Clinically Relevant Circulating Protein Biomarkers for Type 1 Diabetes: Evidence From a Two-Sample Mendelian Randomization Study

OBJECTIVE To identify circulating proteins influencing type 1 diabetes susceptibility using Mendelian randomization (MR). RESEARCH DESIGN AND METHODS We employed a large-scale two-sample MR study, using cis genetic determinants (protein quantative trait loci or pQTL) of up to 1,611 circulating proteins from five large genome-wide association studies, to screen for causal associations of these proteins with type 1 diabetes risk in 9,684 cases with type 1 diabetes and 15,743 controls. Further, pleiotropy-robust MR methods were used in sensitivity analyses using both cis and trans-pQTL. RESULTS We found that a genetically predicted a standard deviation increase in Signal Regulatory Protein Gamma (SIRPG) level was associated with increased risk of type 1 diabetes risk (MR OR = 1.66, 95% 1.36- 2.03; P = 7.1 x 10-7). The risk of type 1 diabetes increased almost two-fold per genetically predicted SD increase in interleukin-27 Epstein-Barr Virus Induced 3 (IL27-EBI3) protein levels (MR OR=1.97, 95% CI = 1.48 – 2.62, P= 3.7 x10-6). However, a SD increase in chymotrypsinogen B1 (CTRB1) was associated with decreased risk of type 1 diabetes (MR OR=0.84, 95% CI = 0.77 – 0.90, P= 6.1 x10-6). <a></a> Sensitivity analyses using MR methods testing for pleiotropy while including trans-pQTL showed similar results. While the MR-Egger suggested no pleotropic effect (p-value MR-Egger intercept = 0.31) there was evidence of pleiotropy in MR-PRESSO (p-value global test =0.006). CONCLUSIONS We identified three novel circulating protein biomarkers associated with type 1 diabetes risk using a MR approach. These biomarkers are promising targets for development of drugs and/or of screening tools for early prediction of type 1 diabetes.

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Clinically Relevant Circulating Protein Biomarkers for Type 1 Diabetes: Evidence From a Two-Sample Mendelian Randomization Study

10.2337/figshare.16826689 ◽

2021 ◽

Author(s):

Nahid Yazdanpanah ◽

Mojgan Yazdanpanah ◽

Ye Wang ◽

Vincenzo Forgetta ◽

Michael Pollak ◽

...

Keyword(s):

Type 1 Diabetes ◽

Mendelian Randomization ◽

Diabetes Risk ◽

Screening Tools ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Protein Biomarkers ◽

Global Test ◽

Standard Deviation Increase

OBJECTIVE To identify circulating proteins influencing type 1 diabetes susceptibility using Mendelian randomization (MR). RESEARCH DESIGN AND METHODS We employed a large-scale two-sample MR study, using cis genetic determinants (protein quantative trait loci or pQTL) of up to 1,611 circulating proteins from five large genome-wide association studies, to screen for causal associations of these proteins with type 1 diabetes risk in 9,684 cases with type 1 diabetes and 15,743 controls. Further, pleiotropy-robust MR methods were used in sensitivity analyses using both cis and trans-pQTL. RESULTS We found that a genetically predicted a standard deviation increase in Signal Regulatory Protein Gamma (SIRPG) level was associated with increased risk of type 1 diabetes risk (MR OR = 1.66, 95% 1.36- 2.03; P = 7.1 x 10-7). The risk of type 1 diabetes increased almost two-fold per genetically predicted SD increase in interleukin-27 Epstein-Barr Virus Induced 3 (IL27-EBI3) protein levels (MR OR=1.97, 95% CI = 1.48 – 2.62, P= 3.7 x10-6). However, a SD increase in chymotrypsinogen B1 (CTRB1) was associated with decreased risk of type 1 diabetes (MR OR=0.84, 95% CI = 0.77 – 0.90, P= 6.1 x10-6). <a></a> Sensitivity analyses using MR methods testing for pleiotropy while including trans-pQTL showed similar results. While the MR-Egger suggested no pleotropic effect (p-value MR-Egger intercept = 0.31) there was evidence of pleiotropy in MR-PRESSO (p-value global test =0.006). CONCLUSIONS We identified three novel circulating protein biomarkers associated with type 1 diabetes risk using a MR approach. These biomarkers are promising targets for development of drugs and/or of screening tools for early prediction of type 1 diabetes.

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Childhood adiposity and risk of type 1 diabetes: A Mendelian randomization study

PLoS Medicine ◽

10.1371/journal.pmed.1002362 ◽

2017 ◽

Vol 14 (8) ◽

pp. e1002362 ◽

Cited By ~ 33

Author(s):

J. C. Censin ◽

Christoph Nowak ◽

Nicholas Cooper ◽

Peter Bergsten ◽

John A. Todd ◽

...

Keyword(s):

Type 1 Diabetes ◽

Mendelian Randomization ◽

Childhood Adiposity

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Estimating the Effect of Liver and Pancreas Volume and Fat Content on Risk of Diabetes: A Mendelian Randomization Study

Diabetes Care ◽

10.2337/dc21-1262 ◽

2021 ◽

Author(s):

Susan Martin ◽

Elena P. Sorokin ◽

E. Louise Thomas ◽

Naveed Sattar ◽

Madeleine Cule ◽

...

Keyword(s):

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Mendelian Randomization ◽

Fat Content ◽

Liver Fat ◽

Liver And Pancreas ◽

Pancreas Volume

OBJECTIVE Fat content and volume of liver and pancreas are associated with risk of diabetes in observational studies; whether these associations are causal is unknown. We conducted a Mendelian randomization (MR) study to examine causality of such associations. RESEARCH DESIGN AND METHODS We used genetic variants associated (P < 5 × 10−8) with the exposures (liver and pancreas volume and fat content) using MRI scans of UK Biobank participants (n = 32,859). We obtained summary-level data for risk of type 1 (9,358 cases) and type 2 (55,005 cases) diabetes from the largest available genome-wide association studies. We performed inverse–variance weighted MR as main analysis and several sensitivity analyses to assess pleiotropy and to exclude variants with potential pleiotropic effects. RESULTS Observationally, liver fat and volume were associated with type 2 diabetes (odds ratio per 1 SD higher exposure 2.16 [2.02, 2.31] and 2.11 [1.96, 2.27], respectively). Pancreatic fat was associated with type 2 diabetes (1.42 [1.34, 1.51]) but not type 1 diabetes, and pancreas volume was negatively associated with type 1 diabetes (0.42 [0.36, 0.48]) and type 2 diabetes (0.73 [0.68, 0.78]). MR analysis provided evidence only for a causal role of liver fat and pancreas volume in risk of type 2 diabetes (1.27 [1.08, 1.49] or 27% increased risk and 0.76 [0.62, 0.94] or 24% decreased risk per 1SD, respectively) and no causal associations with type 1 diabetes. CONCLUSIONS Our findings assist in understanding the causal role of ectopic fat in the liver and pancreas and of organ volume in the pathophysiology of type 1 and 2 diabetes.

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Novel Urinary Protein Biomarkers Predicting the Development of Microalbuminuria and Renal Function Decline in Type 1 Diabetes

Diabetes Care ◽

10.2337/dc11-1491 ◽

2012 ◽

Vol 35 (3) ◽

pp. 549-555 ◽

Cited By ~ 27

Author(s):

D. Schlatzer ◽

D. M. Maahs ◽

M. R. Chance ◽

J.-E. Dazard ◽

X. Li ◽

...

Keyword(s):

Type 1 Diabetes ◽

Renal Function ◽

Urinary Protein ◽

Protein Biomarkers ◽

Renal Function Decline

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Disentangling the direct and indirect effects of childhood adiposity on type 1 diabetes and immune-associated diseases: a multivariable Mendelian randomization study

10.1101/2021.04.19.21255222 ◽

2021 ◽

Author(s):

Tom G Richardson ◽

Daniel J M Crouch ◽

Grace M Power ◽

Fernanda Morales Berstein ◽

Emma Hazelwood ◽

...

Keyword(s):

Type 1 Diabetes ◽

Body Size ◽

Life Course ◽

Direct Effect ◽

Large Scale ◽

Mendelian Randomization ◽

Childhood Adiposity ◽

Associated Diseases ◽

The Life Course

Background: The rising prevalence of childhood obesity has been postulated as an explanation for the increasing rate of individuals diagnosed with type 1 diabetes (T1D). However, robust causal evidence supporting this claim has been extremely challenging to uncover, particularly given the typical early onset of T1D. Methods: In this study, we used genetic variation to separate the direct effect of childhood body size on T1D risk from the effects of body size at different stages in the life course using univariable and multivariable Mendelian randomization (MR). Similar MR analyses were conducted on risk of seven other chronic immune-associated diseases. Findings: Childhood body size provided evidence of an effect on T1D (based on a sample of 5,913 cases and 8,282 controls) using a univariable model (OR=2.05 per change in body size category, 95% CI=1.20 to 3.50, P=0.008), which remained after accounting for body size at birth and during adulthood (OR=2.32, 95% CI=1.21 to 4.42, P=0.013). The direct effect of childhood body size was validated using data from a large-scale T1D meta-analysis based on n=15,573 cases and n=158,408 controls (OR=1.94, 95% CI=1.21 to 3.12, P=0.006). We also obtained evidence that childhood adiposity influences risk of asthma (OR=1.31, 95% CI=1.08 to 1.60, P=0.007), eczema (OR=1.25, 95% CI=1.03 to 1.51, P=0.024) and hypothyroidism (OR=1.42, 95% CI=1.12 to 1.80, P=0.004). However, these estimates all attenuated to the null when accounting for adult body size, suggesting that the effect of childhood adiposity on these outcomes is mediated by adiposity in later life. Interpretation: Our findings support a causal role for higher childhood adiposity on higher risk of being diagnosed with T1D. In contrast, the effect of childhood adiposity on the other immune-associated diseases studied was explained by a long-term effect of remaining overweight for many years over the life course.

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Vitamin D levels and risk of type 1 diabetes: A Mendelian randomization study

PLoS Medicine ◽

10.1371/journal.pmed.1003536 ◽

2021 ◽

Vol 18 (2) ◽

pp. e1003536

Author(s):

Despoina Manousaki ◽

Adil Harroud ◽

Ruth E. Mitchell ◽

Stephanie Ross ◽

Vince Forgetta ◽

...

Keyword(s):

Vitamin D ◽

Type 1 Diabetes ◽

Mendelian Randomization ◽

Diabetes Risk ◽

Sensitivity Analyses ◽

Substantial Impact ◽

Genome Wide ◽

Inverse Variance ◽

Vitamin D Levels

Background Vitamin D deficiency has been associated with type 1 diabetes in observational studies, but evidence from randomized controlled trials (RCTs) is lacking. The aim of this study was to test whether genetically decreased vitamin D levels are causally associated with type 1 diabetes using Mendelian randomization (MR). Methods and findings For our two-sample MR study, we selected as instruments single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels in a large vitamin D genome-wide association study (GWAS) on 443,734 Europeans and obtained their corresponding effect estimates on type 1 diabetes risk from a large meta-analysis of 12 type 1 diabetes GWAS studies (Ntot = 24,063, 9,358 cases, and 15,705 controls). In addition to the main analysis using inverse variance weighted MR, we applied 3 additional methods to control for pleiotropy (MR-Egger, weighted median, and mode-based estimate) and compared the respective MR estimates. We also undertook sensitivity analyses excluding SNPs with potential pleiotropic effects. We identified 69 lead independent common SNPs to be genome-wide significant for 25OHD, explaining 3.1% of the variance in 25OHD levels. MR analyses suggested that a 1 standard deviation (SD) decrease in standardized natural log-transformed 25OHD (corresponding to a 29-nmol/l change in 25OHD levels in vitamin D–insufficient individuals) was not associated with an increase in type 1 diabetes risk (inverse-variance weighted (IVW) MR odds ratio (OR) = 1.09, 95% CI: 0.86 to 1.40, p = 0.48). We obtained similar results using the 3 pleiotropy robust MR methods and in sensitivity analyses excluding SNPs associated with serum lipid levels, body composition, blood traits, and type 2 diabetes. Our findings indicate that decreased vitamin D levels did not have a substantial impact on risk of type 1 diabetes in the populations studied. Study limitations include an inability to exclude the existence of smaller associations and a lack of evidence from non-European populations. Conclusions Our findings suggest that 25OHD levels are unlikely to have a large effect on risk of type 1 diabetes, but larger MR studies or RCTs are needed to investigate small effects.

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Correction: Vitamin D levels and risk of type 1 diabetes: A Mendelian randomization study

PLoS Medicine ◽

10.1371/journal.pmed.1003624 ◽

2021 ◽

Vol 18 (4) ◽

pp. e1003624

Author(s):

Despoina Manousaki ◽

Adil Harroud ◽

Ruth E. Mitchell ◽

Stephanie Ross ◽

Vince Forgetta ◽

...

Keyword(s):

Vitamin D ◽

Type 1 Diabetes ◽

Mendelian Randomization ◽

Vitamin D Levels

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Causal Relationship Between Childhood Asthma and Type 1 Diabetes Mellitus: A Meta-Analysis and Bidirectional Mendelian Randomization Study

SSRN Electronic Journal ◽

10.2139/ssrn.3844918 ◽

2021 ◽

Author(s):

Junyang Xie ◽

weixing liu ◽

Gui Chen ◽

Tianhao Liang ◽

Ang Li ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Causal Relationship ◽

Childhood Asthma ◽

Mendelian Randomization ◽

Meta Analysis

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Estimating the Effect of Liver and Pancreas Volume and Fat Content on Risk of Diabetes: A Mendelian Randomization Study

10.2337/figshare.16959133.v1 ◽

2022 ◽

Author(s):

Susan Martin ◽

Elena P Sorokin ◽

E. Louise Thomas ◽

Naveed Sattar ◽

Madeleine Cule ◽

...

Keyword(s):

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Mendelian Randomization ◽

Fat Content ◽

Liver Fat ◽

Liver And Pancreas ◽

Pancreas Volume

Objective: Fat content and volume of liver and pancreas are associated with risk of diabetes in observational studies; whether these associations are causal is unknown. We conducted a Mendelian randomization (MR) study to examine causality of such associations. Research design and methods: We used genetic variants associated (p < 5×10−8) with the exposures (liver and pancreas volume and fat content) using MRI scans of UK Biobank participants (n=32,859). We obtained summary-level data for risk of type 1 (9,358 cases) and type 2 (55,005 cases) diabetes from the largest available genome-wide association studies. We performed inverse-variance weighted MR as main analysis and several sensitivity analyses to assess pleiotropy and to exclude variants with potential pleiotropic effects. Results: Observationally, liver fat and volume were associated with type 2 diabetes (odds ratio (OR) per one standard deviation (SD) higher exposure 2.16 [2.02 - 2.31] and 2.11 [1.96, 2.27], respectively). Pancreatic fat was associated with type 2 diabetes (1.42 [1.34, 1.51]) but not type 1 diabetes, and pancreas volume was negatively associated with type 1 diabetes (0.42 [0.36, 0.48]) and type 2 diabetes (0.73 [0.68, 0.78]). MR analysis provided evidence only for a causal role of liver fat and pancreas volume on risk of type 2 diabetes (1.27 [1.08,1.49] or 27% increased risk and 0.76 [0.62,0.94] or 24% decreased risk per 1SD, respectively) and no causal associations with type 1 diabetes. Conclusions: Our findings assist in understanding the causal role of ectopic fat in the liver and pancreas and of organ volume in the pathophysiology of type 1 and 2 diabetes.

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