scholarly journals Plasma vitamin C and type 2 diabetes: genome-wide association study and Mendelian randomization analysis in European populations

2020 ◽  
Author(s):  
Ju-Sheng Zheng ◽  
Jian’an Luan ◽  
Eleni Sofianopoulou ◽  
Fumiaki Imamura ◽  
Isobel D Stewart ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Vitamin C ◽  
Mendelian Randomization ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Plasma Vitamin ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
European Populations

<b>Objective</b> Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes. <p><b>Research Design and Methods</b> We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted difference in plasma vitamin C with type 2 diabetes in up-to 80,983 cases and 842,909 non-cases. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 cases and 11,073 non-cases.</p> <p><b>Results</b> We identified 11 genomic regions associated with plasma vitamin C (p<5×10<sup>-8</sup>), with the strongest signal at <i>SLC23A1</i>, and 10 novel genetic loci including <i>SLC23A3</i>, <i>CHPT1</i>,<i> BCAS3</i>, <i>SNRPF</i>, <i>RER1</i>, <i>MAF</i>, <i>GSTA5</i>, <i>RGS14</i>, <i>AKT1</i> and <i>FADS1</i>. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per standard deviation, 0.88, 95%CI: 0.82, 0.94), <a>but there was no association between genetically predicted plasma vitamin C (excluding <i>FADS1</i> variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03, 95%CI: 0.96, 1.10)</a>. </p> <p><b>Conclusions</b> <a>These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of</a> vitamin C supplementation for type 2 diabetes prevention.</p>

scholarly journals Plasma vitamin C and type 2 diabetes: genome-wide association study and Mendelian randomization analysis in European populations

2020 ◽  
Author(s):  
Ju-Sheng Zheng ◽  
Jian’an Luan ◽  
Eleni Sofianopoulou ◽  
Fumiaki Imamura ◽  
Isobel D Stewart ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Vitamin C ◽  
Mendelian Randomization ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Plasma Vitamin ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
European Populations

<b>Objective</b> Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes. <p><b>Research Design and Methods</b> We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted difference in plasma vitamin C with type 2 diabetes in up-to 80,983 cases and 842,909 non-cases. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 cases and 11,073 non-cases.</p> <p><b>Results</b> We identified 11 genomic regions associated with plasma vitamin C (p<5×10<sup>-8</sup>), with the strongest signal at <i>SLC23A1</i>, and 10 novel genetic loci including <i>SLC23A3</i>, <i>CHPT1</i>,<i> BCAS3</i>, <i>SNRPF</i>, <i>RER1</i>, <i>MAF</i>, <i>GSTA5</i>, <i>RGS14</i>, <i>AKT1</i> and <i>FADS1</i>. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per standard deviation, 0.88, 95%CI: 0.82, 0.94), <a>but there was no association between genetically predicted plasma vitamin C (excluding <i>FADS1</i> variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03, 95%CI: 0.96, 1.10)</a>. </p> <p><b>Conclusions</b> <a>These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of</a> vitamin C supplementation for type 2 diabetes prevention.</p>

scholarly journals Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations

Diabetes Care ◽  
2020 ◽  
Vol 44 (1) ◽  
pp. 98-106
Author(s):  
Ju-Sheng Zheng ◽  
Jian’an Luan ◽  
Eleni Sofianopoulou ◽  
Fumiaki Imamura ◽  
Isobel D. Stewart ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Vitamin C ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Genome Wide Association ◽  
Plasma Vitamin ◽  
Genome Wide ◽  
Randomization Analysis ◽  
European Populations

scholarly journals Identification of type 2 diabetes loci in 433,540 East Asian individuals

2019 ◽  
Author(s):  
Cassandra N Spracklen ◽  
Momoko Horikoshi ◽  
Young Jin Kim ◽  
Kuang Lin ◽  
Fiona Bragg ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Association Studies ◽  
Meta Analysis ◽  
East Asian ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
European Populations

SUMMARYMeta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, NKX6-3 and ANK1, in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.Type 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production and/or secretion by the pancreatic β cells and insulin resistance in peripheral tissues1. Most genetic loci associated with T2D have been identified in populations of European (EUR) ancestry, including a recent meta-analysis of genome-wide association studies (GWAS) of nearly 900,000 individuals of European ancestry that identified >240 loci influencing the risk of T2D2. Differences in allele frequency between ancestries affect the power to detect associations within a population, particularly among variants rare or monomorphic in one population but more frequent in another3,4. Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci4. The relative contributions of different pathways to the pathophysiology of T2D may also differ between ancestry groups. For example, in East Asian (EAS) populations, T2D prevalence is greater than in European populations among people of similar body mass index (BMI) or waist circumference5. We performed the largest meta-analysis of East Asian individuals to identify new genetic associations and provide insight into T2D pathogenesis.

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

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.

scholarly journals Mendelian Randomization Study on Amino Acid Metabolism Suggests Tyrosine as Causal Trait for Type 2 Diabetes

Nutrients ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3890
Author(s):  
Susanne Jäger ◽  
Rafael Cuadrat ◽  
Clemens Wittenbecher ◽  
Anna Floegel ◽  
Per Hoffmann ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Amino Acids ◽  
Amino Acid ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Inverse Association ◽  
Genome Wide

Circulating levels of branched-chain amino acids, glycine, or aromatic amino acids have been associated with risk of type 2 diabetes. However, whether those associations reflect causal relationships or are rather driven by early processes of disease development is unclear. We selected diabetes-related amino acid ratios based on metabolic network structures and investigated causal effects of these ratios and single amino acids on the risk of type 2 diabetes in two-sample Mendelian randomization studies. Selection of genetic instruments for amino acid traits relied on genome-wide association studies in a representative sub-cohort (up to 2265 participants) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study and public data from genome-wide association studies on single amino acids. For the selected instruments, outcome associations were drawn from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis, 74,124 cases and 824,006 controls) consortium. Mendelian randomization results indicate an inverse association for a per standard deviation increase in ln-transformed tyrosine/methionine ratio with type 2 diabetes (OR = 0.87 (0.81–0.93)). Multivariable Mendelian randomization revealed inverse association for higher log10-transformed tyrosine levels with type 2 diabetes (OR = 0.19 (0.04–0.88)), independent of other amino acids. Tyrosine might be a causal trait for type 2 diabetes independent of other diabetes-associated amino acids.

scholarly journals A causal relationship between cigarette smoking and type 2 diabetes mellitus: A Mendelian randomization study

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Shuai Yuan ◽  
Susanna C. Larsson
Keyword(s):  
Type 2 Diabetes ◽  
Cigarette Smoking ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Smoking Initiation ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide

AbstractThe causality between smoking and type 2 diabetes is unclear. We conducted a two-sample Mendelian randomization study to explore the causal relationship between smoking initiation and type 2 diabetes. Summary-level data for type 2 diabetes were obtained from a meta-analysis of 32 genome-wide association studies (DIAbetes Genetics Replication And Meta-analysis consortium), which included 898 130 individuals of European ancestry. Totally, 377 single-nucleotide polymorphisms associated with smoking initiation at genome wide significance threshold (p < 5 × 10−8) were identified from the hitherto largest genome-wide association study on smoking. The inverse-variance weighted, weighted median, MR-Egger regression, and MR-PRESSO approaches were used to analyze the data. Genetically predicted smoking initiation was associated with type 2 diabetes with an odds ratio of 1.28 (95% confidence interval, 1.20, 1.37; p = 2.35 × 10−12). Results were consistent across sensitivity analyses and there was no evidence of horizontal pleiotropy. This study provides genetic evidence supporting a causal association between the smoking initiation and type 2 diabetes. Reducing cigarette smoking initiation can now be even more strongly recommended for type 2 diabetes prevention.

Genome-Wide Association Studies Identify Two Novel Loci Conferring Susceptibility to Diabetic Retinopathy in Japanese Patients with Type 2 Diabetes

2021 ◽  
Author(s):  
Minako Imamura ◽  
Atsushi Takahashi ◽  
Masatoshi Matsunami ◽  
Momoko Horikoshi ◽  
Minoru Iwata ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Association Studies ◽  
Meta Analysis ◽  
Japanese Patients ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Stage 1

Abstract Several reports have suggested that genetic susceptibility contributes to the development and progression of diabetic retinopathy. We aimed to identify genetic loci that confer susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes. We analysed 5 790 508 single nucleotide polymorphisms (SNPs) in 8880 Japanese patients with type 2 diabetes, 4839 retinopathy cases and 4041 controls, as well as 2217 independent Japanese patients with type 2 diabetes, 693 retinopathy cases, and 1524 controls. The results of these two genome-wide association studies (GWAS) were combined with an inverse variance meta-analysis (Stage-1), followed by de novo genotyping for the candidate SNP loci (p &lt; 1.0 × 10−4) in an independent case–control study (Stage-2, 2260 cases and 723 controls). After combining the association data (Stage-1 and -2) using meta-analysis, the associations of two loci reached a genome-wide significance level: rs12630354 near STT3B on chromosome 3, p = 1.62 × 10−9, odds ratio (OR) = 1.17, 95% confidence interval (CI) 1.11–1.23, and rs140508424 within PALM2 on chromosome 9, p = 4.19 × 10−8, OR = 1.61, 95% CI 1.36–1.91. However, the association of these two loci were not replicated in Korean, European, or African American populations. Gene-based analysis using Stage-1 GWAS data identified a gene-level association of EHD3 with susceptibility to diabetic retinopathy (p = 2.17 × 10−6). In conclusion, we identified two novel SNP loci, STT3B and PALM2, and a novel gene, EHD3, that confers susceptibility to diabetic retinopathy; however, further replication studies are required to validate these associations.

scholarly journals Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Minako Imamura ◽  
Atsushi Takahashi ◽  
Toshimasa Yamauchi ◽  
Kazuo Hara ◽  
Kazuki Yasuda ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Japanese Population ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

Genome-wide association studies of Type 2 diabetes: are these ready to make an impact in the clinic?

2011 ◽  
Vol 1 (4) ◽  
pp. 379-387
Author(s):  
Gaya Thanabalasingham ◽  
Anna L Gloyn ◽  
Katharine R Owen
Keyword(s):  
Type 2 Diabetes ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

scholarly journals Genome-wide Association Study of Pancreatic Fat: The Multiethnic Cohort Adiposity Phenotype Study

2021 ◽  
Author(s):  
Samantha Streicher ◽  
Unhee Lim ◽  
S. Lani Park ◽  
Yuqing Li ◽  
Xin Sheng ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
European Ancestry ◽  
American Population ◽  
Pancreatic Fat ◽  
Genome Wide ◽  
Multiethnic Cohort

Several studies have found associations between higher pancreatic fat content and adverse health outcomes, such as diabetes and the metabolic syndrome, but investigations into the genetic contributions to pancreatic fat are limited.  This genome-wide association study, comprised of 804 participants with MRI-assessed pancreatic fat measurements, was conducted in the ethnically diverse Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS).  Two genetic variants reaching genome-wide significance, rs73449607 on chromosome 13q21.2 (Beta = -0.67, P = 4.50x10 -8 ) and rs7996760 on chromosome 6q14 (Beta = -0.90, P = 4.91x10 -8 ) were associated with percent pancreatic fat on the log scale.  Rs73449607 was most common in the African American population (13%) and rs79967607 was most common in the European American population (6%).  Rs73449607 was also suggestively associated with lower risk of type 2 diabetes (OR = 0.95, 95% CI = 0.89-1.00, P = 0.047) in the Population Architecture Genomics and Epidemiology (PAGE) Study and the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM), which included substantial numbers of non-European ancestry participants (53,102 cases and 193,679 controls).  Rs73449607 is located in an intergenic region between GSX1 and PLUT , and rs79967607 is in intron 1 of EPM2A .  PLUT, a linkRNA, regulates transcription of an adjacent gene, PDX1 , that controls beta-cell function in the mature pancreas, and EPM2A encodes the protein laforin, which plays a critical role in regulating glycogen production.  If validated, these variants may suggest a genetic component for pancreatic fat and a common etiologic link between pancreatic fat and type 2 diabetes.

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