scholarly journals Transcription factor regulation as a mechanism of confounding effects between distinct human traits

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 1349
Author(s):  
Milos Pjanic ◽  
Clint L. Miller ◽  
Thomas Quertermous
Keyword(s):  
Type 2 Diabetes ◽  
Transcription Factor ◽  
Genetic Variants ◽  
Human Diseases ◽  
Upstream Region ◽  
Hair Color ◽  
Human Populations ◽  
Genome Wide Association Studies ◽  
Transcription Factor Regulation

Genome-wide association studies (GWAS) to date have discovered thousands of genetic variants linked to human diseases and traits, which hold the potential to unravel the mechanisms of complex phenotypes. However, given that the majority of these associated variants reside in non-coding genomic regions, their predicted cis and trans-regulatory functions remain largely undefined. Here we show that correlation between human diseases and traits can follow geographical distribution of human populations, and that the underlying mechanism is at least partly genetically based. We report two Type 2 Diabetes (T2D) GWAS variants (rs7903146 and rs12255372) in the TCF7L2 locus that regulate expression in skin tissues but not lymphoblastoid or adipose tissues, of the KITLG gene that encodes an important regulator of melanogenesis and light hair color in European populations. We also report extensive binding events of TCF7L2 protein in the promoter region, immediate upstream region and first intron of the KITLG gene, which supports a trans-interaction between TCF7L2 and KITLG. We further show that both light hair color and T2D genetic variants are correlated with geographic latitude. Taken together, our observations suggest that natural variation in transcription factor loci in European human populations may be an underlying and confounding factor for the geographical correlation between human phenotypes, such as type 2 diabetes and light hair color. We postulate that transcription factor regulation may confound the correlation between seemingly diverse human traits. Furthermore, our findings demonstrate the importance of dissecting the genomic architecture of GWAS loci using multiple genetic and genomic datasets.

scholarly journals Identification of novel non-synonymous variants associated with type 2 diabetes-related metabolites in Korean population

2019 ◽  
Vol 39 (10) ◽  
Author(s):  
Tae-Joon Park ◽  
Heun-Sik Lee ◽  
Young Jin Kim ◽  
Bong-Jo Kim
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Variants ◽  
Multiple Testing ◽  
Association Studies ◽  
Linear Regression Analysis ◽  
Genetic Regulation ◽  
Genome Wide Association Studies ◽  
Functional Variants ◽  
Genome Wide

Abstract Metabolome-genome wide association studies (mGWASs) are useful for understanding the genetic regulation of metabolites in complex diseases, including type 2 diabetes (T2D). Numerous genetic variants associated with T2D-related metabolites have been identified in previous mGWASs; however, these analyses seem to have difficulty in detecting the genetic variants with functional effects. An exome array focussed on potentially functional variants is an alternative platform to obtain insight into the genetics of biochemical conversion processes. In the present study, we performed an mGWAS using 27,140 non-synonymous variants included in the Illumina HumanExome BeadChip and nine T2D-related metabolites identified by a targetted metabolomics approach to evaluate 2,338 Korean individuals from the Korea Association REsource (KARE) cohort. A linear regression analysis controlling for age, sex, BMI, and T2D status as covariates was performed to identify novel non-synonymous variants associated with T2D-related metabolites. We found significant associations between glycine and CPS1 (rs1047883) and PC ae C36:0 and CYP4F2 (rs2108622) variants (P<2.05 × 10−7, after the Bonferroni correction for multiple testing). One of the two significantly associated variants, rs1047883 was newly identified whereas rs2108622 had been previously reported to be associated with T2D-related traits. These findings expand our understanding of the genetic determinants of T2D-related metabolites and provide a basis for further functional validation.

scholarly journals Haplotypes of Transcription Factor 7–Like 2 (TCF7L2) Gene and Its Upstream Region Are Associated With Type 2 Diabetes and Age of Onset in Mexican Americans

Diabetes ◽  
2007 ◽  
Vol 56 (2) ◽  
pp. 389-393 ◽  
Author(s):  
Donna M. Lehman ◽  
Kelly J. Hunt ◽  
Robin J. Leach ◽  
Jeanette Hamlington ◽  
Rector Arya ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Transcription Factor ◽  
Mexican Americans ◽  
Age Of Onset ◽  
Upstream Region ◽  
Tcf7l2 Gene

scholarly journals Analysis of the interaction between transcription factor 7-like 2 genetic variants with nopal and wholegrain fibre intake: effects on anthropometric and metabolic characteristics in type 2 diabetes patients

2016 ◽  
Vol 116 (6) ◽  
pp. 969-978 ◽  
Author(s):  
M. M. López-Ortiz ◽  
M. E. Garay-Sevilla ◽  
M. E. Tejero ◽  
E. L. Perez-Luque
Keyword(s):  
Type 2 Diabetes ◽  
Transcription Factor ◽  
Genetic Variants ◽  
Repeated Measures ◽  
Anthropometric Measures ◽  
Soluble Fibre ◽  
Metabolic Characteristics ◽  
Treatment Of Diabetes ◽  
Carry Over

AbstractThe transcription factor 7-like 2 (TCF7L2) genetic variants have shown differential effect on low-fat and high-fat diet in obese subjects. Nopal is a Mexican variety of cactus that is a traditional food and has been used in the treatment of diabetes. Its hypoglycaemic effect may be because of its soluble fibre (mucopolysaccharide) content. This study analysed the effects of the rs7903146 and rs12255372TCF7L2 variants on anthropometric, metabolic and hormonal parameters in type 2 diabetes mellitus patients who consumed fibre from either nopal tortilla or wholegrain bread for 8 weeks. We followed-up seventy-four patients who consumed an individualised isoenergetic diet that included nopal tortilla (Diet 1) and sixty-three patients with a diet that included wholegrain bread (Diet 2). Anthropometric, metabolic and hormonal measures were collected at baseline and final intervention. The size effect and carry-over effect were estimated. To assess the interaction of genotype and diets, we used a general linear model repeated-measures analysis. Minor allele frequency of rs7903146T was 0·27 and for rs12255372T it was 0·13. At 8 weeks after Diet 1 intake, weight, BMI, waist and hip circumference decreased (P=0·00015) in rs7903146CC and rs12255372GG genotypes. In particular, patients carrying of the rs7903146CC and consuming Diet 1 showed a reduction in waist circumference of more than 2·5 cm compared with Diet 2 (P<0·001). No significant interaction between rs7903146 or rs12255372 and diet was seen in this study. In conclusion, in the carriers of the rs7903146CC and rs12255372GG wild types, significant changes in all anthropometric measures were observed, and had better response to both diets.

scholarly journals A common variant in the CLDN7/ELP5 locus predicts adiponectin change with lifestyle intervention and improved fitness in obese individuals with diabetes

2015 ◽  
Vol 47 (6) ◽  
pp. 215-224 ◽  
Author(s):  
L. Maria Belalcazar ◽  
George D. Papandonatos ◽  
Jeanne M. McCaffery ◽  
Inga Peter ◽  
Nicholas M. Pajewski ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Weight Loss ◽  
Lifestyle Intervention ◽  
Genetic Variants ◽  
Association Studies ◽  
Lifestyle Changes ◽  
Genome Wide Association Studies ◽  
Look Ahead ◽  
Genome Wide

Overweight/obese individuals with Type 2 diabetes have low adiponectin levels, which may improve with lifestyle changes. We investigated whether genetic variants associated with adiponectin levels in genome-wide association studies (GWAS) would also be related with adiponectin changes in response to an intensive lifestyle intervention (ILI), potentially through mechanisms altering the adipose microenvironment via weight loss and/or improved cardiorespiratory fitness. Look AHEAD was a randomized trial comparing the cardiovascular benefits of ILI-induced weight loss and physical activity compared with diabetes support and education among overweight/obese individuals with Type 2 diabetes. In a subsample of Look AHEAD with adiponectin data and genetic consent ( n = 1,351), we evaluated the effects of 24 genetic variants, demonstrated by GWAS to be cross-sectionally associated with adiponectin, on adiponectin change 1-yr postintervention. We explored via mediational analyses whether any differential effects by treatment arm were occurring through weight loss and/or improved fitness. A variant, rs222857, in the CLDN7 locus, potentially associated with epithelial barrier integrity and tight junction physiology, and a putative cis expression quantitative trail locus for elongator acetyltransferase complex subunit 5 ( ELP5), predicted adiponectin increases within ILI (log-adiponectin in overall sample per copy: β ± SE = 0.05 ± 0.02, P = 0.008; in non-Hispanic whites: 0.06 ± 0.02, P = 0.009). The favorable effects of rs222857 (minor allele frequency 45.5%) appeared to be mediated by mechanisms associated with improved fitness, and not weight loss. This is the first study to identify a genetic variant that modifies adiponectin response to lifestyle intervention in overweight/obese diabetic individuals.

scholarly journals Nonalcoholic fatty liver disease and type 2 diabetes: pathophysiological mechanisms shared between the two faces of the same coin

2020 ◽  
Vol 1 (5) ◽  
Author(s):  
Carlo Acierno ◽  
Alfredo Caturano ◽  
Pia Clara Pafundi ◽  
Riccardo Nevola ◽  
Luigi Elio Adinolfi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Transcription Factor ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Genome Wide Association Studies ◽  
Nonalcoholic Fatty Liver ◽  
Pathophysiological Mechanisms

The pathophysiological mechanisms underlying the close relationship between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are multiple, complex and only partially known. The purpose of this paper was to review the current knowledge of these mechanisms in a unified manner. Subjects with NAFLD and T2DM have established insulin resistance (IR), which exacerbates the two comorbidities. IR worsens NAFLD by increasing the accumulation of free fatty acids (FFAs) in the liver. This occurs due to an increase in the influx of FFAs from peripheral adipose tissue by the activation of hormone-sensitive lipase. In addition, there is de novo increased lipogenesis, a transcription factor, the sterols regulatory element-binding transcription factor 1c (SREBP-1c), which activates the expression of several genes strongly promotes lipogenesis by the liver and facilitate storage of triglycerides. Lipids accumulation in the liver induces a chronic stress in the endoplasmic reticulum of the hepatocytes. Genome-wide association studies have identified genetic variants associated with NAFLD severity, but unrelated to IR. In particular, the alteration of patatin-like phospholipase domain-containing protein 3 contributes to the susceptibility to NAFLD. Furthermore, the lipotoxicity of ceramides and diacylglycerol, well known in T2DM, triggers a chronic inflammatory process favoring the progression from hepatic steatosis to steatohepatitis. Reactive oxygen species produced by mitochondrial dysfunction trigger both liver inflammation and beta-cells damage, promoting the progression of both NAFLD and T2DM. The close association between NAFLD and T2DM is bidirectional, as T2DM may trigger both NAFLD onset and its progression, but NAFLD itself may contribute to the development of IR and T2DM. Future studies on the mechanisms will have to deepen the knowledge of the interaction between the two pathologies and should allow the identification of new therapeutic targets for the treatment of NAFLD, currently substantially absent.

scholarly journals Mendelian randomization studies of biomarkers and type 2 diabetes

2015 ◽  
Vol 4 (4) ◽  
pp. 249-260 ◽  
Author(s):  
Ali Abbasi
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Variants ◽  
Large Scale ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Causal Effects ◽  
Current Evidence ◽  
Genome Wide Association Studies ◽  
Glycaemic Traits

Many biomarkers are associated with type 2 diabetes (T2D) risk in epidemiological observations. The aim of this study was to identify and summarize current evidence for causal effects of biomarkers on T2D. A systematic literature search in PubMed and EMBASE (until April 2015) was done to identify Mendelian randomization studies that examined potential causal effects of biomarkers on T2D. To replicate the findings of identified studies, data from two large-scale, genome-wide association studies (GWAS) were used: DIAbetes Genetics Replication And Meta-analysis (DIAGRAMv3) for T2D and the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) for glycaemic traits. GWAS summary statistics were extracted for the same genetic variants (or proxy variants), which were used in the original Mendelian randomization studies. Of the 21 biomarkers (from 28 studies), ten have been reported to be causally associated with T2D in Mendelian randomization. Most biomarkers were investigated in a single cohort study or population. Of the ten biomarkers that were identified, nominally significant associations with T2D or glycaemic traits were reached for those genetic variants related to bilirubin, pro-B-type natriuretic peptide, delta-6 desaturase and dimethylglycine based on the summary data from DIAGRAMv3 or MAGIC. Several Mendelian randomization studies investigated the nature of associations of biomarkers with T2D. However, there were only a few biomarkers that may have causal effects on T2D. Further research is needed to broadly evaluate the causal effects of multiple biomarkers on T2D and glycaemic traits using data from large-scale cohorts or GWAS including many different genetic variants.

scholarly journals Whole-Exome sequencing identifies a Type 2 Diabetes candidate mutation in PTPRF

2020 ◽  
Author(s):  
Erik J.M. Toonen ◽  
Michael Kwint ◽  
Alexander Hoischen ◽  
Cees J. Tack
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
Association Studies ◽  
Family Members ◽  
Genome Wide Association Studies ◽  
Whole Exome

Objectives: Identification of genetic factors involved in Type 2 diabetes mellitus (T2DM) has been challenging. While genome-wide association studies (GWAS) have identified over 60 loci associated with T2DM, these variants only explain a small proportion of the total heritability of the disease. Whole-exome sequencing has become a powerful approach to identify genetic variants that are not captured by GWAS. We applied exome sequencing to identify causal genetic variants in a family with a 2-generation history of T2DM characterized by substantial insulin resistance, hypertension and isolated hypertriglyceridemia. Methods: Exome sequencing was performed on genomic DNA of two affected family members. Twenty-four identified variants that were present in both family members were further tested for segregation in all other family members by Sanger sequencing. Results: Three rare missense variants, located in the genes PTPRF, FUCA1 and FBXO30, were present in all affected family members but also in one unaffected family member. Protein-protein interaction analysis showed that PTPRF strongly interacts with several members of the insulin signaling pathway. Conclusions: Our results suggest that the variant in the PTPRF gene might be causal for an unusual T2DM subtype that is characterized by a severe insulin resistance and isolated hypertriglyceridemia.

Sign in / Sign up

Export Citation Format

Share Document