MTNR1B Variants Research Articles

Genetics of glucose homeostasis in pregnancy and postpartum.

Pregnancy is accompanied by maternal metabolic adaptations to ensure fetal growth and development, including insulin resistance, which occurs primarily during the second and third trimesters of pregnancy, and a decrease in fasting blood sugar levels over the course of pregnancy. Glucose-related traits are regulated by genetic and environmental factors and modulated by physiological variations throughout the life course. We addressed the hypothesis that there are both overlaps and differences between genetic variants associated with glycaemia-related traits during and outside of pregnancy. Genome-wide SNP data were used to identify genetic variations associated with glycaemia-related traits measured during an OGTT performed at ~28 weeks' gestation in 8067 participants in the Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) Study. Associations outside of pregnancy were determined in 3977 individuals who also participated in the HAPO Follow-Up Study at 11-14 years postpartum. A Bayesian classification algorithm was used to determine whether SNPs associated with fasting and 2 h glucose and fasting C-peptide during pregnancy had a pregnancy-predominant effect vs a similar effect during pregnancy and postpartum. SNPs in six loci (GCKR, G6PC2, GCK, PPP1R3B, PCSK1 and MTNR1B) were significantly associated with fasting glucose during pregnancy, while SNPs in CDKAL1 and MTNR1B were associated with 1 h glucose and SNPs in MTNR1B and HKDC1 were associated with 2 h glucose. Variants in CDKAL1 and MTNR1B were associated with insulin secretion during pregnancy. Variants in multiple loci were associated with fasting C-peptide during pregnancy, including GCKR, IQSEC1, PPP1R3B, IGF1 and BACE2. GCKR and BACE2 were associated with 1 h C-peptide and GCKR, IQSEC1 and BACE2 with insulin sensitivity during pregnancy. The associations of MTNR1B with 2 h glucose, BACE2 with fasting and 1 h C-peptide and insulin sensitivity, and IQSEC1 with fasting C-peptide and insulin sensitivity that we identified during pregnancy have not been previously reported in non-pregnancy cohorts. The Bayesian classification algorithm demonstrated that the magnitude of effect of the lead SNP was greater during pregnancy compared with 11-14 years postpartum in PCSK1 and PPP1R3B with fasting glucose, in three loci, including MTNR1B, with 2 h glucose, and in six loci, including IGF1, with fasting C-peptide. Our findings support the hypothesis that there are both overlaps and differences between the genetic architecture of glycaemia-related traits during and outside of pregnancy. Genetic variants at several loci, including PCSK1, PPP1R3B, MTNR1B and IGF1, appear to influence glycaemic regulation in a unique fashion during pregnancy. Future studies in larger cohorts will be needed to replicate the present findings, fully characterise the genetics of maternal glycaemia during pregnancy and determine similarities to and differences from the non-gravid state.

Healthy Lifestyles Modify the Association of Melatonin Receptor 1B Gene and Ischemic Stroke: A Family-Based Cohort Study in Northern China.

Limited research has reported the association between MTNR1B gene polymorphisms and ischemic stroke (IS), and there is insufficient evidence on whether adopting a healthy lifestyle can mitigate genetic risks in this context. This study aimed to investigate the associations between MTNR1B gene variants (rs10830963 and rs1387153) and IS, examining the potential effect of gene-lifestyle interactions on IS risk. Conducted in northern China, this family-based cohort study involved 5116 initially IS-free subjects. Genotype data for rs10830963 and rs1387153 in MTNR1B were collected. Eight modifiable lifestyle factors, including body mass index (BMI), smoking, alcohol consumption, dietary habits, physical activity, sedentary time, sleep duration, and chronotype, were considered in calculating healthy lifestyle scores. Multilevel Cox models were used to examine the associations between MTNR1B variants and IS. Participants carrying the rs10830963-G and rs1387153-T alleles exhibited an elevated IS risk. Each additional rs10830963-G allele and rs1387153-T allele increased the IS risk by 36% (HR = 1.36, 95%CI, 1.12-1.65) and 32% (HR = 1.32, 95%CI, 1.09-1.60), respectively. Participants were stratified into low, medium, and high healthy lifestyle score groups (1537, 2188, and 1391 participants, respectively). Genetic-lifestyle interactions were observed for rs10830963 and rs1387153 (p for interaction < 0.001). Notably, as the healthy lifestyle score increased, the effect of MTNR1B gene variants on IS risk diminished (p for trend < 0.001). This study underscores the association between the MTNR1B gene and IS, emphasizing that adherence to a healthy lifestyle can mitigate the genetic predisposition to IS.

Metabolomic and genetic architecture of gestational diabetes subtypes.

Physiological gestational diabetes mellitus (GDM) subtypes that may confer different risks for adverse pregnancy outcomes have been defined. The aim of this study was to characterise the metabolome and genetic architecture of GDM subtypes to address the hypothesis that they differ between GDM subtypes. This was a cross-sectional study of participants in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study who underwent an OGTT at approximately 28 weeks' gestation. GDM was defined retrospectively using International Association of Diabetes and Pregnancy Study Groups/WHO criteria, and classified as insulin-deficient GDM (insulin secretion <25th percentile with preserved insulin sensitivity) or insulin-resistant GDM (insulin sensitivity <25th percentile with preserved insulin secretion). Metabolomic analyses were performed on fasting and 1h serum samples in 3463 individuals (576 with GDM). Genome-wide genotype data were obtained for 8067 individuals (1323 with GDM). Regression analyses demonstrated striking differences between the metabolomes for insulin-deficient or insulin-resistant GDM compared to those with normal glucose tolerance. After adjustment for covariates, 33 fasting metabolites, including 22 medium- and long-chain acylcarnitines, were uniquely associated with insulin-deficient GDM; 23 metabolites, including the branched-chain amino acids and their metabolites, were uniquely associated with insulin-resistant GDM; two metabolites (glycerol and 2-hydroxybutyrate) were associated with the same direction of association with both subtypes. Subtype differences were also observed 1h after a glucose load. In genome-wide association studies, variants within MTNR1B (rs10830963, p=3.43×10-18, OR 1.55) and GCKR (rs1260326, p=5.17×10-13, OR 1.43) were associated with GDM. Variants in GCKR (rs1260326, p=1.36×10-13, OR 1.60) and MTNR1B (rs10830963, p=1.22×10-9, OR 1.49) demonstrated genome-wide significant association with insulin-resistant GDM; there were no significant associations with insulin-deficient GDM. The lead SNP in GCKR, rs1260326, was associated with the levels of eight of the 25 fasting metabolites that were associated with insulin-resistant GDM and ten of 41 1h metabolites that were associated with insulin-resistant GDM. This study demonstrates that physiological GDM subtypes differ in their metabolome and genetic architecture. These findings require replication in additional cohorts, but suggest that these differences may contribute to subtype-related adverse pregnancy outcomes.

Association of rotating night shift work, CLOCK, MTNR1A, MTNR1B genes polymorphisms and their interactions with type 2 diabetes among steelworkers: a case–control study

BackgroundThe purpose of this study is to investigate the association of rotating night shift work, CLOCK, MTNR1A, MTNR1B genes polymorphisms and their interactions with type 2 diabetes among steelworkers.MethodsA case–control study was conducted in the Tangsteel company in Tangshan, China. The sample sizes of the case group and control group were 251 and 451, respectively. The logistic regression, log-linear model and generalized multifactor dimensionality (GMDR) method were used to investigate the interaction between circadian clock gene, melatonin receptor genes and rotating night shift work on type 2 diabetes among steelworkers. Relative excess risk due to interaction (RERI) and attributable proportions (AP) were used to evaluate additive interactions.ResultsRotating night shift work, current shift status, duration of night shifts, and average frequency of night shifts were associated with an increased risk of type 2 diabetes after adjustment for confounders. Rs1387153 variants in MTNR1B was found to be associated with an increased risk of type 2 diabetes, which was not found between MTNR1A gene rs2119882 locus, CLOCK gene rs1801260 locus and the risk of type 2 diabetes. The association between rotating night shift work and risk of type 2 diabetes appeared to be modified by MTNR1B gene rs1387153 locus (RERI = 0.98, (95% CI, 0.40–1.55); AP = 0.60, (95% CI, 0.07–1.12)). The interaction between MTNR1A gene rs2119882 locus and CLOCK gene rs1801260 locus was associated with the risk of type 2 diabetes (RERI = 1.07, (95% CI, 0.23–1.91); AP = 0.77, (95% CI, 0.36–1.17)). The complex interaction of the MTNR1A-MTNR1B-CLOCK-rotating night shift work model based on the GMDR methods may increase the risk of type 2 diabetes (P = 0.011).ConclusionsRotating night shift work and rs1387153 variants in MTNR1B were associated with an increased risk of type 2 diabetes among steelworkers. The complex interaction of MTNR1A-MTNR1B-CLOCK-rotating night shift work may increase the risk of type 2 diabetes.

Development of pharmacogenomic algorithm to optimize nateglinide dose for the treatment of type 2 diabetes mellitus.

Nateglinide is a meglitinide used for the treatment of type 2 diabetes mellitus. Individual studies demonstrated the association of CYP2C9, SLCO1B1, and MTNR1B variants with the safety and efficacy of nateglinide. The current study aimed to develop a pharmacogenomic algorithm to optimize nateglinide therapy. Multiple linear regression (MLR) and classification and regression tree (CART) were used to develop a pharmacogenomic algorithm for nateglinide dosing based on the published nateglinide pharmacokinetic data on the area under the curve data (AUC) and Cmax (n = 143). CYP2C9 metabolizer phenotype, SLCO1B1, MTNR1B genotypes, and CYP2C9 inhibitor usage were used as the input variables. The results and associations were further confirmed by meta-analysis and in silico studies. The MLR models of AUC and Cmax explain 87.4% and 59% variability in nateglinide pharmacokinetics. The Bland and Altman analysis of the nateglinide dose predicted by these two MLR models showed a bias of ± 26.28mg/meal. The CART algorithm was proposed based on these findings. This model is further justified by the meta-analysis showing increased AUCs in CYP2C9 intermediate metabolizers and SLCOB1 TC and CC genotypes compared to the wild genotypes. The increased AUC in SLCO1B1 mutants is due to decreased binding affinity of nateglinide to the mutant affecting the influx of nateglinide into hepatocytes. MTNR1B rs10830963 G-allele-mediated poor response to nateglinide is attributed to increased transcriptional factor binding causing decreased insulin secretion. CYP2C9, SLCO1B1, and MTNR1B genotyping help in optimizing nateglinide therapy based on this algorithm and ensuring safety and efficacy.

Association between MTNR1B polymorphisms and obesity in African American: findings from the Jackson Heart Study

BackgroundMelatonin is a hormone that is secreted at night by the pineal gland. It exerts its function by binding to the MT1 and MT2 receptors, which are encoded by the MTNR1A and MTNR1B genes, respectively. Previous studies reveal that MTNR1B variants are associated with insulin secretion impairments and an increased body mass index (BMI) in individuals of European and Asian ancestries. Obesity is highly prevalent in the US and disproportionately affects African Americans. Here, we hypothesized that common single nucleotide polymorphisms (SNPs) imputed in 1000 Genomes in the MTNR1B gene are associated with adiposity in African American adult men and women and that the association is modified by insomnia.MethodsWe used an additive genetic model to describe the association between the adiposity traits (BMI and waist circumference) and selected MTNR1B variants in 3,029 Jackson Heart Study participants, with an average age of 55.13 ± 12.84 years, and 62% were women. We regressed the adiposity measures on the estimated allelic or genotypic dosage at every selected SNP and adjusted for age, sex, population stratification, and insomnia. Thirty common SNPs, spanning the MTNR1B gene, with a minor allele frequency ≥ 5%, a call rate ≥ 90%, a Hardy–Weinberg equilibrium p value > 10–6, were available for the analysis.ResultsThe allele T of rs76371840 was associated with adiposity (OR = 1.47 [1.13—1.82]; PFDR-adjusted = 0.0499), and the allele A of rs8192552 showed a significant association with waist circumference (β = 0.023 ± 0.007; PFDR-adjusted = 0.0077) after correcting for multiple testing. When insomnia was included in the adiposity analysis model, the following four variants became significantly associated with adiposity: rs6483208; rs4388843; rs4601728; and rs12804291.ConclusionsOur data indicate that polymorphisms in the MTNR1B gene are associated with obesity traits in African Americans. To the best of our knowledge, this is the first study to explore the effect of insomnia on the association between the circadian MTNR1B genetic variants and metabolic traits in an African American sample population. We observed that insomnia affected the association between the MTNR1B variants and adiposity.

Association of Common Genetic Risk Variants With Gestational Diabetes Mellitus and Their Role in GDM Prediction

ObjectiveWe aimed to explore the associations between common genetic risk variants with gestational diabetes mellitus (GDM) risk in Russian women and to assess their utility in the identification of GDM cases.MethodsWe conducted a case-control study including 1,142 pregnant women (688 GDM cases and 454 controls) enrolled at Almazov National Medical Research Centre. The International Association of Diabetes and Pregnancy Study Groups criteria were used to diagnose GDM. A total of 11 single- nucleotide polymorphisms (SNPs), including those in HKDC1 (rs10762264), GCK (rs1799884), MTNR1B (rs10830963 and rs1387153), TCF7L2 (rs7903146 and rs12255372), KCNJ11 (rs5219), IGF2BP2 (rs4402960), IRS1 (rs1801278), FTO (rs9939609), and CDKAL1 (rs7754840) were genotyped using Taqman assays. A logistic regression model was used to calculate odds ratios (ORs) and their confidence intervals (CIs). A simple-count genetic risk score (GRS) was calculated using 6 SNPs. The area under the receiver operating characteristic curve (c-statistic) was calculated for the logistic regression model predicting the risk of GDM using clinical covariates, SNPs that had shown a significant association with GDM in our study, GRS, and their combinations.ResultsTwo variants in MTNR1B (rs1387153 and rs10830963) demonstrated a significant association with an increased risk of GDM. The association remained significant after adjustment for age, pre-gestational BMI, arterial hypertension, GDM in history, impaired glucose tolerance, polycystic ovary syndrome, family history of diabetes, and parity (P = 0.001 and P < 0.001, respectively). After being conditioned by each other, the effect of rs1387153 on GDM predisposition weakened while the effect of rs10830963 remained significant (P = 0.004). The risk of GDM was predicted by clinical variables (c-statistic 0.712, 95 % CI: 0.675 – 0.749), and the accuracy of prediction was modestly improved by adding GRS to the model (0.719, 95 % CI 0.682 – 0.755), and more by adding only rs10830963 (0.729, 95 % CI 0.693 – 0.764).ConclusionAmong 11 SNPs associated with T2D and/or GDM in other populations, we confirmed significant association with GDM for two variants in MTNR1B in Russian women. However, these variants showed limited value in the identification of GDM cases.

Diabetes Risk Variants Associate With Impaired Insulin Sensitivity In Healthy Adults Following Bed Rest

More than 80 genetic variants increase risk for type 2 diabetes. We hypothesized that increased genetic risk for diabetes may increase susceptibility to impaired insulin sensitivity following bed rest. PURPOSE: To determine whether type 2 diabetes genetic risk variants in healthy older adults are associated with impaired insulin sensitivity following bed rest. METHODS: 37 nondiabetic adults (65.9 ± 7.9 years, BMI 27.1 ± 3.0, 82.2 ± 6.4 mg/dL fasting blood glucose) completed bed rest studies at the University of Texas Medical Branch. The protocol consisted of a 3 day run-in period, 7 days of bed rest and 7 days of rehabilitation. OGTT (75g) were administered before and after bed rest protocol and following rehabilitation. Venous blood was collected at baseline, 0, 30, 60, 90, and 120 minutes, and the Matsuda Insulin Sensitivity Index (Mat-ISI), HOMA-IR, Insulinogenic Index (II), and the Disposition Index (DI) were calculated. DNA from whole blood was used to genotype for MTNR1B (rs10830963), NOTCH2 (rs10923931), RASGRP1 (rs7403531), PROX1 (rs2075423), HHEX (rs1111875), IGF2BP2 (rs4402960), CDKAL1 (rs7754840), SLC30A8 (rs13266634), ZFAND6 (rs11634397), and TCF7L2 (rs7903146) risk variants using TaqMan Assays. Results were collated into an unweighted risk score based on the total number of risk alleles (possible range from 0-20).SPSS version 26 (IBM, Chicago, IL) was used to build a multivariate model including all outcome indices and risk variants. RESULTS: Genetic risk scores ranged from 5 to 11. HOMA-IR and II were not associated with risk scores at any point in the study. Higher overall risk scores were inversely associated with the Mat-ISI and the DI only immediately after the completion of the bed rest period (p= 0.035 and p= 0.017, respectively), but not at baseline or after rehabilitation. Post-bed rest Mat-ISI ranged from 18.1 ± 11.6 for those in the lowest risk group vs. 6.8 ± 0.26 in the highest risk group. Post-bed rest DI was 16.8 ± 12.9 for those in the lowest risk group and 5.8 ± 3 in the highest risk group. CONCLUSION: These results indicate that people with a higher genetic risk for type 2 diabetes may be at increased risk of disuse-related loss of insulin sensitivity.The work was supported by the Claude D. Pepper Older Americans Independence Center (P30 AG024832).

Genetic susceptibility, lifestyle intervention and glycemic changes among women with prior gestational diabetes.

Women with prior gestational diabetes mellitus (GDM) or high genetic susceptibility are prone to development of type 2 diabetes. We examined whether a lifestyle intervention modified the genetic effect on changes in glycemic markers among women with prior GDM. This study included 560 women with prior GDM from a randomized controlled trial, the Tianjin Gestational Diabetes Mellitus Prevention Program, who were assigned into an intervention arm (improved physical activity and healthy dietary intakes) or a control arm. We assessed associations of GDM related genetic variants in/near the CDKAL1 (rs7754840) and MTNR1B (rs10830962) genes with changes in fasting levels of glucose and insulin, β-cell function (HOMA-B) and insulin resistance (HOMA-IR) at 1 year and 2 years after the baseline. We found significant interactions between CDKAL1 variant rs7754840 and lifestyle intervention on changes in fasting insulin and HOMA-IR at 1 year (P for interactions=0.008 and 0.006, respectively). The GDM-increasing C allele was associated with a 0.07-unit greater increase in fasting insulin (P=0.048) and HOMA-IR (P=0.045) in the control group, while opposite-directional associations were observed in the intervention group; women with the C allele seemed to decrease more in these glycemic markers than the non-C-carriers (both P≤0.06). The interactions between the CDKAL1 genetic variant and lifestyle intervention on changes in fasting insulin (P=0.035) and HOMA-IR (P=0.024) remained significant over the 2-year period, even though the effects of lifestyle intervention were attenuated at 2-year. The MTNR1B variant rs10830962 did not show interaction with lifestyle intervention on changes in the glycemic markers. Healthy lifestyle intervention may be beneficial for women with the GDM predisposing CDKAL1 genetic variant in improvement of insulin resistance. ClinicalTrials.gov NCT01554358. URL OF REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01554358.

Type 2 diabetes-associated variants of the MT2 melatonin receptor affect distinct modes of signaling.

Melatonin is produced during the night and regulates sleep and circadian rhythms. Loss-of-function variants in MTNR1B, which encodes the melatonin receptor MT2, a G protein-coupled receptor (GPCR), are associated with an increased risk of type 2 diabetes (T2D). To identify specific T2D-associated signaling pathway(s), we profiled the signaling output of 40 MT2 variants by monitoring spontaneous (ligand-independent) and melatonin-induced activation of multiple signaling effectors. Genetic association analysis showed that defects in the melatonin-induced activation of Gαi1 and Gαz proteins and in spontaneous β-arrestin2 recruitment to MT2 were the most statistically significantly associated with an increased T2D risk. Computational variant impact prediction by in silico evolutionary lineage analysis strongly correlated with the measured phenotypic effect of each variant, providing a predictive tool for future studies on GPCR variants. Together, this large-scale functional study provides an operational framework for the postgenomic analysis of the multiple GPCR variants present in the human population. The association of T2D risk with signaling pathway-specific defects opens avenues for pathway-specific personalized therapeutic intervention and reveals the potential relevance of MT2 function during the day, when melatonin is undetectable, but spontaneous activity of the receptor occurs.

Association of Native American ancestry and common variants in ACE, ADIPOR2, MTNR1B, GCK, TCF7L2 and FTO genes with glycemic traits in Colombian population

Insulin resistance and defects in other related glycemic traits are common findings in the context of Metabolic Syndrome. Although genetic factors are clearly implied in susceptibility, and some gene variants have been identified mainly in populations of European ancestry, little is known about this aspect in admixed populations. The association of insulin resistance, β-cell function, fasting insulin and glucose levels with 48 gene variants, previously related to metabolic syndrome components, and with the ancestral genetic composition, estimated on 50 ancestry informative markers, was evaluated in 417 individuals from the Colombian admixed population. The Native American genetic ancestry was associated with a low β-cell function (odds ratio (OR) of 1.73 and 95% confidence interval (95% CI) of 1.07–2.81, p = 0.026). Significant genotypic associations were obtained (q-value < 0.05) for gene variants in ACE (rs4340; OR (95% CI): 2.79 (1.58–4.91), insulin resistance; mean difference (95% CI): 0.273 (0.141; 0.406), fasting insulin), ADIPOR2 (rs11061971; OR (95% CI): 0.14 (0.04–0.48), low β-cell function), MTNR1B (rs10830963; mean difference (95% CI): 0.032 (0.013; 0.051), fasting glucose) and GCK (rs4607517; mean difference (95% CI): 0.038 (0.020;0.056) and rs1799884; mean difference (95% CI): 0.027 (0.013–0.041), fasting glucose). Also the well-known gene variants rs7903146 in TCF7L2, and rs17817449 in FTO, were nominally associated with hyperglycemia (rs7903146), as well as with higher fasting insulin levels (rs17817449). Our findings indicate that gene variants in ACE, ADIPOR2, MTNR1B, GCK, TCF7L2 and FTO, are associated with glycemic traits in the admixed Colombian population, while a higher Native American genetic component is related to lower β-cell function.

Exposure to Night-Time Traffic Noise, Melatonin-Regulating Gene Variants and Change in Glycemia in Adults.

Traffic noise has been linked to diabetes, with limited understanding of its mechanisms. We hypothesize that night-time road traffic noise (RTN) may impair glucose homeostasis through circadian rhythm disturbances. We prospectively investigated the relationship between residential night-time RTN and subsequent eight-year change in glycosylated hemoglobin (ΔHbA1c) in 3350 participants of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA), adjusting for diabetes risk factors and air pollution levels. Annual average RTN (Lnight) was assigned to participants in 2001 using validated Swiss noise models. HbA1c was measured in 2002 and 2011 using liquid chromatography. We applied mixed linear models to explore RTN–ΔHbA1c association and its modification by a genetic risk score of six common circadian-related MTNR1B variants (MGRS). A 10 dB difference in RTN was associated with a 0.02% (0.003–0.04%) increase in mean ΔHbA1c in 2142 non-movers. RTN–ΔHbA1c association was modified by MGRS among diabetic participants (Pinteraction = 0.001). A similar trend in non-diabetic participants was non-significant. Among the single variants, we observed strongest interactions with rs10830963, an acknowledged diabetes risk variant also implicated in melatonin profile dysregulation. Night-time RTN may impair glycemic control, especially in diabetic individuals, through circadian rhythm disturbances. Experimental sleep studies are needed to test whether noise control may help individuals to attain optimal glycemic levels.

Analysis of MTNR1B gene polymorphisms in relationship with IRS2 gene variants, epicardial fat thickness, glucose homeostasis and cognitive performance in the elderly

ABSTARCTGenome-wide association studies pinpointed common variants in or near the MTNR1B gene encoding MT2 melatonin receptor to be strongly associated with fasting glucose levels. IRS2 gene polymorphisms impact insulin resistance and epicardial fat (EF) thickness, which in turn is correlated with visceral adiposity, cognitive ability and risk for metabolic plus cardiovascular disease. We aimed to discover the interactions between MTNR1B and IRS2 gene polymorphisms, insulin sensitivity, EF thickness and cognitive performance in the elderly. In 60 subjects aged 60 years and older, we evaluated five single nucleotide polymorphisms (SNPs) within the MTNR1B locus (rs10830962, rs4753426, rs12804291, rs10830963, rs3781638), the Gly1057Asp variant of IRS2 gene (rs1805097), biochemical parameters, cognitive performance by the Mini Mental State Examination (MMSE) and EF thickness by transthoracic echocardiography. We found that MTNR1B and IRS2 gene variants impacted EF thickness, lipid profile and glucose homeostasis. IRS2 but not MTNR1B variants impacted MMSE scores. In conclusion, MTNR1B SNPs interact with IRS2 gene variant, correlate with the amount of epicardial adipose tissue and impact glucose homeostasis and lipid profile influencing cardiometabolic risk.

Troponin T levels associated with genetic variants in NOTCH2 and MTNR1B in women with psychosis

Psychosis patients have increased prevalence of metabolic disorders, which increase the risk for cardiovascular disease. Elevated troponin T level is an early biomarker of cardiovascular damage. We tested for association between troponin T levels and genetic risk variants of elevated blood glucose level in psychosis. Glucose and troponin T levels correlated positively. MTNR1B rs10830963 and NOTCH2 rs10923931 associated with troponin T levels in women, adjusted for glucose levels. These findings may indicate metabolic genetic influences on troponin T levels among women with psychosis.

Association Study with 77 SNPs Confirms the Robust Role for the rs10830963/G of MTNR1B Variant and Identifies Two Novel Associations in Gestational Diabetes Mellitus Development.

ContextGenetic variation in human maternal DNA contributes to the susceptibility for development of gestational diabetes mellitus (GDM).ObjectiveWe assessed 77 maternal single nucleotide gene polymorphisms (SNPs) for associations with GDM or plasma glucose levels at OGTT in pregnancy.Methods960 pregnant women (after dropouts 820: case/control: m99’WHO: 303/517, IADPSG: 287/533) were enrolled in two countries into this case-control study. After genomic DNA isolation the 820 samples were collected in a GDM biobank and assessed using KASP (LGC Genomics) genotyping assay. Logistic regression risk models were used to calculate ORs according to IADPSG/m’99WHO criteria based on standard OGTT values.ResultsThe most important risk alleles associated with GDM were rs10830963/G of MTNR1B (OR = 1.84/1.64 [IADPSG/m’99WHO], p = 0.0007/0.006), rs7754840/C (OR = 1.51/NS, p = 0.016) of CDKAL1 and rs1799884/T (OR = 1.4/1.56, p = 0.04/0.006) of GCK. The rs13266634/T (SLC30A8, OR = 0.74/0.71, p = 0.05/0.02) and rs7578326/G (LOC646736/IRS1, OR = 0.62/0.60, p = 0.001/0.006) variants were associated with lower risk to develop GDM. Carrying a minor allele of rs10830963 (MTNR1B); rs7903146 (TCF7L2); rs1799884 (GCK) SNPs were associated with increased plasma glucose levels at routine OGTT.ConclusionsWe confirmed the robust association of MTNR1B rs10830963/G variant with GDM binary and glycemic traits in this Caucasian case-control study. As novel associations we report the minor, G allele of the rs7578326 SNP in the LOC646736/IRS1 region as a significant and the rs13266634/T SNP (SLC30A8) as a suggestive protective variant against GDM development. Genetic susceptibility appears to be more preponderant in individuals who meet both the modified 99’WHO and the IADPSG GDM diagnostic criteria.

Impact of Common Diabetes Risk Variant in MTNR1B on Sleep, Circadian, and Melatonin Physiology.

The risk of type 2 diabetes (T2D) is increased by abnormalities in sleep quantity and quality, circadian alignment, and melatonin regulation. A common genetic variant in a receptor for the circadian-regulated hormone melatonin (MTNR1B) is associated with increased fasting blood glucose and risk of T2D, but whether sleep or circadian disruption mediates this risk is unknown. We aimed to test if MTNR1B diabetes risk variant rs10830963 associates with measures of sleep or circadian physiology in intensive in-laboratory protocols (n = 58–96) or cross-sectional studies with sleep quantity and quality and timing measures from self-report (n = 4,307–10,332), actigraphy (n = 1,513), or polysomnography (n = 3,021). In the in-laboratory studies, we found a significant association with a substantially longer duration of elevated melatonin levels (41 min) and delayed circadian phase of dim-light melatonin offset (1.37 h), partially mediated through delayed offset of melatonin synthesis. Furthermore, increased T2D risk in MTNR1B risk allele carriers was more pronounced in early risers versus late risers as determined by 7 days of actigraphy. Our results provide the surprising insight that the MTNR1B risk allele influences dynamics of melatonin secretion, generating a novel hypothesis that the MTNR1B risk allele may extend the duration of endogenous melatonin production later into the morning and that early waking may magnify the diabetes risk conferred by the risk allele.

Diabetes Pathology and Risk of Primary Open-Angle Glaucoma: Evaluating Causal Mechanisms by Using Genetic Information.

Although type 2 diabetes (T2D) predicts glaucoma, the potential for unmeasured confounding has hampered causal conclusions. We performed separate sample genetic instrumental variable analyses using the Genetic Epidemiology Research Study on Adult Health and Aging cohort (n = 69,685; 1995-2013) to estimate effects of T2D on primary open-angle glaucoma (POAG; 3,554 cases). Genetic instrumental variables for overall and mechanism-specific (i.e., linked to T2D via influences on adiposity, β-cell function, insulin regulation, or other metabolic processes) T2D risk were constructed by using 39 genetic polymorphisms established to predict T2D in other samples. Instrumental variable estimates indicated that T2D increased POAG risk (odds ratio = 2.53, 95% confidence interval: 1.04, 6.11). The instrumental variable for β-cell dysregulation also significantly predicted POAG (odds ratioβ-cell = 5.26, 95% confidence interval: 1.75, 15.85), even among individuals without diagnosed T2D, suggesting that metabolic dysregulation may increase POAG risk prior to T2D diagnosis. The T2D risk variant in the melatonin receptor 1B gene (MTNR1B) predicted risk of POAG independently of T2D status, indicating possible pleiotropic physiological functions of melatonin, but instrumental variable effect estimates were significant even excluding MTNR1B variants. To our knowledge, this is the first genetic instrumental variable study of T2D and glaucoma, providing a novel approach to evaluating this hypothesized relationship. Our findings substantially bolster observational evidence that T2D increases POAG risk.

The Impact of Genetic Variants for Different Physiological Characterization of Type 2 Diabetes Loci on Gestational Insulin Signaling in Nondiabetic Pregnant Chinese Women.

We investigate the impact of genetic variants on transiently upregulated gestational insulin signaling. We recruited 1152 unrelated nondiabetic pregnant Han Chinese women (age 28.5 ± 4.1 years; body mass index [BMI] 21.4 ± 2.6 kg/m(2)) and gave them oral glucose tolerance tests. Matsuda index of insulin sensitivity, homeostatic model assessment of insulin resistance, indices of insulin disposition, early-phase insulin release, fasting state, and 0 to 120 minute's proinsulin to insulin conversion were used to dissect insulin physiological characterization. Several variants related to β-cell function were genotyped. The genetic impacts were analyzed using logistic regression under an additive model. By adjusting for maternal age, BMI, and the related interactions, the genetic variants in ABCC8, CDKAL1, CDKN2A, HNF1B, KCNJ11, and MTNR1B were detected to impact gestational insulin signaling through heterogeneous mechanisms; however, compared with that in nonpregnant metabolism, the genetic effects seem to be eminently and heavily influenced by maternal age and BMI, indicating possible particular mechanisms underlying gestational metabolism and diabetic pathogenesis.

Common type 2 diabetes risk variant in MTNR1B worsens the deleterious effect of melatonin on glucose tolerance in humans

AimsThe common MTNR1B genetic variant rs10830963 is associated with an increased risk of type 2 diabetes (T2D). To date, no experimental study has tested the effect of the MTNR1B variant on glucose metabolism in humans during exposure of the melatonin receptors to their ligand. The aim of this study was to investigate whether this MTNR1B variant influenced the effect of melatonin (5mg) on glucose tolerance assessed by an oral glucose tolerance test (OGTT; 75g) at different times of the day (morning and evening) as compared to a placebo. MethodsSeventeen normoglycemic women (24±6years; BMI 23.0±3.3kg/m2) completed the study (11 carriers of the risk allele [CG] and 6 noncarriers [CC]). ResultsThe effect of melatonin on glucose tolerance depended on the genotype. In the morning, the effect of melatonin (melatonin-placebo) on the glucose area under the curve (AUC) above baseline differed significantly (P=0.036) between the carriers and noncarriers. This effect of melatonin in the carriers was six times as large as that in the noncarriers. The MTNR1B SNP explained over one-quarter (26%) of the inter-individual differences in the effect of melatonin on glucose AUC. However, in the evening, the effect of melatonin on glucose AUC of the carriers and noncarriers did not differ significantly (P>0.05). ConclusionsMTNR1B rs10830963 risk variant worsens the effect of melatonin on glucose tolerance, suggesting the importance of genotyping and personalized recommendations, especially in people consuming food when melatonin levels are elevated. Large-scale studies in vulnerable populations are necessary to translate these results into real-world, clinically relevant recommendations.

A common variant in the MTNR1b gene is associated with increased risk of impaired fasting glucose (IFG) in youth with obesity.

ObjectiveTo explore the role of MTNR1B rs10830963 and G6PC2 rs560887 variants in the pathogenesis of impaired fasting glucose (IFG) in obese adolescents.Design and Methods346 Caucasians, 218 African Americans and 217 Hispanics obese children and adolescents underwent an oral glucose tolerance test (OGTT) and 518 underwent the evaluation of insulin secretion by the oral minimal model (OMM). Also, 274 subjects underwent a second OGTT after 3.0±2.1 years.ResultsThe MTNR1B rs10830963 variant was associated with higher fasting glucose levels and lower dynamic beta cell response in Caucasians and Hispanics (p<0.05) and conferred an increased risk of showing IFG to Caucasians (p=0.05), African Americans (p=0.0066) and Hispanics (p=0.024). Despite the association between the G6PC2 rs560887 and higher fasting glucose levels (p<0.05), there was no association between this variant and IFG at baseline or at follow-up (all p>0.10).ConclusionsWe show for the first time in obese youth that the MTNR1B variant is associated with an increased risk of IFG.