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Background: Transcription factor 7-like 2 (TCF7L2) gene polymorphisms are known risk factors for type 2 diabetes mellitus (T2DM). However, the relationship between TCF7L2 polymorphism and diabetic nephropathy (DN) is inconclusive. Objectives: to explore the association of TCF7L2 rs7903146 (C/T) gene polymorphism and DN in T2DM Egyptian patients. Methods: 80 patients with T2DM (40 patients without DN and 40 patients with DN) were enrolled in the study. Genotyping for the rs7903146 (C/T) polymorphism in TCF7L2 gene was performed by real time PCR. Results: The frequency of rs7903146 genotypes in diabetic patients without DN was ( CC: 57.5%; CT: 37.5%; TT: 5%), while in diabetic patients with DN was (CC: 2.5%; CT: 40%; TT: 57.5%). Patients with DN were exposed to the TT 25.7 times more than who didn’t develop DN (OR= 25.7, 95% CI= 0.43-94, P= 0.001**). Upon examining the allelic discrimination, C allele was present in 77.5% of patients without DN versus 23.8% of patients with DN, While T allele was found in 22.5% of patients without DN versus 76.3% of patients with DN. Patients with DN were exposed to the T allele 11 times more than who didn’t develop nephropathy (OR=11, 95% CI= 5.3-23.1 , P=

Objectives To contribute to a better understanding of the maternal genetic mechanisms that influence obstetric outcomes and that are involved in maternal and child health, this study aimed to evaluate the association between maternal genetic variants and the offspring birth weight by analyzing single-nucleotide polymorphisms (SNPs) in genes related to glucose homeostasis. Methods Three polymorphisms were analyzed (GCK rs1799884, TCF7L2 rs7903146 and LEPR rs1137101) in 250 pregnant women who participated in a Brazilian prospective cohort study. Genotyping was performed by Real-Time Polymerase Chain Reaction (qPCR) using pre-designed TaqMan® SNP genotyping assays. Vitamin D dosage was performed by chemiluminescence. Variance, Pearson's chi-square test and multiple linear regression were used for the statistical analysis. Results It was possible to verify a significant association between birth weight and maternal GCK rs1799884 when obstetric outcomes, clinical and anthropometric characteristics were taken into consideration. The children of homozygous women for the minor allele GCK rs1799884 presented lower birth weight (β = -335.25, 95% CI = -669.39; -1.17, p = 0.04). Furthermore, a direct link between a leptin receptor variant and gestational duration was found (p = 0.037). Conclusion The variant GCK rs1799884 (mm) was associated with a reduction in newborn weight in the miscegenated Brazilian population.

Background: African ancestry seems to be a risk factor for hypertension; however, few genetic studies have addressed this issue. This study aimed to investigate the prevalence of polymorphisms NOS3; rs1799983, IGFBP3; rs11977526 and TCF7L2; rs7903146 in Brazilian women of African descent and their association with hypertension.Methods: This is a cross-sectional study with a sample of 1021 women (19–59 years old) from the quilombola communities of Alagoas (Brazil). Demographic, socioeconomic, lifestyle, anthropometric, biochemical, and blood pressure data were collected. DNA was extracted from mucosa epithelial cells of the participants’ cheek. Genotyping was performed by PCR allelic discrimination. Prevalence ratio (PR) was the measure of association, calculated by Poisson regression, with a hierarchical selection of variables.Results: The prevalences of the less frequent genotypes were 26.5% TT genotype of NOS3; rs1799983, 16.7% AA genotype of IGFBP3; rs11977526, and 18.3% TT genotype of TCF7L2; rs7903146. For these conditions, the prevalence of hypertension and PR (adjusted) relatively to the ancestral genotype were, respectively: 52.0% vs 24.5% (PR=1.54; pp<0.001), and 38.9% vs 27.9% (PR=0.86; p=0.166). Associations with hypertension were statistically significant, except for the TCF7L2; rs7903146 polymorphism, after adjusted analysis. Conclusions: Brazilian Afro-descendant women with the TT genotype for the NOS3 gene and the AA genotype for the IGFBP3 gene are more susceptible to hypertension. The understanding of underlying mechanisms involving the pathogenesis of hypertension can motivate research for the development of new therapeutic targets related to nitric oxide metabolism and the management of oxidative stress.

Background: Type 2 diabetes mellitus (T2DM) is the most prevalent component of metabolic syndrome. Environmental factors and various complex genes like transcription factor 7-like 2 (TCF7L2) gene have involved in the disease development. Objective: To determine TCF7L2 genetic association (rs7903146C/T and rs12255372G/T) in T2DM patients of Khyber Pakhtunkhwa population of Pakistan. Subjects and methods: This study comprised of 176 subjects including 118 T2DM patients and 58 healthy controls. Genomic DNA was extracted and genotype of common variants (rs7903146 C/T and rs12255372 G/T) was carried out by amplification-refractory mutation system (ARMS)-PCR of sequence specific oligonucleotides. Results: The distribution of genotype of TCF7L2 SNPs (rs7903146 C/T and rs12255372 G/T) was significantly associated with T2DM as compared to the controls (p

Rates of type 2 diabetes (T2D) and hypertension are increasing rapidly in urbanizing sub-Saharan Africa (SSA). While lifestyle factors drive the increases in T2D and hypertension prevalence, evidence across populations shows that genetic variation, which is driven by evolutionary forces including a natural selection that shaped the human genome, also plays a role. Here we report the evidence for the effect of selection in African genomes on mechanisms underlying T2D and hypertension, including energy metabolism, adipose tissue biology, insulin action and salt retention. Selection effects found for variants in genes PPARA and TCF7L2 may have enabled Africans to respond to nutritional challenges by altering carbohydrate and lipid metabolism. Likewise, African-ancestry-specific characteristics of adipose tissue biology (low visceral adipose tissue [VAT], high intermuscular adipose tissue and a strong association between VAT and adiponectin) may have been selected for in response to nutritional and infectious disease challenges in the African environment. Evidence for selection effects on insulin action, including insulin resistance and secretion, has been found for several genes including MPHOSPH9, TMEM127, ZRANB3 and MC3R. These effects may have been historically adaptive in critical conditions, such as famine and inflammation. A strong correlation between hypertension susceptibility variants and latitude supports the hypothesis of selection for salt retention mechanisms in warm, humid climates. Nevertheless, adaptive genomics studies in African populations are scarce. More work is needed, particularly genomics studies covering the wide diversity of African populations in SSA and Africans in diaspora, as well as further functional assessment of established risk loci.

Цель исследования - оценить вклад полиморфных вариантов g.15661G> T (ген ADIPOQ), p.A222V (ген MTHFR), p.Q192R (ген PON1), p.K23E (ген KCNJ11), g.53341C>T (ген TCF7L2), p.V109D (ген ITLN1) и p.P12A (ген PPARG) в развитие ожирения для лиц кыргызской национальности. Исследование было проведено по типу «случай-контроль» и включало 130 пациентов с ожирением (мужчин - 65 (50,0%), женщин - 65 (50,0%)). Группа сравнения - 115 человек без ожирения, метаболических нарушений и сердечно-сосудистых заболеваний в анамнезе (мужчин - 62 (53,9%), женщин - 53 (46,1%). Генотипирование осуществляли методом ПЦР-ПДРФ. Анализ межгенных взаимодействий проводился с использованием программы MDR 3.0.2. Маркерами развития ожирения в кыргызской популяции являются аллель V и генотип VV локуса p.A222V (MTHFR), а также аллель K и генотип KK локуса p.K23E (KCNJ11). При наличии генетического профиля AV (p.A222V, MTHFR) / EK (p.K23E, KCNJ11) вероятность развития ожирения возрастает более чем в 3 раза, ОШ=3,49, 95% ДИ=[1,44-8,45], p=0,001. In this study, we investigated whether polymorphisms g.15661G>T (ADIPOQ), p.A222V (MTHFR), p.Q192R (PON1), p.K23E (KCNJ11), g.53341C>T (TCF7L2), p.V109D (ITLN1) and p.P12A (PPARG) are associated with obesity in the Kyrgyz population. We genotyped 245 nonrelated adults Kyrgyz individuals. 130 patients (male - 65 (50,0%), female - 65 (50,0%) with obesity and 115 non-obese control subjects (male - 62 (53,9%), female - 53 (46,1%). Genotyping of single-nucleotide polymorphism was performed by PCR-RFLP method. Analysis of intergenic interactions conducted with MDR v.3.0.2 program. Тhe V allele and the VV genotype of the p.A222V locus (MTHFR), as well as the K allele and the KK genotype of the p.K23E locus (KCNJ11) increase risk of obesity in the Kyrgyz population. Subjects having the VV genotype of p.A222V locus (MTHFR) and KK genotype of the p.K23E locus (KCNJ11) had 3-fold [OR = 3,49 (1,44-8,45); p = 0,001] higher risk of developing compared with subjects carrying neither of these genotypes.

The aim of this work was to review studies in which genetic variants were assessed with respect to metabolic response to treatment with novel glucose-lowering drugs: dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium–glucose cotransporter 2 inhibitors (SGLT2i). In total, 22 studies were retrieved from the literature (MEDLINE). Variants of the GLP-1 receptor gene (GLP1R) were associated with a smaller reduction in HbA1c in response to DPP-4i. Variants of a number of other genes (KCNQ1, KCNJ11, CTRB1/2, PRKD1, CDKAL1, IL6 promoter region, TCF7L2, DPP4, PNPLA3) have also been related to DPP-4i response, although replication studies are lacking. The GLP1R gene was also reported to play a role in the response to GLP-1 RA, with larger weight reductions being reported in carriers of GLP1R variant alleles. There were variants of a few other genes (CNR1, TCF7L2, SORCS1) described to be related to GLP-1 RA. For SGLT2i, studies have focused on genes affecting renal glucose reabsorption (e.g. SLC5A2) but no relationship between SLC5A2 variants and response to empagliflozin has been found. The relevance of the included studies is limited due to small genetic effects, low sample sizes, limited statistical power, inadequate statistics (lack of gene–drug interactions), inadequate accounting for confounders and effects modifiers, and a lack of replication studies. Most studies have been based on candidate genes. Genome-wide association studies, in that respect, may be a more promising approach to providing novel insights. However, the identification of distinct subgroups of type 2 diabetes might also be necessary before pharmacogenetic studies can be successfully used for a stratified prescription of novel glucose-lowering drugs. Graphical abstract

Metastatic colorectal cancer (mCRC) patients have various metastasis patterns, which reflect diverse biological characteristics of different patient subgroups. We analyse the prognosis of mCRC patients according to the metastatic site and clarify the relationship between tumor or patient characteristics and the metastatic sites. The whole sequencing and clinical data of 2329 CRC patients were obtained from TCGA and a database of the MSKCC. Kruskal Wallis Tests were used to analyse measurement data. Survival was illustrated by Kaplan-Meier curves, with P value determined by Log-rank Test. Hazard’s ratio was determined through the univariate and multivariate COX proportional hazards regression model. The mortality rate of CRC patients with liver-only metastasis (mCRC-liver) did not increase versus nonmetastatic patients. The survival rate of patients with non-regional lymph node-only metastasis (mCRCNRLN) was lower versus mCRC-liver. Mutations of KRAS and TCF7L2 genes were associated with mortality of mCRC-liver. APC mutation was associated with reduced mortality in mCRC-lung and mCRCNRLN. BRAF mutation was associated with increased mortality of mCRC-peritoneum. In a multivariate COX analysis, gender affected the survival rate of mCRC-liver. Age and the number of gene mutations affected the survival rate of mCRC-lung and mCRC-NRLN respectively. Receiving chemotherapy is an unfavourable factor for prognosis of mCRC-liver, but the length of chemotherapy treatment is an advantageous prognosis factor. This study depicts the long-term survival features of a group of mCRC patients. These findings promoted our understanding of the prognosis characteristics of CRC and have positive guiding significance for clinical management of CRC patients.

The genetic predispositions related to type 2 diabetes (T2D) in the Middle East are poorly understood. One of the most common single-nucleotide polymorphisms (SNP) located in the transcription factor 7-like-2 (TCF7L2) gene is rs12255372 variant which elucidated a significant role in developing T2D, especially in the European population. The current study is the first to have examined the association between TCF7L2 rs12255372 variant and T2D among the Iraqi Kurdish population from Iraq. Three hundred participants were enrolled in this study: 150 were type 2 diabetic patients and 150 were normoglycemic controls. For genotyping rs12255372 (G > T) variant, Tetra ARMS-PCR was used which is high-throughput, cost and time effective technique. The genotypic frequencies in the additive genetic model (co-dominant) for GG, GT, and TT were 62.7%, 24%, and 13.3% in the normoglycemic controls, respectively, and for the diabetic patients were 50.7%, 20%, and 29.3%, respectively. The TT genotype was found considerably higher in cases when matched to the normoglycemic controls in both co-dominant and recessive models with OR (95% CI) = 2.64 (1.29–5.41) (p value = 0.006) and OR (95% CI) = 1.531 (1.232–1.902) (p value = 0.001), respectively. These frequencies indicated that the carriers of the TT genotype were more susceptible to T2D compared to other genotypes. The T allele showed a high significant frequency in T2D patients compared to the normoglycemic controls with OR (95% CI) = 1.38 (1.16–1.59) (p value = 0.000). Our results suggest rs12255372 T allele as a putative risk factor that increases the susceptibility of T2D among the Iraqi Kurdish population.

The prevalence of type 2 diabetes in youth has increased substantially, yet the genetic underpinnings remain largely unexplored. To identify genetic variants predisposing to youth-onset type 2 diabetes, we formed ProDiGY, a multiethnic collaboration of three studies (TODAY, SEARCH, and T2D-GENES) with 3,006 youth case subjects with type 2 diabetes (mean age 15.1 ± 2.9 years) and 6,061 diabetes-free adult control subjects (mean age 54.2 ± 12.4 years). After stratifying by principal component–clustered ethnicity, we performed association analyses on ∼10 million imputed variants using a generalized linear mixed model incorporating a genetic relationship matrix to account for population structure and adjusting for sex. We identified seven genome-wide significant loci, including the novel locus rs10992863 in PHF2 (P = 3.2 × 10−8; odds ratio [OR] = 1.23). Known loci identified in our analysis include rs7903146 in TCF7L2 (P = 8.0 × 10−20; OR 1.58), rs72982988 near MC4R (P = 4.4 × 10−14; OR 1.53), rs200893788 in CDC123 (P = 1.1 × 10−12; OR 1.32), rs2237892 in KCNQ1 (P = 4.8 × 10−11; OR 1.59), rs937589119 in IGF2BP2 (P = 3.1 × 10−9; OR 1.34), and rs113748381 in SLC16A11 (P = 4.1 × 10−8; OR 1.04). Secondary analysis with 856 diabetes-free youth control subjects uncovered an additional locus in CPEB2 (P = 3.2 × 10−8; OR 2.1) and consistent direction of effect for diabetes risk. In conclusion, we identified both known and novel loci in the first genome-wide association study of youth-onset type 2 diabetes.

This study was conducted to assess the possible association between polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene and obese Iraqi adults. DNA was obtained from 158 obese subjects and 142 controls. Two specific PCR fragments were designed to incorporate two highly frequent single nucleotide polymorphism (SNP)s within TCF7L2, rs11196208 and rs7908486. Both amplified loci were genotyped by PCR-single-strand conformation polymorphism (SSCP) followed by sequencing. Logistic regression analysis was performed to detect the association between both genetic variants and obesity. Concerning rs11196208-based amplicons, PCR-SSCP genotyping showed homogeneous banding patterns for all investigated samples. In contrast with rs11196208, three SSCP banding patterns in the rs7908486-based amplicons, GG, AG and AA, were observed. Individuals with the AA genotype showed significantly higher (P

Introduction: Women with family history of diabetes (FHD) are at significantly increased risk of developing gestational diabetes mellitus which may eventually lead to type 2 diabetes mellitus (T2DM) in later life. Objective: This study investigates the role of FHD on metabolic markers and gene polymorphisms and hence on T2DM susceptibility in nondiabetic pregnant women and the subsequent risks in their newborns. Materials and Methods: The present study was conducted on 200 healthy (nondiabetic and normotensive) adult Asian Indian women, including 100 with and 100 without FHD, living in and around Kolkata, India. During the gestational period, they were studied twice and followed up till delivery. During delivery, both mothers’ venous blood and cord blood were collected to estimate serum CRP, glucose, and lipid profiles of the respective mothers and their newborns. Genotyping of PPARγ and TCF7L2 polymorphisms was done from these blood samples. Results: A comparison of the metabolic variables among the subjects with and without FHD revealed significant differences among them. We also found close relationship between mothers and their newborn babies in terms of both PPARγ (rs1801282) C/G and TCF7L2 (rs7903146) C/T polymorphisms. More specifically, genotyping results for mothers with FHD and their newborn babies showed high concordance in inheritance of alleles: (i) for PPARγ via the risk allele G (74.0%) which is carried over to the newborn babies (64.5%) and (ii) for TCF7L2 via the risk allele T (73.0%) which is carried over to the newborn babies (68.5%). Conclusion: This study leads to the conclusion that Asian Indian women population based in Kolkata, India, are ethnically and genetically predisposed to the risk factors of diabetes through FHD, which is reflected in their gestational phase, and it has a significant implication on their birth outcomes.

O presente artigo é uma revisão integrativa que tem como alvo explorar a relação entre o polimorfismo genético TCF7L2 e a diabetes Mellitus tipo 2 com foco em estudos recentes sobre nutrigenética para assim indicar melhor profilaxia nutricional. Para a realização deste trabalho, utilizou-se a base de dados MedLine utilizando as seguintes palavras-chave: Nutrigenomics, Nutrigenetics, Single Nucleotide Polymorphis, TCF7L2, Mediterranean Diet, Diabetes Mellitus Type 2 e rs7903146. As pesquisas demonstram que essa variação genética estará presente em um indivíduo quando houver uma substituição do aminoácido citosina pela timina, no cromossomo 10, posição 114,748 e 339. Esta variação genética exerce influência sobre as funções fisiológicas do pâncreas ocasionando uma superprodução de insulina com menor secreção, o que futuramente fadigará o órgão levando, como consequência, ao desencadeamento da diabetes Mellitus tipo 2. Neste caso, nutrigenética se torna essencial ao profissional nutricionista que, com base nestes conhecimentos, pode modular os efeitos causados por este polimorfismo ao indicar uma dieta do mediterrâneo capaz de reduzir a glicemia e lipídios no plasma reduzindo a sobrecarga pancreática devido a presença de nutrientes chaves envolvidos nestes processos metabólicos.

To study the possibility of using polymorphisms of genesTCF7L2,FABP2,KCNQ1,ADIPOQas markers for predicting the development of type 2 diabetes mellitus (T2D) in the population of Novosibirsk.On the basis of prospective observation of a representative population sample of residents of Novosibirsk (HAPIEE), 2 groups were formed according to the case-control principle (case people who had diabetes mellitus 2 over 10 years of observation, and control people who did not developed disorders of carbohydrate metabolism). T2D group (n=443, mean age 56.26.7 years, men 29.6%, women 70.4%), control group (n=532, mean age 56.17.1 years, men 32.7%, women 67.3%). DNA was isolated by phenol-chloroform extraction. Genotyping was performed by the method of polymerase chain reaction with subsequent analysis of restriction fragment length polymorphism, polymerase chain reaction in real time. Statistical processing was carried out using the SPSS 16.0 software package.No significant effect of rs1799883 of theFABP2gene, rs2237892 of theKCNQ1gene, and rs6773957 of theADIPOQgene on the risk of developing T2D was found. Genotypes TT and TC rs7903146 of theTCF7L2gene are genotypes for the risk of developing T2D (relative risk RR 3.90, 95% confidence interval CI 2.316.61,p0.001; RR 1.86, 95% CI 1.422.43,p0.001, respectively). The CC genotype rs7903146 of theTCF7L2gene is associated with a protective effect against T2D (RR 0.37, 95% CI 0.290.49,p0.001). When theTCF7L2gene is included in the model for assessing the risk of developing T2D rs7903146, it retains its significance in both men and women.The rs7903146 polymorphism of theTCF7L2gene confirmed its association with the prognosis of the development of T2D, which indicates the possibility of considering it as a candidate for inclusion in a diabetes risk meter. Variants of risk meters have been developed to assess the prognosis of the development of diabetes mellitus 2 in men and women aged 4569 years during 10 years of follow-up. The association with the prognosis of the development of T2D polymorphisms rs1799883 of theFABP2gene, rs2237892 of theKCNQ1gene and rs6773957 of theADIPOQgene was not found.Цель.Изучить возможность использования в популяции г. Новосибирска в качестве маркеров прогноза развития сахарного диабета 2-го типа (СД 2) полиморфизмов геновTCF7L2,FABP2,KCNQ1,ADIPOQ. Материалы и методы.На основе проспективного наблюдения репрезентативной популяционной выборки жителей Новосибирска (HAPIEE) сформированы 2 группы по принципу случайконтроль (случай лица, у которых за 10 лет наблюдения выявлен СД 2, и контроль лица, у которых за 10-летний период не развились нарушения углеводного обмена). Группа СД 2 (n=443, средний возраст 56,26,7 года, мужчины 29,6%, женщины 70,4%), группа контроля (n=532, средний возраст 56,17,1 года, мужчины 32,7%, женщины 67,3%). ДНК выделена методом фенол-хлороформной экстракции. Генотипирование выполнено методом полимеразной цепной реакции с последующим анализом полиморфизма длин рестрикционных фрагментов, полимеразной цепной реакции с обратной транскрипцией. Статистическая обработка проведена с использованием программного пакета SPSS 16.0. Результаты и обсуждение.Не обнаружено значимого влияния rs1799883 генаFABP2, rs2237892 генаKCNQ1и rs6773957 генаADIPOQна риск развития СД 2. Генотипы ТТ и TC rs7903146 генаTCF7L2являются генотипами риска развития СД 2 (относительный риск ОР 3,90, 95% доверительный интервал ДИ 2,316,61,р0,001; ОР 1,86, 95% ДИ 1,422,43,р0,001 соответственно). Генотип СС rs7903146 генаTCF7L2ассоциирован с протективным эффектом в отношении СД 2 (ОР 0,37, 95% ДИ 0,290,49,р0,001). При включении в модель оценки риска развития СД 2 rs7903146 генаTCF7L2он сохраняет свою значимость и у мужчин, и у женщин. Заключение.Полиморфизм rs7903146 генаTCF7L2подтвердил свою ассоциацию с прогнозом развития СД 2, что указывает на возможность его рассмотрения в качестве кандидата на внесение в рискометр СД 2. Разработаны варианты рискометров для оценки прогноза развития СД 2 у мужчин и женщин в возрасте 4569 лет в течение 10 лет наблюдения. Ассоциация с прогнозом развития СД 2 полиморфизмов rs1799883 генаFABP2, rs2237892 генаKCNQ1и rs6773957 генаADIPOQ не обнаружена.

Objective Colorectal cancer is one of the most prevalent types of cancer worldwide. Right-sided and left-sided colorectal cancer (RCC and LCC) patients respond differently to treatment. We aimed to identify the different mutational profile between RCC and LCC and provided evidence for future precision therapy. Methods A total of 630 Chinese colorectal cancer patients, including 467 (74.1%) LCC and 163 (25.9%) RCC, were enrolled in this cohort. Both formalin-fixed paraffin-embedded tumor tissues and matching blood samples were collected and deep sequenced targeting 450 cancer genes for genomic alteration analysis. Tumor mutational burden was measured by an algorithm developed in-house. Correlation analysis was performed by Fisher’s exact test. Results The most common mutated genes were TP53 (77.0%), APC (71.7%), KRAS (50.0%), SMAD4 (19.8%), PIK3CA (18.3%), FBXW7 (17.5%), TCF7L2 (12.5%), SOX9 (11.3%), LRP1B (10.8%), ARID1A (10.3%) and FAT4 (10.3%). The mutation frequencies of TP53 and APC in LCC were significantly higher than that of RCC, while the mutation frequency of PIK3CA was lower than that of RCC. Six gene fusions were specifically detected in RCC patients. Colorectal cancer sites were associated with gender (P = 4.15 × 10−5) and tumor differentiation (P = 0.059). In LCC, the gender-associated genes were FAT4, EP300, FAT1, LRP1, ARID1B, AR, FYN and TAF1, while in RCC, they were ARID1A, SMARCA4, LRP1 and GRIN2A. The mutations of 18 genes were associated with tumor differentiation (8 for LCC and 10 for RCC). High tumor mutational burden was more common in RCC. Our results implied more potential targeted drug therapy opportunities for RCC. Conclusion We describe the different molecular characteristics of LCC and RCC. Our result supported a better prognosis of RCC than LCC in Chinese colorectal cancer patients.

While minimally invasive follicular thyroid cancer (miFTC) generally has low risk of recurrence or death, encapsulated angioinvasive (eaFTC) or widely invasive (wiFTC) histological subtypes display significantly worse prognosis. Drivers of invasion are incompletely understood. Therefore, tissue samples including miFTC, eaFTC, and wiFTC tumors, as well as histologically normal thyroid adjacent to benign follicular adenomas, were selected from a cohort (n = 21) of thyroid tumor patients, and the gene expression of selected transcription factors was characterized with quantitative PCR. Invasion-relevant spatial expression patterns of selected transcription factors were subsequently characterized with immunohistochemistry. E2F1 was over-expressed in all 3 subtypes (pSP1 was differentially expressed in eaFTC and wiFTC compared with normal (p=0.01 and 0.04, respectively). TCF7L2 was significantly upregulated in wiFTC specifically (p

Approximately 462 million people suffer from type 2 diabetes mellitus (T2DM) worldwide, and its prevalence is projected to increase to 7079 individuals per 100,000 by 2030. The rapid increase in the prevalence of this disease is likely a result of multiple environmental factors as increased food intake and decreased physical activity in genetically predisposed individuals. Patients with T2DM are vulnerable to developing secondary complications like retinopathy, and nephropathy. For that reason, great effort has been made to identify genes associated with T2DM. Many loci were found to be associated with T2DM risk in various populations and ethnic groups as the transcription factor 7-like-2 gene (TCF7L2) gene (rs7903146) [C/T] polymorphism locus on chromosome 10q. The TCF7L2 (rs7903146) (C/T) contributes to the disease through the Wnt/β-catenin signaling pathway affecting pancreatic islet development, expression of several genes involved in insulin granules exocytosis, and the incretin glucagon-like peptide 1 (GLP-1) gene.

WOS:000583273800010 PubMed ID: 33122478 Objective: TCF7L2 is a repressor and transactivator of genes, and its variants are strongly associated with diabetes. This study aimed to evaluate the sex-specific relationship between the most common TCF7L2 gene variants (-98368G>T, rs12255372 and -47833C>T, rs7903146) with diabetes and coronary heart disease in Turkish Adult Risk Factor (TARF) Study. Methods: Single nucleotide variants (SNVs) have been genotyped using the TaqMan allelic discrimination assays in 2,024 (51.3% in women, age: 55 +/- 11.8) Turkish adults participating in the TARF study. Statistical analyses were used to investigate the association of genotypes with clinical and biochemical measurements. Results: Among the TARF study participants, 11.7%, 24.3%, 14.1%, and 38.3% had diabetes, hypertension, coronary heart disease (CHD), and obesity, respectively. The frequencies of T allele for -47833C>T and -98368G>T in Turkish adults were determined to be 0.35 and 0.33, respectively. -47833C>T was significantly associated with higher fasting glucose concentrations in all participants, especially in men. Both SNVs were significantly associated with diabetes and CHD in all participants (pT was associated with diabetes in women (p=0.041) and -47833C>T was associated with diabetes and CHD in men (p=0.018 and p=0.032, respectively). Also, both SNVs and the diplotypes of common haplotype (H1) remained strongly associated with type 2 diabetes after risk factors were adjusted (p

The greatest risk of developing type2 diabetes (T2DM) was conferred by rs7903146 SNP of Transcription factor7-like2 (TCF7L2) gene in many ethnic populations. The aim was to investigate the association of TCF7L2 (rs7903146) gene polymorphism among newly diagnosed diabetes subjects with different parental diabetes registry. A total of 171 subjects were categorized into 3 groups based on parental diabetes registry i.e. Conjugal Diabetes Registry (CDR) (n = 50), One Parental Diabetes Registry (OPDR) (n = 56) and Non Parental Diabetes Registry (NPDR) (n = 62) (control group). Kompetitive allele specific PCR (KASP) genotyping assay was used in real time PCR for identifying the genotypes. None of the biochemical parameters showed any significant difference between groups except age at onset of diabetes (p = 0.001). The T allele of TCF7L2 (rs7903146) was associated with significant risk of diabetes. TT genotype which doubles the diabetes risk showed significant association among OPDR whereas in CDR both CT and TT genotypes showed significant association than CC wild type. The ‘T’ allele of TCF7L2 SNP was associated with significant risk when compared between OPDRvsNPDR (OR 2.45, p = 0.003) and CDRvsNPDR (OR 2.82, p = 0.0007). In conclusion, TCF7L2 gene polymorphism and positive family history of diabetes are strongly associated irrespective of the presence of other risk factors among diabetes subjects.

Type 2 diabetes (T2D) is defined by a single metabolite, glucose, but is increasingly recognized as a highly heterogeneous disease, including individuals with varying clinical characteristics, disease progression, drug response, and risk of complications. Identification of subtypes with differing risk profiles and disease etiologies at diagnosis could open up avenues for personalized medicine and allow clinical resources to be focused to the patients who would be most likely to develop diabetic complications, thereby both improving patient health and reducing costs for the health sector. More homogeneous populations also offer increased power in experimental, genetic, and clinical studies. Clinical parameters are easily available and reflect relevant disease pathways, including the effects of both genetic and environmental exposures. We used six clinical parameters (GAD autoantibodies, age at diabetes onset, HbA1c, BMI, and measures of insulin resistance and insulin secretion) to cluster adult-onset diabetes patients into five subtypes. These subtypes have been robustly reproduced in several populations and associated with different risks of complications, comorbidities, genetics, and response to treatment. Importantly, the group with severe insulin-deficient diabetes (SIDD) had increased risk of retinopathy and neuropathy, whereas the severe insulin-resistant diabetes (SIRD) group had the highest risk for diabetic kidney disease (DKD) and fatty liver, emphasizing the importance of insulin resistance for DKD and hepatosteatosis in T2D. In conclusion, we believe that subclassification using these highly relevant parameters could provide a framework for personalized medicine in diabetes.

OBJECTIVE The risk genotype for the common variant rs7903146 of the transcription factor 7-like-2 (TCF7L2) gene has been found to affect the incretin response in healthy and obese adults; however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the rs7903146 variant in the TCF7L2 gene on the incretin effect and determined its translational metabolic manifestation by performing deep phenotyping of the incretin system, β-cell function relative to insulin sensitivity, the gastrointestinal-induced glucose disposal (GIGD) in obese youth with normal and impaired glucose tolerance. RESEARCH DESIGN AND METHODS Thirty-nine obese adolescents without diabetes (median age 15 [25th, 75th percentile 14, 18] years; BMI 37 [33, 43] kg/m2) were genotyped for the rs7903146 variant of TCF7L2 and underwent a 3-h oral glucose tolerance test (OGTT) followed by an isoglycemic intravenous glucose infusion (iso-intravenous glucose tolerance test [IVGTT]) to match the plasma glucose concentrations during the OGTT and a hyperglycemic clamp with arginine stimulation. The incretin effect was measured as 100 * (AUC-SROGTT − AUC-SRiso-IVGTT) / AUC-SROGTT, where AUC-SR = area under the curve of C-peptide secretion rate. Participants were grouped into tertiles according to the percentage incretin effect (high, moderate, and low) to describe their metabolic phenotype. RESULTS The presence of T risk allele for TCF7L2 was associated with a markedly reduced incretin effect compared with the wild-type genotype (0.3% [−7.2, 14] vs. 37.8% [12.5, 52.4], P < 0.002). When the cohort was stratified by incretin effect, the high, moderate, and low incretin effect groups did not differ with respect to anthropometric features, while the low incretin effect group exhibited higher 1-h glucose (P = 0.015) and a reduced disposition index, insulin sensitivity, and insulin clearance compared with the high incretin effect group. GIGD was reduced in the low incretin effect group (P = 0.001). The three groups did not differ with respect to intravenous glucose-induced insulin secretion and arginine response during the hyperglycemic clamp. CONCLUSIONS A reduced incretin effect and its association with the TCF7L2 variant rs7903146 identify an early metabolic phenotype in obese youth without diabetes, featuring a higher plasma glucose peak at 1 h; lower insulin secretion, sensitivity, and clearance; and GIGD.

Despite the extensive efforts of scientists, the genetic background of diabetic nephropathy (DN) has not yet been clarified. To elucidate the genetic variants that predispose to the development of DN, we conducted a systematic review and meta-analysis of all available genetic association studies (GAS) of DN. We searched in the Human Genome Epidemiology Navigator (HuGE Navigator) and PubMed for available GAS of DN. The threshold for meta-analysis was three studies per genetic variant. The association between genotype distribution and DN was examined using the generalized linear odds ratio (ORG). For variants with available allele frequencies, the examined model was the allele contrast. The pooled OR was estimated using the DerSimonian and Laird random effects model. The publication bias was assessed with Egger’s test. We performed pathway analysis of significant genes with DAVID 6.7. Genetic data of 606 variants located in 228 genes were retrieved from 360 GASs and were synthesized with meta-analytic methods. ACACB, angiotensin I-converting enzyme (ACE), ADIPOQ, AGT, AGTR1, AKR1B1, APOC1, APOE, ATP1B2, ATP2A3, CARS, CCR5, CGNL1, Carnosine dipeptidase 1 (CNDP1), CYGB-PRCD, EDN1, Engulfment and cell motility 1 (ELMO1), ENPP1, EPO, FLT4, FTO, GLO1, HMGA2, IGF2/INS/TH cluster, interleukin 1B (IL1B), IL8, IL10, KCNQ1, KNG, LOC101927627, Methylenetetrahydrofolate reductase, nitric oxide synthase 3 (NOS3), SET domain containing seven, histone lysine methyltransferase (SETD7), Sirtuin 1 (SIRT1), SLC2A1, SLC2A2, SLC12A3, SLC19A3, TCF7L2, TGFB1, TIMP1, TTC39C, UNC13B, VEGFA, WTAPP1, WWC1 as well as XYLT1 and three intergenic polymorphisms showed significant association with DN. Pathway analysis revealed the overrepresentation of six signalling pathways. The significant findings provide further evidence for genetic factors implication in DN offering new perspectives in discovery of new therapies.

In this article, we analyze the role of different variants of the KCNJ11, TCF7L2, SLC22A1, SLC22A3, CYP2C9, CYP2C8, PPARγ genes polymorphisms in efficacy of diabetes mellitus pharmacotherapy. T allele of the KCNJ11 rs2285676 gene polymorphism and G allele of KCNJ11 rs5218 gene polymorphism are associated with the response to IDPP-4 therapy; the presence of KCNJ11 gene rs5210 polymorphism A allele is a predictor of poor response. The effect of rs7903146 polymorphism of TCF7L2 gene was evaluated on the response to treatment of patients taking linagliptin. Linagliptin significantly reduced HbA1c levels for all three rs7903146 genotypes (CC: –0.82 %; CT: –0.77 %; TT: –0.57 %). A significantly smaller effect of therapy was observed with the genotype with ТТ. The rs622342 polymorphism of SLC22A1 gene was studied in effectiveness of metformin. The researches demonstrated that carriers of variant AA had an average decrease of HbA1c of 0.53 %, heterozygous – decrease of 0.32 %, and carriers of a minor variant of SS had an increase of 0.2 % in the level of HbA1c. A significant effect of CYP2C9 polymorphisms on the pharmacokinetic parameters of PSM was noted. When studying the kinetics of glibenclamide, it was found that carriage of the allele *2 significantly reduces glibenclamide metabolism: homozygous carriers had clearance 90 % lower than homozygous carriers of the wild variant. The studies confirmed the association of the allelic variants of Thr394Thr and Gly482Ser of PPARγ gene with higher efficacy of the rosiglitazone. The data obtained from the analysis of the association of the Pro12Ala polymorphism of PPARγ gene and the response to therapy is contradictory. Thus the personalized approach, based on the knowledge of polymorphism options, will allow choosing the most effective drug with transparent kinetics for each individual patient.

We studied the association between the presence of 2 or more stemness gene amplifications as well as copy number aberrations (CNAs) of WNT signaling genes in residual breast tumor and metastasis. WNT pathway genes associated with metastasis were identified.Material and Methods. The study included 30 patients with breast cancer, who had 2 or more stemness gene amplifications in the residual tumor after neoadjuvant chemotherapy. Fifteen of the thirty patients developed hematogenous metastases; they constituted a group with metastases, the remaining 15 patients entered the second group without metastases. The tumor DNA was examined using a CytoScanHD Array microarray (Affymetrix, USA).Results. By subtracting amplification and deletion frequencies in 852 cytobands between groups with metastases and without metastases, 21 cytobands were identified with the largest difference in deletion and amplification frequencies. They contain 19/150 of WNT genes (12 activators: SKP1, WNT8A, MAPK9, CCND3, FZD9, WNT8B, CCND1, PLCB2, PRKCB, FZD2, WNT3, WNT9B and 7 negative regulators: GSK3B, APC, CSNK2B, SFRP5, BTRC, TCF7L2, CSNK2A2). A point system was developed: when amplifying WNT-signaling activators or deletion of negative regulators, one point was added to the total score, and vice versa when deleting WNT-signaling activators or amplification of negative regulators, one point was taken from the total amount. It was shown that 93% (14/15) of patients with metastases had a total score higher than 0, while 93% (14/15) of patients without metastases had a total score of zero or less than zero. The differences between the groups were statistically significant according to the two-sided Fisher test with a high level of confidence probability (p=0.000003) and the log-rank test (p=0.00004) when assessing non-metastatic survival by the Kaplan-Mayer method.Conclusion. Nineteen WNT signaling genes were identified. Copy number aberrations of these genes in combination with stemness gene amplifications in residual tumors were associated with metastasis. A new highly effective prognostic factor for breast cancer was identified.

Diabetic retinopathy (DR) is one of the most common diabetic complications. Genetic factors play an important role in the development and progression of DR. So, the present study aimed to investigate the association ofThis work is a case-control study in which 550 diabetic patients were enrolled. Among them, 280 diabetics with DR (120 T1DM and 160 with T2DM) and 270 diabetic patients without DR (120 T1DM and 150 with T2DM). Besides, 120 healthy subjects as a control group. Genotyping ofC allele and CC genotype ofThe present study revealed the association of

The genetic predispositions responsible for developing type 2 diabetes mellitus (T(2)DM) in the Middle East are poorly understood. The rs7903146 single nucleotide polymorphism (SNP) located in transcription factor 7-like-2 (TCF7L2) gene has been recognized to have a vital role in the development of T(2)DM disorder. The current study is the first to have researched the possible association between TCF7L2 rs7903146 SNP and T(2)DM among Kurdish population in Kurdistan region of Iraq. The study included 212 participants, half of them were T(2)DM patients, and the other half were disease-free and normoglycemic controls. Genotyping was performed by using a high throughput cost and time effective tetra-primer amplification refractory mutation system-polymerase chain reaction (Tetra ARMS-PCR) assay. The rs7903146 genotypic frequencies for CC, CT and TT were 24.5%, 69.8%, and 5.7% in T(2)DM group respectively, and for the controls were 45.3%, 50.9%, and 3.8% respectively. The frequency of CT genotype was found significantly higher in the cases when compared to the controls (OR = 2.53, 95% CI 1.40–4.57, P value

Background Obesity is a major health threat worldwide. It predisposes individuals to diabetes, cardiovascular complications, and cancer. Genetic and environmental factors are responsible for the increasing incidence of obesity. In this study, we investigated the genetic factors associated with obesity in young Saudi women. Subjects and methods In this cross-sectional study, 131 young Saudi female students were recruited. Body mass index (BMI), waist-hip ratio, blood glucose, triglyceride, cholesterol, HDL, LDL, and vitamin D3 levels of the subjects were determined. Twelve SNPs of different genes that showed a correlation with obesity in different population were tested, namely GNPDA2 (rs10938397), TCF7L2 (rs10885409), FTO (rs1477196), ADIPOQ (rs1501299), MC4R (rs17782313), ABCA1 (rs1800977), FTO (rs1861868), VDR (rs2228570), VDR (rs731236), VDR (rs7975232), ADIPOQ (rs266729), and PFPK (rs6602024). Student's t-test was conducted for all parameters. Pearson correlation was performed to identify the correlated variables. The frequencies of different risk alleles were determined by direct counting of the test allele divided by the total number of alleles and compared. Results Only two SNPs, rs1861868 of FTO and rs7975232 of VDR, of the twelve tested SNPs showed significant protective associations with the BMI with odds ratio 0.3886 (0.1761-0.8572); p 0.0192 and odds ratio 0.4563 (0.2343-0.8888); p 0.0211, respectively. Conclusion The current study showed that minor alleles, "T" of FTO and "A" of VDR, might be protective factors against increased BMI in young Saudi female subjects. To elucidate this association, further studies with larger sample size involving both sexes are required.

Bingqi Wang, Min Wang, Xianping Li, Min Yang, Lei Liu Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, People’s Republic of ChinaCorrespondence: Min WangDepartment of Laboratory Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha 410011, Hunan, People’s Republic of ChinaTel/Fax +86 132 9869 7558Email wangmin0000@csu.edu.cnBackground: Cervical cancer is the fourth most common and fatal tumor among women worldwide. The Wnt/β-catenin signaling pathway was etiologically involved in the cervical cancer model. Herein, we aimed to investigate whether germline genetic variations within the Wnt/β-catenin pathway can be genetic risk factors of cervical cancer.Patients and Methods: A total of 305 samples (147 patients, 158 controls) were included. Eight genetic variations located in APC (rs454886), GSK3β (rs3755557), CTNNB1 (rs11564475, rs1798802, rs3864004, rs2293303, and rs4135385), and TCF7L2 (rs7903146) were genotyped via Sanger sequencing. The χ2 test and non-conditional logistic regression were used in the single-locus analysis. Gene–gene interactions and haplotype construction in case–control samples were performed by the GMDR method and Haploview software, respectively.Results: The frequency of CTNNB1 rs1798802 GA+AA genotype was significantly lower in cervical cancer patients adjusted for age (OR=0.626, 95% CI=0.398– 0.984). The mutant alleles of rs3864004 (A) and rs2293303 (T) located in CTNNB1 showed 1.513 (1.038– 2.207), and 1.654 (1.020– 2.683) fold increased risk of cervical cancer, respectively. Haplotype analysis showed no association between haplotypes of the CTNNB1 gene and cervical cancer risk. No significant contribution of interactions among genes in the Wnt pathway was identified.Conclusion: We concluded that the genetic variants in the CTNNB1 gene might contribute to the development of cervical cancer.Keywords: cervical cancer, Wnt/β-catenin signaling pathway, single nucleotide polymorphism, APC, GSK3β, CTNNB1, TCF7L2

Genome-wide association studies have identified hundreds of single nucleotide polymorphisms (SNPs) that are associated with BMI and diabetes. However, lack of adequate data has for long time prevented investigations on the pathogenesis of diabetes where BMI was a mediator of the genetic causal effects on this disease. Of our particular interest is the underlying causal mechanisms of diabetes. We leveraged the summary statistics reported in two studies: UK Biobank (N = 336,473) and Genetic Investigation of ANthropometric Traits (GIANT, N = 339,224) to investigate BMI-mediated genetic causal pathways to diabetes. We first estimated the causal effect of BMI on diabetes by using four Mendelian randomization methods, where a total of 76 independent BMI-associated SNPs (R2 ≤ 0.001, P −8) were used as instrumental variables. It was consistently shown that higher level of BMI (kg/m2) led to increased risk of diabetes. We then applied two Bayesian colocalization methods and identified shared causal SNPs of BMI and diabetes in genes TFAP2B, TCF7L2, FTO and ZC3H4. This study utilized integrative analysis of Mendelian randomization and colocalization to uncover causal relationships between genetic variants, BMI and diabetes. It highlighted putative causal pathways to diabetes mediated by BMI for four genes.