of tolbutamide. In elderly twins, the G-allele associated with hepatic insulin resistance (P = 0.017).
The G-allele of MTNR1B rs10830963 increases risk of type 2 diabetes through a state of i-IFG and not through i-IGT. The same allele associates with estimates of beta-cell dysfunction and hepatic insulin resistance.

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    • "To investigate how glucose metabolism was related to MTNR1B, we analyzed individuals with impaired glucose regulation (impaired glucose tolerance and/or impaired fasting glucose). The data on genotypes of the rs10830963 polymorphism among impaired glucose regulation cases and controls were available in 8 (including 10, 810 cases and 26, 478 controls) studies [17], [18], [23], [24], [28], [33], [34], [37]. For IGR risk and the rs10830963 polymorphism of MTNR1B, our meta-analysis gave an overall per-allele OR of 1.19 (95% CI: 1.10–1.29; "
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    ABSTRACT: Melatonin receptor 1B (MTNR1B) belongs to the seven-transmembrane G protein-coupled receptor superfamily involved in insulin secretion, which has attracted considerable attention as a candidate gene for type 2 diabetes (T2D) since it was first identified as a loci associated with fasting plasma glucose level through genome wide association approach. The relationship between MTNR1B and T2D has been reported in various ethnic groups. The aim of this study was to consolidate and summarize published data on the potential of MTNR1B polymorphisms in T2D risk prediction. PubMed, EMBASE, ISI web of science and the CNKI databases were systematically searched to identify relevant studies. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Heterogeneity and publication bias were also tested. A total of 23 studies involving 172,963 subjects for two common polymorphisms (rs10830963, rs1387153) on MTNR1B were included. An overall random effects per-allele OR of 1.05 (95% CI: 1.02-1.08; P<10(-4)) and 1.04 (95% CI: 0.98-1.10; P = 0.20) were found for the two variants respectively. Similar results were also observed using dominant or recessive genetic model. There was strong evidence of heterogeneity, which largely disappeared after stratification by ethnicity. Significant results were found in Caucasians when stratified by ethnicity; while no significant associations were observed in East Asians and South Asians. Besides, we found that the rs10830963 polymorphism is a risk factor associated with increased impaired glucose regulation susceptibility. This meta-analysis demonstrated that the rs10830963 polymorphism is a risk factor for developing impaired glucose regulation and T2D.
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    • "Differences in either rates of melatonin synthesis or signal transduction can lead to the same consequence as an otherwise induced decrease of the hormone. A list of respective gene polymorphisms [103] [143] [144] [145] [146] [147] [148] [149] [150] [151] [152] [153] [154] [155] [156] [157] [158] [159] [160] [161] [162] [163] [164] [165] [166] [167] [168] [169] [170] [171] [172] [173] [174] [175] [176] [177] [178] [179] [180] [181] [182] [183] is presented in Table 2. These polymorphisms have been detected in the genes of the melatonin membrane receptors, MT 1 and MT 2 , of the enzymes of melatonin biosynthesis, AANAT and HIOMT, and also of the orphan receptor GPR50. "
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    • "Several large-scale genome-wide association analyses demonstrated that common variants in or near the MTNR1B gene to be robustly associated with fasting glucose level in European populations [6-8], with polymorphism rs10830963 showing the most significant association signal [7]. Several replication studies in European [9-12], Indian [13], Sri Lankan and Japanese populations [14] confirmed that MTNR1B rs10830963 contributed to raised fasting glucose level and increased risk of type 2 diabetes. "
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