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Evaluation of the effect of MTNR1B rs10830963 gene variant on the therapeutic efficacy of nateglinide in treating type 2 diabetes among Chinese Han patients.

ABSTRACT: Genetic polymorphisms in the MTNR1B gene is associated with type 2 diabetes mellitus (T2DM); however, there is no evidence about its impact on the therapeutic efficacy of nateglinide. This prospective case-control study was designed to investigate the effect of MTNR1B rs10830963 gene variant on the therapeutic efficacy of nateglinide in treating T2DM. We genotyped untreated T2DM patients (N = 200) and healthy controls (N = 200) using the method of the high resolution of melting curve (HRM). Newly diagnosed T2DM patients (n = 60) with CYP2C9*1 and SLCO1B1 521TT genotypes were enrolled and given oral nateglinide (360 mg/d) for 8 weeks. The outcome was measured by collecting the venous blood samples before and at the 8th week of the treatment. The risk G allelic frequency of MTNR1B rs10830963 was higher in T2DM patients than the healthy subjects (P < 0.05). Post 8-week of treatment, newly diagnosed T2DM patients showed a less reduction in fasting plasma glucose levels and less increase in the carriers of genotype CG + GG at rs10830963 when compared with the CC genotype (P < 0.05). MTNR1B rs10830963 polymorphism was associated with the therapeutic efficacy of nateglinide in T2DM patients. Also, the CC homozygotes had a better effect than G allele carriers.Trial registration Chinese Clinical Trial Register ChiCTR13003536, date of registration: May 14, 2013.

SUBMITTER: Song JF

PROVIDER: S-EPMC8196487 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Polymorphisms in Four Genes (KCNQ1 rs151290, KLF14 rs972283, GCKR rs780094 and MTNR1B rs10830963) and Their Correlation with Type 2 Diabetes Mellitus in Han Chinese in Henan Province, China.

Project description:Genetic variants at KCNQ1 rs151290, KLF14 rs972283, GCKR rs780094 and MTNR1B rs10830963 have been associated with type 2 diabetes mellitus (T2DM), but the results are contradictory in Chinese populations. The aim of the present study was to investigate the association of these four SNPs with T2DM in a large population of Han Chinese at Henan province, China. Seven-hundred-thirty-six patients with T2DM (cases) and Seven-hundred-sixty-eight healthy glucose-tolerant controls were genotyped for KCNQ1 rs151290, KLF14 rs972283, GCKR rs780094 and MTNR1B rs10830963. The association of genetic variants in these four genes with T2DM was analyzed using multivariate logistic regression. Genotypes and allele distributions of KCNQ1 rs151290 were significantly different between the cases and controls (p < 0.05). The AC and CC genotypes and the combined AC + CC genotype of rs151290 in KCNQ1 were associated with increases risk of T2DM before (OR = 1.482, 95% CI = 1.062-2.069; p = 0.021; OR = 1.544, 95% CI = 1.097-2.172, p = 0.013; and OR = 1.509, 95% CI = 1.097-2.077, p = 0.011, respectively) and after (OR = 1.539, 95% CI = 1.015-2.332, p = 0.042; OR = 1.641, 95% CI = 1.070-2.516, p = 0.023; and OR = 1.582, 95% CI = 1.061-2.358, p = 0.024; respectively) adjustment for sex, age, anthropometric measurements, biochemical indexes, smoking and alcohol consumption. Consistent with results of genotype analysis, the C allele of rs151290 in KCNQ1 was also associated with increased risk of T2DM (OR = 1.166, 95% CI = 1.004-1.355, p = 0.045). No associations between genetic variants of KLF14 rs972283, GCKR rs780094 or MTNR1B rs10830963 and T2DM were detected. The AC and CC genotypes and the C allele of rs151290 in KCNQ1 may be risk factors for T2DM in Han Chinese in Henan province.

| S-EPMC4808923 | biostudies-literature

Association of the rs10830963 polymorphism in MTNR1B with fasting glucose levels in Chinese children and adolescents.

Project description:AIMS:We aimed to identify whether the risk G-allele was associated with fasting glucose level and other pre-diabetic and obesity-related phenotypes in Chinese children and adolescents. METHODS:The rs10830963 polymorphism in MTNR1B was genotyped in 2,030 Chinese children and adolescents of two independent studies. Association with fasting glucose levels and risk of impaired fasting glucose (IFG) were initially tested. Subsequently we analyzed the association with fasting insulin, homeostasis model assessment for insulin resistance (HOMA-IR) and for beta cell function (HOMA-B), the quantitative insulin sensitivity check index (QUICK) and obesity-related phenotypes (BMI standard deviation score, waist circumference etc.). RESULTS:The G-allele of rs10830963 was associated with increased fasting glucose level in Chinese children and adolescents (increase of 0.072 mmol/l per G-allele, 95% CI 0.034-0.111, p = 2.46 × 10(-4)). The G-allele was also associated with an increased risk of IFG (OR = 1.21, 95% CI 1.00-1.46, nominal p = 0.048). We found the glucose-raising G-allele was nominally associated with reduced HOMA-B. No association to other pre-diabetic or obesity-related phenotypes was detected. CONCLUSIONS:The rs10830963 polymorphism in MTNR1B was associated with increased fasting glucose and risk of IFG in Chinese children and adolescents. The effect may result from reduced pancreatic beta cell function, but the mechanism awaits further studies.

| S-EPMC6444495 | biostudies-literature

Increased Risk of Myocardial Infarction Among Patients With Type 2 Diabetes Who Carry the Common rs10830963 Variant in the <i>MTNR1B</i> Gene.

Project description:ObjectiveThe common MTNR1B single nucleotide polymorphism rs10830963 associates with risk of type 2 diabetes (T2D). Here, we examine the association between this gene variant and the risk of myocardial infarction (MCI) among patients with T2D. MCI is a main cause of death and disability among such individuals.Research design and methodsData from the UK Biobank cohort were used in order to examine the association between rs10830963 and incidence of MCI (fatal and nonfatal) among 13,655 participants with probable T2D during a follow-up period of 6.8 years.ResultsAssuming an additive genetic model, a positive association was found between the rs10830963 variant in the MTNR1B gene and the risk for incident MCI during the 6.8-year follow-up (adjusted hazard ratio per G allele 1.19 [95% CI 1.02, 1.40], P = 0.03).ConclusionsThe rs10830963 polymorphism may be a useful genetic marker for MCI in patients with T2D.

| S-EPMC7440907 | biostudies-literature

PPARD rs2016520 (T/C) and NOS1AP rs12742393 (A/C) polymorphisms affect therapeutic efficacy of nateglinide in Chinese patients with type 2 diabetes mellitus.

Project description:BackgroundGenetic polymorphisms in the PPARD and NOS1AP is associated with type 2 diabetes mellitus (T2DM); however, there is no evidence about its impact on the therapeutic efficacy of nateglinide. This study was designed to investigate a potential association of PPARD rs2016520 (T/C) and NOS1AP rs12742393 (A/C) polymorphisms with efficacy of nateglinide in newly diagnosed Chinese patients with type 2 diabetes mellitus (T2DM).MethodsSixty patients with newly diagnosed T2DM were enrolled to identify PPARD rs2016520 and NOS1AP rs12742393 genotypes using the polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). All subjects were treated with nateglinide (360 mg/day) for 8 weeks. Anthropometric measurements, clinical laboratory tests were obtained at baseline and after 8 weeks of nateglinide treatment.ResultsAfter nateglinide treatment for 8 consecutive weeks, patients with at least one C allele of PPARD rs2016520 showed a smaller decrease in post plasma glucose (PPG), homeostasis model assessment for beta cell function (HOMA-B) than those with the TT genotype did (P < 0.05). In patients with the AA genotype of NOS1AP rs12742393, the drug showed better efficacy with respect to levels of fasting plasma glucose (FPG), fasting serum insulin (FINS), HOMA-B and homeostasis model assessment for insulin resistance (HOMA-IR) than in patients with the AC + CC genotype (P < 0.05). NOS1AP rs12742393 genotype distribution and allele frequency were associated with responsiveness of nateglinide treatment (P < 0.05).ConclusionsThe PPARD rs2016520 and NOS1AP rs12742393 polymorphisms were associated with nateglinide monotherapy efficacy in Chinese patients with newly diagnosed T2DM.Trial registrationChinese Clinical Trial Register ChiCTR13003536, date of registration: May 14, 2013.

| S-EPMC8588701 | biostudies-literature

The Association between Dietary Iron Intake, SNP of the MTNR1B rs10830963, and Glucose Metabolism in Chinese Population.

Project description:Type 2 diabetes is associated with both dietary iron intake and single-nucleotide polymorphism (SNP) of intronic rs10830963 in melatonin receptor 1B (MTNR1B); however, it is unclear whether they interact. The aim of this study was to examine the associations between dietary iron intake, SNP of rs10830963, and glucose metabolism. Data were obtained from the Shanghai Diet and Health Survey (SDHS) during 2012-2018. Standardized questionnaires were carried out through face-to-face interviews. A 3-day 24 h dietary recall was used to evaluate dietary iron intake. Anthropometric and laboratory measurements were applied. Logistic regression and general line models were used to evaluate the association between dietary iron intake, SNP of the MTNR1B rs10830963, and glucose metabolism. In total, 2951 participants were included in this study. After adjusting for age, sex, region, years of education, physical activity level, intentional physical exercise, smoking status, alcohol use, and total energy, among G allele carriers, dietary iron intake was associated with a risk of elevated fasting glucose, higher fasting glucose, and higher HbA1c, while no significant results were observed among G allele non-carriers. The G allele of intronic rs10830963 in MTNR1B potentially exacerbated unfavorable glucose metabolism with the increasing dietary iron intake, and it was possibly a risk for glucose metabolism homeostasis in the Chinese population.

| S-EPMC10142655 | biostudies-literature

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.

Project description: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.

| S-EPMC5224877 | biostudies-literature

MTNR1B rs10830963 is associated with fasting plasma glucose, HbA1C and impaired beta-cell function in Chinese Hans from Shanghai.

Project description:Genome-wide association studies (GWAS) in White Europeans have shown that genetic variation rs10830963 in melatonin receptor 1B gene (MTNR1B) is associated with fasting glucose and type 2 diabetes, which has also been replicated in several Asian populations. As a variant in the gene involved in the regulation of circadian rhythms, the effect of the variant on sleep status remains unknown. This study aimed to investigate the effects of MTNR1B rs10830963 on fasting glucose, type 2 diabetes and sleep status in Chinese Hans.MTNR1B rs10830963 was genotyped in a population-based cohort including 3,210 unrelated Chinese Hans from Beijing and Shanghai, and tested for associations with risk of type 2 diabetes, diabetes-related traits and sleep status.We confirmed the associations of MTNR1B rs10830963 with fasting glucose (beta = 0.11 mmol/l, 95%CI [0.03, 0.18], P = 0.005), glycated hemoglobin (HbA1c) (beta = 0.07%, 95%CI [0.02,0.12], P = 0.004) and homeostasis model assessment of beta-cell function (HOMA-B) (beta = -5.01%, 95%CI [-8.24,-1.77], P = 0.003) in the Shanghai, but not in the Beijing subpopulation (P >or= 0.58). The effect size of MTNR1B rs10830963 on fasting glucose in Shanghai Chinese Hans was comparable to that reported from other Asian populations. We found no evidence of associations with type 2 diabetes (OR 1.05 [0.90-1.23], P = 0.54), homeostasis model assessment of insulin sensitivity (HOMA-S) (P = 0.86) or sleep status (P >or= 0.44).A common variant in MTNR1B was associated with fasting glucose, HbA1C and HOMA-B but not with sleep status in Chinese Hans from Shanghai, strengthening the role of MTNR1B rs10830963 in fasting glycemia and impaired beta-cell function.

| S-EPMC2873324 | biostudies-literature

A common polymorphism rs3781637 in MTNR1B is associated with type 2 diabetes and lipids levels in Han Chinese individuals.

Project description:BackgroundSeveral studies have shown that common variants in the MTNR1B gene were associated with fasting glucose level and type 2 diabetes. The purpose of this study was to examine whether tagging single nucleotide polymorphisms (SNPs) in the MTNR1B region were associated with type 2 diabetes and related traits in a Han Chinese population.MethodsWe investigated the association of polymorphisms in the MTNR1B gene with type 2 diabetes by employing a case-control study design (1118 cases and 1161 controls). Three tagging SNPs (rs10830963, rs3781637, and rs1562444) with R2>0.8 and minor allele frequency>0.05 across the region of the MTNR1B gene were studied. Genotyping was performed by matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy using a MassARRAY platform.ResultsThe polymorphism rs3781637 was associated with type 2 diabetes adjusted for age, sex and body mass index (BMI) in the additive model and recessive model (OR = 1.22, 95% CI 1.01-1.46, p = 0.038 and OR = 2.81, 95% CI 1.28-6.17, p = 0.01, respectively). In the non-diabetic controls, rs3781637 was nominally associated with plasma triglyceride, total cholesterol and low density lipoprotein cholesterol (LDL-C) levels in the recessive model (p = 0.018, 0.008 and 0.038, respectively). After adjustment for multiple comparisons, the associations of rs3781637 with total cholesterol and LDL-C remained significant in the recessive model (the empirical p = 0.024 and 0.045, respectively), but the association between rs3781637 and triglyceride became non-significant (the empirical p = 0.095). The associations of rs10830963 and rs1562444 with type 2 diabetes and related traits were not significant in the additive, dominant and recessive models.ConclusionsThe rs3781637 A/G polymorphism of the MTNR1B gene is associated with type 2 diabetes, plasma, total cholesterol and LDL-C levels in the Han Chinese population.

| S-EPMC3079619 | biostudies-literature

The <i>MTNR1B</i> rs10830963 Variant in Interaction with Pre-Pregnancy BMI is a Pharmacogenetic Marker for the Initiation of Antenatal Insulin Therapy in Gestational Diabetes Mellitus.

Project description:The rs10830963 variant of the Melatonin Receptor 1B (MTNR1B) gene is associated with the development of gestational diabetes mellitus (GDM). We hypothesized that carrying the rs10830963/G risk allele had effect on antenatal insulin therapy (AIT) initiation in GDM in a body mass index (BMI)-dependent manner. Design: In this post hoc analysis the MTNR1B rs10830963 genotype and the clinical data of 211 Caucasian GDM patients were assessed. As a first step, a pre-pregnancy BMI threshold was determined where the effect of MTNR1B rs10830963/G allele carrying on AIT initiation was the most significant using logistic regression. Maternal age adjusted real-life odds ratios (OR) values were calculated. The chi-square test was also used to calculate the p value and 10.000 bootstrap simulations were performed in each case to re-assess the statistical power and the OR. Carrying the MTNR1B rs10830963/G allele increased the odds of AIT initiation (OR = 5.2, p = 0.02 [χ² test], statistical power = 0.53) in GDM patients with pre-pregnancy BMI ≥ 29 kg/m². The statistical power reached 0.77, when the pre-pregnancy BMI cutoff of 27 kg/m² was used and the genetic effect on AIT initiation was still significant, but only using the logistic regression model. Carrying the MTNR1B rs10830963/G risk allele-in interaction with pre-pregnancy BMI-is likely be considered as a candidate pharmacogenetic marker of antenatal insulin therapy initiation and should be further assessed in precision medicine trials in GDM.

| S-EPMC6321391 | biostudies-literature

Genetics and Clinical Characteristics of PPARγ Variant-Induced Diabetes in a Chinese Han Population.

Project description:ObjectivesPPARγ variants cause lipodystrophy, insulin resistance, and diabetes. This study aimed to determine the relationship between PPARγ genotypes and phenotypes and to explore the pathogenesis of diabetes beyond this relationship.MethodsPPARγ2 exons in 1,002 Chinese patients with early-onset type 2 diabetes (diagnosed before 40 years of age) were sequenced. The functions of variants were evaluated by in vitro assays. Additionally, a review of the literature was performed to obtain all reported cases with rare PPARγ2 variants to evaluate the characteristics of variants in different functional domains.ResultsSix (0.6%) patients had PPARγ2 variant-induced diabetes (PPARG-DM) in the early-onset type 2 diabetes group, including three with the p.Tyr95Cys variant in activation function 1 domain (AF1), of which five patients (83%) had diabetic kidney disease (DKD). Functional experiments showed that p.Tyr95Cys suppresses 3T3-L1 preadipocyte differentiation. A total of 64 cases with damaging rare variants were reported previously. Patients with rare PPARγ2 variants in AF1 of PPARγ2 had a lower risk of lipodystrophy and a higher rate of obesity than those with variants in other domains, as confirmed in patients identified in this study.ConclusionThe prevalence of PPARG-DM is similar in Caucasian and Chinese populations, and DKD was often observed in these patients. Patients with variants in the AF1 of PPARγ2 had milder clinical phenotypes and lack typical lipodystrophy features than those with variants in other domains. Our findings emphasize the importance of screening such patients via genetic testing and suggest that thiazolidinediones might be a good choice for these patients.

| S-EPMC8576343 | biostudies-literature

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