The Protective Effect of Transcription Factor 7-Like 2 Risk Allele rs7903146 against Elevated Fasting Plasma Triglyceride in Type 2 Diabetes: A Meta-Analysis

Background. The results from published studies regarding association of transcription factor 7-like 2 (TCF7L2) variant rs7903146 with dyslipidemia have been conflicting and inconclusive.Methods. We carried out a meta-analysis that aimed to investigate the association of the rs7903146 variant with plasma lipid levels using electronic database and published studies. Data was extracted by a standard algorithm. Dominant, recessive, homozygote, and heterozygote comparison models were utilized.Results. 24 studies incorporating 52,785 subjects were included in this meta-analysis. Overall, the minor allele (T) was associated with lower risk for hypertriglyceridemia in subjects with type 2 diabetes (dominant model: SMD = −0.04, 95% CI (−0.08, 0.00),P= 0.048,Pheterogeneity= 0.47; recessive model: SMD = −0.10, 95% CI (−0.18, −0.02),P= 0.01,Pheterogeneity= 0.56). No association was found between minor (T) allele and plasma TC, LDL-c, or HDL-c levels in subjects with type 2 diabetes or metabolic syndrome (MetS) and no association was found between minor (T) allele and plasma TG levels in nondiabetic subjects.Conclusions. Our meta-analysis indicated the association between TCF7L2 rs7903146 polymorphism and low plasma triglyceride (TG) level in subjects with type 2 diabetes. No association was found between rs7903146 variant and plasma lipids in nondiabetic subjects.

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Genetic associations between Transcription Factor 7 Like 2 rs7903146 polymorphism and type 2 diabetes mellitus: a meta-analysis of 115,809 subjects

Diabetology & Metabolic Syndrome ◽

10.1186/s13098-019-0451-9 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Liying Lou ◽

Jingjing Wang ◽

Jing Wang

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Transcription Factor ◽

Meta Analysis ◽

Genetic Associations

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Genome-Wide Association Meta-Analysis Using a Recessive Model Illuminates Genetic Architecture of Type 2 Diabetes

10.1101/2021.07.08.21258700 ◽

2021 ◽

Author(s):

Mark J O'Connor ◽

Alicia Huerta-Chagoya ◽

Paula Cortés-Sánchez ◽

Silvía Bonàs-Guarch ◽

Joanne B Cole ◽

...

Keyword(s):

Type 2 Diabetes ◽

Meta Analysis ◽

Recessive Model ◽

Additive Models ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Recessive Effects

Objective: Most genome-wide association studies (GWAS) of complex traits are performed using models with additive allelic effects. Hundreds of loci associated with type 2 diabetes have been identified using this approach. Additive models, however, can miss loci with recessive effects, thereby leaving potentially important genes undiscovered. Research Design and Methods: We conducted the largest GWAS meta-analysis using a recessive model for type 2 diabetes. Our discovery sample included 33,139 cases and 279,507 controls from seven European-ancestry cohorts including the UK Biobank. We then used two additional cohorts, FinnGen and a Danish cohort, for replication. For the most significant recessive signal, we conducted a phenome-wide association study across hundreds of traits to make inferences about the pathophysiology underlying the increased risk seen in homozygous carriers. Results: We identified 51 loci associated with type 2 diabetes, including five variants with recessive effects undetected by prior additive analyses. Two of the five had minor allele frequency less than 5% and were each associated with more than doubled risk. We replicated three of the variants, including one of the low-frequency variants, rs115018790, which had an odds ratio in homozygous carriers of 2.56 (95% CI 2.05-3.19, P=1×10-16) and a stronger effect in men than in women (interaction P=7×10-7). Colocalization analysis linked this signal to reduced expression of the nearby PELO gene, and the signal was associated with multiple diabetes-related traits, with homozygous carriers showing a 10% decrease in LDL and a 20% increase in triglycerides. Conclusions: Our results demonstrate that recessive models, when compared to GWAS using the additive approach, can identify novel loci, including large-effect variants with pathophysiological consequences relevant to type 2 diabetes.

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The association of TNF-α −308G/A and −238G/A polymorphisms with type 2 diabetes mellitus: a meta-analysis

Bioscience Reports ◽

10.1042/bsr20191301 ◽

2019 ◽

Vol 39 (12) ◽

Author(s):

Xiaoliang Guo ◽

Chenxi Li ◽

Jiawei Wu ◽

Qingbu Mei ◽

Chang Liu ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Meta Analysis ◽

Recessive Model ◽

Dominant Model ◽

Codominant Model ◽

Tnf Α ◽

Allele Model

Abstract Tumor necrosis factor-α (TNF-α) is involved in insulin resistance and has long been a candidate gene implicated in type 2 diabetes mellitus (T2DM), however the association between TNF-α polymorphisms -308G/A and -238G/A and T2DM remains controversial. The present study sought to verify associations between these polymorphisms and T2DM susceptibility using a meta-analysis approach. A total of 49 case–control studies were selected up to October 2018. Statistical analyses were performed by STATA 15.0 software. The odds ratios (ORs) and 95% confidence intervals were calculated to estimate associations. Meta-analyses revealed significant associations between TNF-α −308G/A and T2DM in the allele model (P=0.000); the dominant model (P=0.000); the recessive model (P=0.001); the overdominant model (P=0.008) and the codominant model (P=0.000). Subgroup analyses also showed associations in the allele model (P=0.006); the dominant model (P=0.004) and the overdominant model (P=0.005) in the Caucasian and in the allele model (P=0.007); the dominant model (P=0.014); the recessive model (P=0.000) and the codominant model (P=0.000) in the Asian. There were no associations between TNF-α −238G/A and T2DM in the overall and subgroup populations. Meta-regression, sensitivity analysis and publication bias analysis confirmed that results and data were statistically robust. Our meta-analysis suggests that TNF-α −308G/A is a risk factor for T2DM in Caucasian and Asian populations. It also indicates that TNF-α −238G/A may not be a risk factor for T2DM. More comprehensive studies will be required to confirm these associations.

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