Rs9939609 Variant Research Articles

1317-P: Static, but Nondynamic, ß-Cell Responsiveness to Glucose Is Affected by the Risk Variant rs7903146 of TCF7L2 and Associated with a Delayed Time-to-Glucose-Peak in Obese Youths

Background: Beta-cell function can be dissected into a dynamic component, estimating the immediate secretion after glucose change, and a static component representing the insulin secreted at any given glucose level. We evaluated their clinical and genetic determinants as well as their effect on glucose time to peak in obese youths. Methods: A 3hOGTT was performed in 630 obese youths (374F, 13.6±3.1y, 33.3±7.5kg/m2); dynamic (DId) and static (DIs) components of beta-cell function were estimated by the oral minimal model. Participants were genotyped for the rs7903146 of TCF7L2 and grouped into 3 tertiles for DId and DIs. Effect of sex, BMI, age, ethnicity and TCF7L2 on DIs/DId was estimated by multivariate regression model. Results: Lower DId, as well as DIs, were associated with higher BMI and 2h-glucose, while fasting glucose was increased in the lower DIs tertile. The risk genotype (TT) for the TCF7L2 and the BMI, were both associated to a lower DIs (p<0.01), while TCF7L2 did not affect DId (p=0.22). Glucose time to peak>30min was more likely in the lower DIs, without a difference among the DId tertiles (Figure). Conclusion: The risk variant of TCF7L2 is associated with a blunted DIs, in the absence of an effect on the DId, and accompanied by a delayed glucose time to peak. The role of TCF7L2 in the incretin response might be responsible for this effect. Disclosure A. Galderisi: None. D. Trico: None. C. Dalla Man: None. S. Siebel: None. N. Santoro: None. B. Pierpont: None. C. Cobelli: None. S. Caprio: None. Funding National Institutes of Health (R01DK085577-01, R01HD40787, R01HD28016, P30DK045735, K12DK094714-02, R01DK111038-01A1); Robert E. Leet and Clara Guthrie Patterson Trust; European Medical International Framework (EMIF115372)

Effects of TCF7L2 rs7903146 variant on metformin response in patients with type 2 diabetes.

The response to metformin, the most commonly used drug for the treatment of type 2 diabetes (T2D), is highly variable. The common variant rs7903146 C>T within the transcription factor 7-like 2 gene (TCF7L2) is the strongest genetic risk factor associated with T2D to date. In this study, we explored the effects of the TCF7L2 rs7903146 genotype on metformin response in T2D. The study included 86 newly diagnosed patients with T2D, incident users of metformin. Levels of fasting glucose, insulin, HbA1c, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and anthropometric parameters were measured prior to metformin therapy, and 6 and 12 months after the treatment. Genotyping of the TCF7L2 rs7903146 was performed by the Sequenom MassARRAY® iPLEX® platform. At baseline, the diabetes risk allele (T) showed an association with lower triglyceride levels (p = 0.037). After 12 months of metformin treatment, the T allele was associated with 25.9% lower fasting insulin levels (95% CI 10.9-38.3%, p = 0.002) and 29.1% lower HOMA-IR index (95% CI 10.1-44.1%, p = 0.005), after adjustment for baseline values. Moreover, the T allele was associated with 6.7% lower fasting glucose levels (95% CI 1.1-12.0%, p = 0.021), adjusted for baseline glucose and baseline HOMA-%B levels, after 6 months of metformin treatment. This effect was more pronounced in the TT carriers who had 16.8% lower fasting glucose levels (95% CI 7.0-25.6%, p = 0.002) compared to the patients with CC genotype. Our results suggest that the TCF7L2 rs7903146 variant affects markers of insulin resistance and glycemic response to metformin in newly diagnosed patients with T2D within the first year of metformin treatment.

The clinical effectiveness of essential oils and aromatherapy for the treatment of Acne Vulgaris (Acne): A randomised controlled trial

Hypertriglyceridemia is associated with an increased risk of cardiovascular disease. The potential favorable effects of artichoke leaf extract (ALE) on anthropometric and metabolic indices may affect by fat mass and obesity associated (FTO)-rs9939609 polymorphism. This study was designed to evaluate the effects of ALE supplementation on cardiometabolic risk factors in hypertriglyceridemic patients regarding the interaction of rs9939609-FTO polymorphism with intervention outcomes.In this double-blind placebo-controlled randomized clinical trial, 52 patients with hypertriglyceridemia randomly allocated to receive ALE (1800 mg/day as four tablets) or matching placebo (consisting of corn starch, lactose, and avicel) for 12 weeks. The measurement of anthropometric indices, fasting blood sugar (FBS), and lipid profile was performed before and after the intervention. The FTO-rs9939609 polymorphism was genotyped by polymerase chain reaction-restriction length polymorphism (PCR-RFLP). The interaction was tested using two-way ANOVA.Forty-eight patients completed the trial (intervention, n = 24, placebo = 24). ALE and placebo groups were similar in the baseline characteristics. ALE supplementation did not change anthropometric indices and metabolic parameters. However, there was a significant interaction between FTO-rs9939609 polymorphism and TC, LDL-C, and TG level response to ALE supplementation. Moreover, significant changes in TG level were observed in A allele carriers compared to subjects with TT genotype.No significant effect of ALE supplementation was shown on anthropometric and biochemical indices in Iranian hypertriglyceridemic patients. However, rs9939609 variant of FTO gene seems to affect lipid profile response to ALE supplementation. Further clinical trials with larger sample size are suggested to clarify the possible interaction between rs9939609 variant or other variants of FTO gene and ALE supplementation in hypertriglyceridemia.

Associations between vitamin D receptor genetic variants and tuberculosis: a meta-analysis.

We performed a meta-analysis to evaluate potential associations between vitamin D receptor (VDR) genetic variants and tuberculosis (TB). Systematic literature research was conducted in PubMed, Web of Science, and Embase. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) to estimate strength of associations in all possible genetic models, and P values ≤ 0.05 were considered to be statistically significant. In total, 42 studies were enrolled for analyses. Pooled overall analyses suggested that VDR rs1544410 (dominant model: P = 0.02; allele model: P = 0.03) and rs731236 (dominant model: P = 0.04; recessive model: P = 0.02; allele model: P = 0.01) variants were significantly associated with TB. Further subgroup analyses by ethnicity revealed that rs1544410 (dominant and allele models) and rs731236 (dominant, recessive, and allele models) variants were both significantly associated with TB in South Asians. When we stratified data by type of disease, positive results were detected for rs7975232 variant in EPTB (dominant, recessive, over-dominant, and allele models) subgroup, and for rs2228570 variant in PTB (dominant, recessive, and allele models) and EPTB (dominant, recessive, over-dominant, and allele models) subgroups. Our meta-analysis supported that rs7975232, rs1544410, rs2228570, and rs731236 variants might serve as genetic biomarkers of certain types of TB.

The Role of Genetic Variant rs13266634 in SLC30A8/ZnT8 in Postoperative Hyperglycemia After Major Abdominal Surgery.

Following major surgery, postoperative hyperglycemia (POHG) is associated with suboptimal outcomes among patients with diabetes and nondiabetic patients. A specific genetic variant, rs13266634 (c.973C>T; p.ARG325TRP) in zinc transporter SLC30A8/ZnT8, is associated with protection against type 2 diabetes (T2D), suggesting it may be actionable for predicting and preventing POHG. To determine independent and mediated influences of a genetic variant on POHG in patients undergoing a model major operation, complex ventral hernia repair (cVHR). For 110 patients (mean body mass index, 34.9 ± 5.8; T2D history, 28%) undergoing cVHR at a tertiary referral center (January 2012 to March 2017), multivariable regression was used to correlate the rs13266634 variant to preoperative clinical, laboratory, and imaging-based indices of liver steatosis and central abdominal adiposity to POHG. Causal mediation analysis (CMA) was used to determine direct and mediated contributions of SLC30A8/ZnT8 status to POHG. Variant rs13266634 was present in 61 patients (55.4%). In univariate models, when compared with patients with homozygous wild-type genotype (C/C, n = 49), rs13266634 was associated with significantly lower risks of POHG (OR, 0.30; 95% CI, 0.14 to 0.67; P = 0.0038). Multivariable regression indicated that the association was independent (OR, 0.39; 95% CI, 0.15 to 0.97; P = 0.040). Additionally, CMA suggested that rs13266634 protects against POHG directly and indirectly through its influence on liver steatosis and central adiposity. In medically complex patients undergoing major operations, the rs13266634 variant protects against POHG and its associated outcomes, through independent and mediated contributions. In C/C patients undergoing major operations, SLC30A8/ZnT8 may prove useful to stratify the risk of POHG and potentially as a therapeutic target.

GENETIC SUSCEPTIBILITY OF TRANSCRIPTION FACTOR 7-LIKE 2 GENE VARIANT AND RISK OF TYPE 2 DIABETES IN ASIAN INDIANS

Background: The variants of transcription factor 7-like 2 (TCF7L2) gene have been shown to be associated with type 2 diabetes mellitus (T2DM) and its related complications.
 Objectives: We aimed to explore the possible association of rs7903146 (C/T) variant in TCF7L2 with the risk of T2DM in the North Indian population.
 Methods: The present case–control study included a total of 638 human subjects (318 T2DM subjects and 320 healthy controls). Various anthropometric, biochemical, and genetic parameters were studies in all the subjects. Genotyping of TCF7L2 gene was carried out using allele-specific polymerase chain reaction method.
 Results: The results of this study indicate significantly higher values of body mass index, waist circumference, waist-to-hip ratio, and body fat (%) in T2DM subjects than controls (p≤0.001). Dyslipidemia represented by higher levels of triglycerides and reduced values of high-density lipoprotein was more predominant in diabetic subjects compared to healthy subjects. The frequency of risk genotype (TT) frequency was significantly higher in T2DM subjects (16.4%) compared to controls (11.6%). The “T” allele was more dominant in diabetic subjects than controls. Logistic regression analysis of the data revealed a significant association of TT genotype with 2-fold (odds ratio with 95% of confidence interval; 2.09 [1.29–3.42] p=0.003) and CT genotype with 1.7-fold (1.73 [1.23–2.44] p=0.002) increased risk of developing T2DM.
 Conclusions: The present study demonstrated a significant association of rs7903146 (C/T) variant in TCF7L2 with the augmented risk of T2DM in North Indian population.

Association of variants rs7903146 and rs290487 of TCF7L2 gene with diabetic nephropathy and co-morbidities (hypertension and dyslipidemia) in type 2 diabetes mellitus

BackgroundDiabetes mellitus is a metabolic disorder which can affects the body's ability to produce or use of the hormone insulin leads to high blood sugar levels and it may serves as a host of complications. Emerging evidence suggests that common and rare genetic polymorphisms can influence the risk of developing diabetic complications. We attempt to evaluate the association of (rs7903146 and rs290487) variants of TCF7L2 gene with diabetic nephropathy and co-morbidities (hypertension and dyslipidemia) in T2DM. Material & methodsA total of 370 cases including 122 T2DM with Nephropathy, 119 T2DM with Hypertension, 129 T2DM with Dyslipidemia and 120 ethnicity matched healthy controls were included in this case-control study. TCF7L2 gene polymorphism was evaluated using polymerase chain reaction followed by restriction fragment length polymorphism analysis. ResultsSignificant difference in TCF7L2 (rs7903146) gene was observed when the genotype frequencies of group 1, 2 and 3 compare with control (p = 0.048, 0.005 and 0.004) whereas, no association of TCF7L2 (rs290487) gene was found with group 1, group 2 and group 3 (p = 0.808, 0.466 and 0.285). Significant difference in TCF7L2 (rs7903146) gene was observed when the genotype frequencies of group 1 and group 3 compare with group 2 (p < 0.001). ConclusionOur findings suggest that TCF7L2 (rs7903146) gene polymorphism might be involved in the pathogenesis of diabetic nephropathy and co-morbidities (hypertension and dyslipidemia) in T2DM.

Effects of MTNR1B genetic variants on the risk of type 2 diabetes mellitus: A meta-analysis.

BackgroundWhether melatonin receptor 1B (MTNR1B) variants are associated with type 2 diabetes mellitus (T2DM) remains unclear. Therefore, we performed this meta‐analysis to better explore correlations between MTNR1B variants and T2DM.MethodsLiterature research was performed in PubMed, Medline, and Embase. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.ResultsTotally 21 studies were enrolled to analyses. Pooled overall analyses showed that MTNR1B rs10830963 variant was significantly correlated with the susceptibility to T2DM (allele model: p = 0.02, OR = 0.97, 95% CI 0.95–1.00). Further subgroup analyses by ethnicity of participants revealed that rs10830963 variant was significantly correlated with the susceptibility to T2DM in South Asians, but not in Caucasians or East Asians. No any other positive results were found in overall and subgroup analyses.ConclusionsOur findings indicated that MTNR1B rs10830963 variant might serve as a genetic biomarker of T2DM, especially in South Asians.

A meta-analysis on associations between vitamin D receptor genetic variants and tuberculosis

ObjectivesWe aimed to analyze potential associations between vitamin D receptor (VDR) genetic variants and tuberculosis (TB) through a meta-analysis. MethodsSystematic literature research of PubMed, Web of Science, Embase and CNKI was performed to identify eligible articles. Statistical analyses were conducted by using Review Manager. ResultsTotally 54 studies were enrolled for analyses. Pooled overall analyses suggested that VDR rs1544410 (dominant model: p = 0.02; allele model: p = 0.04), rs2228570 (recessive model: p = 0.01; allele model: p = 0.03) and rs731236 (recessive model: p = 0.02; allele model: p = 0.02) variants were significantly associated with TB. Further subgroup analyses by ethnicity revealed that rs1544410 variant was significantly associated with TB in South Asians (dominant and allele models) and Caucasians (dominant, recessive and allele models), rs2228570 variant was significantly associated with TB in East Asians (recessive model), and rs731236 variant was significantly associated with TB in South Asians (dominant, recessive and allele models). ConclusionsOur meta-analysis suggested that VDR rs1544410, rs2228570 and rs731236 variants might serve as genetic biomarkers of TB in certain populations.

Pilot studies on the prevalence and association of TCF7L2 polymorphisms in non-diabetic participants and type 2 diabetic patients of South Tamil Nadu

Background: Genetic predisposition plays a critical role in the incidence of type 2 diabetes mellitus (T2DM). While a few reports strongly associate TCF7L2 gene polymorphisms in the T2DM incidence in India, data pertaining to the prevalence of these polymorphisms in the south Tamil Nadu population has been lacking. Hence, the present study aims to determine the prevalence and association of the TCF7L2 gene variants rs7903146, rs12255372 in the regional population of south Tamil Nadu.Methods: Peripheral blood samples from controls, T2DM patients were utilized to isolate genomic DNA and genotyping was carried out using PCR based strategies, direct sequencing. Socio-demographic details, anthropometric measurements, determination of postprandial, random blood glucose levels and oral glucose tolerance test (OGTT) were further carried out to evaluate the predisposition risk for T2DM.Results: 50% of the control group participants and 73.9% of the T2DM patients were positive (CT/TT) for the TCF7L2 polymorphism rs7903146. The rs12255372 SNP was less prevalent in the controls, patients and was dispersed in only 25% of the controls and 60.9% (GT/TT) of the patients. The 60 minutes plasma glucose levels for the oral glucose tolerance test (OGTT) was higher (143.3±19.8) in the rs7903146 and rs12255372 positive control participants.Conclusions: The study results reveal that TCF7L2 polymorphisms are dispersed in the regional population and further large scale, long term follow up studies will aid preventive and therapeutic measures in T2DM.

Gene x Gene Interactions Highlight the Role of Incretin Resistance for Insulin Secretion.

Introduction: Genetic polymorphisms in TCF7L2 are the strongest common risk variants for type 2 diabetes mellitus (T2D). We and others have shown that genetic variation in TCF7L2 and WFS1 affect incretin-stimulated insulin secretion. A recent genome-wide association study discovered genetic variants associated with incretin levels. We hypothesized that these SNPs (single nucleotide polymorphisms) interact with the well-known TCF7L2 variant rs7903146 on insulin secretion due to their incretin altering effect.Methods: In this retrospective analysis, we used data from the cross-sectional TUEF-cohort (n = 2929) and a hyperglycemic clamp study using additional GLP-1 infusion at the end of the clamp (n = 76). Insulin secretion was measured by evaluating OGTT-derived indexes of insulin secretion and insulin/C-peptide levels during clamp. We genotyped rs7903146 in TCF7L2, rs10010131 in WFS1, and six SNPs associated with GLP-1 and GIP levels.Results: One of the six incretin-associated SNPs, rs17681684 in GLP2R, exhibited significant SNP x SNP interactions with rs7903146 in TCF7L2 on insulin secretion (p = 0.0024) after correction for multiple testing. Three further SNP‘s showed nominally significant interactions (p < 0.05). In the hyperglycemic clamp study, rs7903146 in TCF7L2 also interacted with rs17681684 on AUC C-peptide during the GLP-1 stimulation phase, thereby replicating the above finding.Conclusion: The findings exemplify the role of SNP x SNP interactions in the genetics of type 2 diabetes mellitus and corroborate the existence of clinically relevant differences in incretin sensitivity.

Correlation between PLCE1 rs2274223 variant and digestive tract cancer: A meta‐analysis

BackgroundThe relationship between phospholipase C ε‐1 (PLCE1) rs2274223 variant and digestive tract cancer remains inconclusive despite extensive investigations. Therefore, we performed this meta‐analysis to obtain a more credible conclusion.MethodsPubMed, Medline, and Embase were systematic searched. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.ResultsA total of 27 studies were finally included. Pooled analyses suggested that PLCE1 rs2274223 variant was significantly correlated with the likelihood of esophageal cancer (dominant model: p < 0.001, OR = 0.77, 95% CI 0.72–0.83; recessive model: p < 0.001, OR = 1.28, 95% CI 1.12–1.45; additive model: p < 0.001, OR = 1.20, 95% CI 1.11–1.29; allele model: p < 0.001, OR = 0.80, 95% CI 0.74–0.88) and gastric cancer (recessive model: p = 0.001, OR = 1.27, 95% CI 1.10–1.47; allele model: p = 0.03, OR = 0.88, 95% CI 0.78–0.98) in overall population. Further subgroup analyses showed that the positive results were mainly driven by the East Asians. However, no positive results were detected in Caucasians and West Asians.ConclusionOur findings indicated that the PLCE1 rs2274223 variant might serve as a promising genetic biomarker of esophageal and gastric cancer in East Asians.

Single and multi-locus association study of TCF7L2 gene variants with susceptibility to type 2 diabetes mellitus in an Iranian population

Prior studies indicated that some of transcription factor 7-like 2 (TCF7L2) gene variants such as rs7903146, rs12255372 and rs11255372 are constantly associated with Type 2 diabetes mellitus (T2DM) in various populations and ethnic groups. The purpose of this study was to assess the association between TCF7L2 variants (rs7903146, rs11196205, and rs11255372) and T2DM by TaqMan assay. Statistical analysis was performed through SNPAlyze and SPSS. Significant associations of rs7903146 (P = 1.9 × 10–7), and rs11255372 (P = 2.98 × 10–10) both under a dominant model were found. Based on allele frequency, there was a significant difference between the two study groups at rs7903146 and rs12255372 variants (P = 6.8 × 10–10, and P = 9.3 × 10–11, respectively). Two haplotypes including Hap-1 (C-G-G) and Hap-2 (T-G-T) indicated a significant difference between the two study groups (P = 1.174 × 10-9and P = 7.432 × 109 respectively). In conclusion, rs7903146 and rs12255372 were significantly associated with T2DM in the specified Northern Iranian population.

The Interaction between Genetic Polymorphisms in FTO and TCF7L2 Genes and Dietary Intake with Regard to Body Mass and Composition: An Exploratory Study.

In contrast to the large number of genetic studies on obesity, there has been significantly less nutrigenetics investigation of the interaction between diet and single nucleotide polymorphisms (SNPs) in obesity, especially within Eastern Mediterranean populations. The aim of this study was to evaluate the potential interactions between three candidate SNPs, namely, rs1558902 and rs9939609 in the fat mass and obesity (FTO) gene and the rs7903146 variant of the Transcription factor 7 like 2 (TCF7L2) gene, and macronutrient intake with regard to obesity, body fat, and muscle composition. Three hundred and eight healthy Lebanese adults were included in this study. Data collection included a questionnaire for demographics and lifestyle in addition to a detailed dietary assessment using a culture-specific 80-item semi-quantitative food frequency questionnaire. This was coupled with anthropometric measurements and peripheral blood withdrawal for DNA and genotyping using Taqman allele discrimination assays. The two FTO candidate SNPs were not associated with risk of obesity in this population sample, yet there was a trend, though not a significant one, towards lower muscle mass among carriers of the risk allele of either FTO SNPs. To our knowledge, these results have not been previously reported. As for the TCF7L2 rs7903146 variant, results were congruent with the literature, given that individuals who were homozygous for the risk allele had significantly higher body mass index (BMI) and body fat despite lower intakes of saturated fat. Similar interactions, though not significant, were shown with muscle mass, whereby individuals who were homozygous for the risk allele had lower muscle mass with higher intakes of saturated fat, a result that, to our knowledge, has not been previously reported.

TCF7L2 Expression Is Regulated by Cell Differentiation and Overfeeding in Human Adipose Tissue

ABSTRACTAim: The TCF7L2 gene variant rs7903146 has the largest effect on type 2 diabetes risk reported in genome-wide association studies, however its role in adipose tissue development and function is unknown. We investigate the association between gene variant rs7903146 and metabolic parameters and examine in vitro and ex vivo gene expression of TCF7L2 in human adipose tissue and progenitor cells from two independent populations of young healthy men with increased risk of type 2 diabetes due to low birth weight (LBW). Design: Adipose tissue biopsies were excised from 40 healthy young men with low and normal birth weights (NBW) after a control and 5-day high-fat overfeeding diet. In another cohort including 13 LBW and 13 NBW men, adipocyte progenitor cells were isolated and cultivated. Transcriptome-wide expression was performed on RNA extracted from biopsies or cell cultures. Results: Diet-induced peripheral insulin resistance is more pronounced in carriers of the T-risk allele rs7903146, whereas no association with hepatic insulin resistance was shown. TCF7L2 expression increased during adipogenesis in isolated preadipocytes from both LBW and NBW men (p < 0.001) and correlated positively with markers of progenitor cell proliferation and maturation capacity. In the mature adipose tissue, LBW men had lower expression of TCF7L2 compared to NBW men at baseline (p = 0.03) and TCF7L2 expression was suppressed by short-term overfeeding in NBW men (p = 0.005). Conclusions: The results suggest a regulation of TCF7L2 expression during adipogenesis and in mature adipose tissue upon overfeeding, and further that young men exposed to an adverse intrauterine environment have reduced mature adipose tissue TCF7L2 expression.

The role of the genetic variants IRX3 rs3751723 and FTO rs9939609 in the obesity phenotypes of children and adolescents

ObjectiveWe investigated the association of IRX3 SNP rs3751723 with anthropometric characteristics related to adiposity and potential relationships with FTO SNP rs9939609 in a population of Brazilian children and adolescents. MethodsA total of 871 children and adolescents between 7 and 17 years of age were recruited. Adiposity measurements and biochemical parameters were assessed. The variants were genotyped by real-time PCR. Analysis of multiple linear regression, multiple logistic regression, and generalised multifactor dimensionality reduction (GMDR) adjusted for sex, age and ethnicity were applied to test the polymorphisms association with obesity-related phenotypes and the interaction between them. ResultsThe analyses showed that IRX3 was associated with obesity and fat percentage (BF%). An association of FTO rs9939609 with body mass index (BMI) Z-Score and with waist circumference (WC) was detected. The odds ratios (OR) showed that IRX3 rs3751723 was associated with risk of obesity in additive model (p=0.017), recessive model (p=0.016) and with high BF% in all models. FTO rs9939609 was associated with risk of obesity in additive model (p=0.031), recessive (p=0.033) and with altered WC in all models. GMDR-based predictive models for the risk of obesity, altered WC and high BF% adjusted by age, ethnicity and sex suggested no interaction of the two loci. ConclusionsThe genetic variants rs3751723 and rs9939609 have an influence on the characteristics of adiposity; however, the effects of IRX3 and FTO investigated polymorphisms are independent in relation to adiposity parameters.

Effect of TCF7L2 polymorphism on pancreatic hormones after exenatide in type 2 diabetes

BackgroundGlucagon-like peptide 1 (GLP-1) stimulates insulin secretion and reduces blood glucose in type 2 diabetes mellitus (T2DM). TCF7L2 rs7903146 polymorphism has been associated with decreased insulin secretion, reduced GLP-1 action, and possible impaired peripheral insulin sensitivity.ObjectivesTo evaluate the postprandial pancreatic hormone response in patients with T2DM carriers of the TCF7L2 variant rs7903146 (CT/TT) compared with noncarriers of this variant (CC) after treatment with the GLP-1 agonist exenatide.MethodsIntervention study. Patients with T2DM (n = 162) were genotyped for the TCF7L2 rs7903146 single nucleotide polymorphism (SNP). Individuals with CT/TT and CC genotypes were compared regarding basal serum levels of glucose, glycosylated hemoglobin A1C (HbA1c), HDL, uric acid, insulin, and C-peptide. A subset of 56 individuals was evaluated during a 500-calorie mixed-meal test with measurements of glucose, insulin, proinsulin, C-peptide and glucagon before and after treatment with exenatide for 8 weeks.ResultsPatients with genotypes CC and CT/TT presented similar glucose area under the curve (AUC) 0–180 min before treatment and a similar decrease after treatment (p < 0.001). Before exenatide, insulin levels at 30–120 min were higher in CT/TT versus CC subjects (p < 0.05). After treatment with exenatide, only CT/TT individuals demonstrated insulin reduction at 30–180 min during the meal test (p < 0.05). Patients with the CC genotype presented no differences in insulin concentrations before and after treatment. The areas under the glucagon curve between 0 and 180 min were similar before treatment and reduced after treatment in both groups (p < 0.001).ConclusionsThe presence of the TCF7L2 rs7903146 T allele in patients with T2DM was associated with increased secretion of insulin response to a mixed-meal test. Furthermore, after treatment with exenatide, only the carriers of the T allele showed significantly decreased postprandial plasma insulin peak levels comparing with non carriers.

The Influence of FTO Polymorphism rs9939609 on Obesity, Some Clinical Features, and Disturbance of Carbohydrate Metabolism in Patients with Psoriasis.

Background Psoriasis is often accompanied by obesity, hyperlipidemia, diabetes, and metabolic syndrome as risk factors of cardiovascular conditions and premature mortality. Objective The study was aimed at investigating whether psoriatic patients, who carry risk allele of obesity-related FTO gene, are more predisposed to obesity and metabolic disturbances and whether it influences the severity of psoriasis. Methods 197 patients with psoriasis, representing Lower Silesia region of Poland, underwent physical examination and anthropometric measurements. Blood samples for biochemical and genetic analysis were collected. All patients were genotyped for FTO gene rs9939609 variant. Identification of SNP was conducted with the use of minisequencing method. Results Around 63% of patients were carriers of at least one risk allele A and 20% were AA homozygotes. The A allele was associated with increased BMI and hip and waist circumferences. The carriers of risk allele had increased PASI and CRP values and tended to have an increased insulin concentration. Conclusion Psoriatic patients, carriers of risk allele of FTO gene rs9939609, have an increased risk for more severe psoriasis and obesity and may develop obesity-induced insulin resistance.

The associations of daylight and melatonin receptor 1B gene rs10830963 variant with glycemic traits: the prospective PPP-Botnia study

Background: Seasonal variation in glucose metabolism might be driven by changes in daylight. Melatonin entrains circadian regulation and is directly associated with daylight. The relationship between melatonin receptor 1B gene variants with glycemic traits and type 2 diabetes is well established. We studied if daylight length was associated with glycemic traits and if it modified the relationship between melatonin receptor 1B gene rs10830963 variant and glycemic traits.Materials: A population-based sample of 3422 18–78-year-old individuals without diabetes underwent an oral glucose tolerance test twice, an average 6.8 years (SD = 0.9) apart and were genotyped for rs10830963. Daylight data was obtained from the Finnish Meteorological Institute.Results: Cross-sectionally, more daylight was associated with lower fasting glucose, but worse insulin sensitivity and secretion at follow-up. Longitudinally, individuals studied on lighter days at follow-up than at baseline showed higher glucose values during the oral glucose tolerance test and lower Corrected Insulin Response at follow-up. GG genotype carriers in the rs10830963 became more insulin resistant during follow-up if daylight length was shorter at follow-up than at baseline.Conclusions: Our study shows that individual glycemic profiles may vary according to daylight, MTNR1B genotype and their interaction. Future studies may consider taking daylight length into account.Key messagesIn Western Finland, the amount daylight follows an extensive annual variation ranging from 4 h 44 min to 20 h 17 min, making it ideal to study the associations between daylight and glycemic traits. Moreover, this allows researchers to explore if the relationship between the melatonin receptor 1B gene rs10830963 variant and glycemic traits is modified by the amount of daylight both cross-sectionally and longitudinally.This study shows that individuals, who participated in the study on lighter days at the follow-up than at the baseline, displayed to a greater extent worse glycemic profiles across the follow-up.Novel findings from the current study show that in the longitudinal analyses, each addition of the minor G allele of the melatonin receptor 1B gene rs10830963 was associated with worsening of fasting glucose values and insulin secretion across the 6.8-year follow-up.Importantly, this study shows that in those with the rs10830963 GG genotype, insulin sensitivity deteriorated the most significantly across the 6.8-year follow-up if the daylight length on the oral glucose tolerance testing date at the follow-up was shorter than at the baseline.Taken together, the current findings suggest that the amount of daylight may affect glycemic traits, especially fasting glucose and insulin secretion even though the effect size is small. The association can very according to the rs10830963 risk variant. Further research is needed to elucidate the mechanisms behind these associations.

Determination of individual type 2 diabetes risk profile in the North East Indian population & its association with anthropometric parameters.

Background & objectives:Diabetes genomics research has illuminated single nucleotide polymorphism (SNP) in several genes including, fat mass and obesity associated (FTO) (rs9939609 and rs9926289), potassium voltage-gated channel subfamily J member 11 (rs5219), SLC30A8 (rs13266634) and peroxisome proliferator-activated receptor gamma 2 (rs1805192). The present study was conducted to investigate the involvement of these polymorphisms in conferring susceptibility to type 2 diabetes (T2D) in the North East Indian population, and also to establish their association with anthropometric parameters.Methods:DNA was extracted from blood samples of 155 patients with T2D and 100 controls. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing. To confirm the association between the inheritance of SNP and T2D development, logistic regression analysis was performed.Results:For the rs9939609 variant (FTO), the dominant model AA/(AT+TT) revealed significant association with T2D [odds ratio (OR)=2.03, P=0.021], but was non-significant post correction for multiple testing (P=0.002). For the rs13266634 variant (SLC30A8), there was considerable but non-significant difference in the distribution pattern of genotypic polymorphisms between the patients and the controls (P=0.004). Significant association was observed in case of the recessive model (CC+CT)/TT (OR=4.56 P=0.001), after adjusting for age, gender and body mass index. In addition, a significant association (P=0.001) of low-density lipoprotein (mg/dl) could be established with the FTO (rs9926289) polymorphism assuming dominant model.Interpretation & conclusions:The current study demonstrated a modest but significant effect of SLC30A8 (rs13266634) polymorphisms on T2D predisposition. Considering the burgeoning prevalence of T2D in the Indian population, the contribution of these genetic variants studied, to the ever-increasing number of T2D cases, appears to be relatively low. This study may serve as a foundation for performing future genome-wide association studies (GWAS) involving larger populations.