Abstract P072: Circulating Phylloquinone Concentrations and Type 2 Diabetes Incidence: A Mendelian Randomization Study

Introduction: This study aims to investigate the causal relation of genetically conferred circulating phylloquinone levels and the risk of type 2 diabetes (T2D) via a Mendelian Randomization approach. Methods: We used data from the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study comprising 10,071 diabetes cases and 13,309 subcohort members from eight European countries. We calculated a weighted genetic risk score (wGRS) including four SNPs (rs2192574, rs6862071, rs4645543 and rs2108622) likely to be related to circulating phylloquinone levels from a genome wide association study. Inverse-variance weighted (IVW) analysis was used to obtain a Hazard Ratio (HR) for the unconfounded relation between circulating phylloquinone levels and T2D incidence. All analyses were adjusted for sex, center, principal components of ancestry, genetic platform, triglycerides and hours fasting. Furthermore, we assessed the robustness of our results with a MR Egger analyses. In follow-up analyses, we have included data from the Diabetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, increasing our dataset to 21,571 participants with diabetes. Results: The median follow-up time was 10.9 years. In IVW analysis, genetically conferred higher circulating phylloquinone levels were associated with a reduced risk of T2D with a HR of 0.87 (0.78;0.97) for every ln-nmol/L increase in circulating phylloquinone. The MR Egger method resulted in a HR of 0.88 (0.72;1.08).Adding DIAGRAM data resulted in a summary odds ratio of 0.90 (0.81;1.00). Conclusion: Our study suggests that the association between higher circulating phylloquinone levels and lower T2D incidence may be causal.

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Elevated circulating follistatin associates with an increased risk of type 2 diabetes

Nature Communications ◽

10.1038/s41467-021-26536-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Chuanyan Wu ◽

Yan Borné ◽

Rui Gao ◽

Maykel López Rodriguez ◽

William C. Roell ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

Genome Wide Association Study ◽

Regulatory Protein ◽

Alcoholic Fatty Liver ◽

Increased Risk

AbstractThe hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04–1.47, p < 0.05) during 19-year follow-up (n = 4060, Sweden); and 1.31 (CI: 1.09–1.58, p < 0.01) during 4-year follow-up (n = 883, Finland). High circulating follistatin associates with adipose tissue insulin resistance and non-alcoholic fatty liver disease (n = 210, Germany). In human adipocytes, follistatin dose-dependently increases free fatty acid release. In genome-wide association study (GWAS), variation in the glucokinase regulatory protein gene (GCKR) associates with plasma follistatin levels (n = 4239, Sweden; n = 885, UK, Italy and Sweden) and GCKR regulates follistatin secretion in hepatocytes in vitro. Our findings suggest that GCKR regulates follistatin secretion and that elevated circulating follistatin associates with an increased risk of T2D by inducing adipose tissue insulin resistance.

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A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants

Science ◽

10.1126/science.1142382 ◽

2007 ◽

Vol 316 (5829) ◽

pp. 1341-1345 ◽

Cited By ~ 1938

Author(s):

L. J. Scott ◽

K. L. Mohlke ◽

L. L. Bonnycastle ◽

C. J. Willer ◽

Y. Li ◽

...

Keyword(s):

Type 2 Diabetes ◽

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome

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Genetic Risk Score of 46 Type 2 Diabetes Risk Variants Associates With Changes in Plasma Glucose and Estimates of Pancreatic -Cell Function Over 5 Years of Follow-Up

Diabetes ◽

10.2337/db13-0362 ◽

2013 ◽

Vol 62 (10) ◽

pp. 3610-3617 ◽

Cited By ~ 28

Author(s):

E. A. Andersson ◽

K. H. Allin ◽

C. H. Sandholt ◽

A. Borglykke ◽

C. J. Lau ◽

...

Keyword(s):

Type 2 Diabetes ◽

Risk Score ◽

Plasma Glucose ◽

Genetic Risk ◽

Cell Function ◽

Genetic Risk Score ◽

Pancreatic Cell ◽

Risk Variants

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Use of diverse electronic medical record systems to identify genetic risk for type 2 diabetes within a genome-wide association study

Journal of the American Medical Informatics Association ◽

10.1136/amiajnl-2011-000439 ◽

2012 ◽

Vol 19 (2) ◽

pp. 212-218 ◽

Cited By ~ 159

Author(s):

Abel N Kho ◽

M Geoffrey Hayes ◽

Laura Rasmussen-Torvik ◽

Jennifer A Pacheco ◽

William K Thompson ◽

...

Keyword(s):

Type 2 Diabetes ◽

Association Study ◽

Medical Record ◽

Genetic Risk ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome ◽

Electronic Medical Record Systems

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Early metabolic features of genetic liability to type 2 diabetes: cohort study with repeated metabolomics across early life

10.2337/figshare.12058923.v1 ◽

2020 ◽

Author(s):

Joshua A. Bell ◽

Caroline J. Bull ◽

Marc J. Gunter ◽

David Carslake ◽

Anubha Mahajan ◽

...

Keyword(s):

Type 2 Diabetes ◽

Amino Acids ◽

Early Life ◽

Genome Wide Association Study ◽

Genetic Risk Score ◽

Lipoprotein Subclass ◽

Adult Type ◽

Genetic Liability ◽

Branched Chain

Objective: Type 2 diabetes develops for many years before diagnosis. We aimed to reveal early metabolic features characterising liability to adult disease by examining genetic liability to adult type 2 diabetes in relation to metabolomic traits across early life. Research Design and Methods: <a>Up to 4,761 offspring from the Avon Longitudinal Study of Parents and Children</a> were studied. Linear models were used to examine effects of a genetic risk score (162 variants) for adult type 2 diabetes on 229 metabolomic traits (lipoprotein-subclass-specific cholesterol and triglycerides, amino acids, glycoprotein acetyls, others) measured at age 8y, 16y, 18y, and 25y. Two-sample Mendelian randomization (MR) was also conducted using genome-wide association study data on metabolomic traits in an independent sample of 24,925 adults. Results: At age 8y, associations were most evident for type 2 diabetes liability (per SD-higher) with lower lipids in high-density lipoprotein (HDL) subtypes, e.g. -0.03 SD (95% CI=-0.06, -0.003) for total lipids in very-large HDL. At 16y, associations were stronger with pre-glycemic traits including citrate and with glycoprotein acetyls (0.05 SD, 95% CI=0.01, 0.08), and at 18y, associations were stronger with branched chain amino acids. At 25y, associations had strengthened with VLDL lipids and remained consistent with previously altered traits including HDL lipids. Two-sample MR estimates among adults indicated persistent patterns of effect of disease liability. Conclusions: Our results support perturbed HDL lipid metabolism as one of the earliest features of <a>type 2 diabetes liability, alongside higher branched chain amino acid and inflammatory levels. Several features are apparent in childhood as early as age 8y, decades before the clinical onset of disease. </a>

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Leveraging IgG N-glycosylation quantitative-trait loci to characterize the relationship between Type 2 Diabetes and hypertension: A network with bidirectional mendelian randomization study

10.21203/rs.3.rs-38821/v1 ◽

2020 ◽

Author(s):

Di Liu ◽

Jie Zhang ◽

Xiaoyu Zhang ◽

Qiuyue Tian ◽

Xiaoni Meng ◽

...

Keyword(s):

Type 2 Diabetes ◽

Quantitative Trait Loci ◽

Quantitative Trait ◽

Mendelian Randomization ◽

Hypertension Risk ◽

Bidirectional Regulation ◽

A Genome ◽

Trait Loci ◽

The Relationship

Abstract Background: The relationship between IgG N-glycosylation, type 2 diabetes (T2D) and hypertension is not well understood.Methods: A genome-wide association study (GWAS) of IgG N-glycosylation traits from 536 individuals was performed and 1203 IgG N-glycan quantitative trait loci (IgG N-glycan-QTL) variants targeting 24 IgG N-glycosylation were mapped traits after multi-testing correction. Network with bidirectional mendelian randomization (MR) analysis was performed to examine the causal association between IgG N-glycosylation, T2D and hypertension.Results: By linking IgG N-glycan-QTL variants with GWAS results for T2D and hypertension, 19 putatively causal IgG N-glycans for T2D and 21 putatively causal IgG N-glycans for hypertension were identified. IgG N-glycan-QTL determined IgG N-glycosylation to higher T2D was associated with higher hypertension risk (β [95% CI] =1.234 [0.939-1.529], P <0.001). In addition, IgG N-glycan-QTL determined IgG N-glycosylation to higher hypertension was associated with higher T2D risk (β [95% CI] =0.753 [0.140-1.3669], P =0.016). No evidence of pleiotropic bias was detected in MR-Egger analysis.Conclusions: Overall, our study showed that IgG N-Glycosylation-QTLs determined T2D is associated with higher hypertension risk, and vice versa, performing bidirectional regulation through IgG N-Glycosylation.

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A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

Diabetes ◽

10.2337/db17-0914 ◽

2018 ◽

Vol 67 (7) ◽

pp. 1414-1427 ◽

Cited By ~ 48

Author(s):

Natalie R. van Zuydam ◽

Emma Ahlqvist ◽

Niina Sandholm ◽

Harshal Deshmukh ◽

N. William Rayner ◽

...

Keyword(s):

Type 2 Diabetes ◽

Kidney Disease ◽

Association Study ◽

Diabetic Kidney Disease ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Diabetic Kidney ◽

Genome Wide ◽

A Genome

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Faculty Opinions recommendation of A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1083852.536792 ◽

2007 ◽

Author(s):

Terri Beaty

Keyword(s):

Type 2 Diabetes ◽

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome

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Daily Yogurt Consumption Improves Glucose Metabolism and Insulin Sensitivity in Young Nondiabetic Japanese Subjects with Type-2 Diabetes Risk Alleles

Nutrients ◽

10.3390/nu10121834 ◽

2018 ◽

Vol 10 (12) ◽

pp. 1834 ◽

Cited By ~ 6

Author(s):

Daiki Watanabe ◽

Sachi Kuranuki ◽

Akiko Sunto ◽

Naoki Matsumoto ◽

Teiji Nakamura

Keyword(s):

Type 2 Diabetes ◽

Test Meal ◽

Genetic Risk ◽

Serum Insulin ◽

Genetic Risk Score ◽

Postprandial Plasma Glucose ◽

Risk Alleles ◽

Weighted Genetic Risk Score ◽

Insulin Responses

This study investigated whether the association between postprandial plasma glucose (PPG) is affected by five type 2 diabetes mellitus (T2DM) susceptibility genes, and whether four weeks of yogurt consumption would affect these responses. We performed a single-arm intervention study in young nondiabetic Japanese participants, who consumed 150 g yogurt daily for four weeks, after which a rice test meal containing 50 g carbohydrate was administered. PPG and postprandial serum insulin (PSI) were measured between 0 and 120 mins at baseline and after the intervention. Genetic risk was evaluated by weighted genetic risk score (GRS) according to published methodology, and participants were assigned to one of two groups (n = 17: L-GRS group and n = 15: H-GRS group) according to the median of weighted GRS. At baseline, the H-GRS group had higher glucose area under the curve0–120 min after intake of the test meal than the L-GRS group (2175 ± 248 mg/dL.min vs. 1348 ± 199 mg/dL.min, p < 0.001), but there were no significant differences after the yogurt intervention. However, there was an improvement in PSI in the H-GRS group compared with baseline. These results suggest that habitual yogurt consumption may improve glucose and insulin responses in nondiabetic subjects who have genetically higher PPG.

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