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

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 <p>To identify circulating proteins influencing type 1 diabetes susceptibility using Mendelian randomization (MR). </p> <p>RESEARCH DESIGN AND METHODS</p> <p>We employed a large-scale two-sample MR study, using <i>cis</i> 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 <i>cis </i>and <i>trans</i>-pQTL.</p> <p>RESULTS </p> <p>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<sup>-7</sup>). 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<sup>-6</sup>). 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<sup>-6</sup>). <a></a></p> <p>Sensitivity analyses using MR methods testing for pleiotropy while including <i>trans</i>-pQTL showed similar results. While the MR-Egger suggested no pleotropic effect (<i>p</i>-value MR-Egger intercept = 0.31) there was evidence of pleiotropy in MR-PRESSO (<i>p</i>-value global test =0.006). </p> <p>CONCLUSIONS</p> <p>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. </p>

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

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 <p>To identify circulating proteins influencing type 1 diabetes susceptibility using Mendelian randomization (MR). </p> <p>RESEARCH DESIGN AND METHODS</p> <p>We employed a large-scale two-sample MR study, using <i>cis</i> 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 <i>cis </i>and <i>trans</i>-pQTL.</p> <p>RESULTS </p> <p>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<sup>-7</sup>). 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<sup>-6</sup>). 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<sup>-6</sup>). <a></a></p> <p>Sensitivity analyses using MR methods testing for pleiotropy while including <i>trans</i>-pQTL showed similar results. While the MR-Egger suggested no pleotropic effect (<i>p</i>-value MR-Egger intercept = 0.31) there was evidence of pleiotropy in MR-PRESSO (<i>p</i>-value global test =0.006). </p> <p>CONCLUSIONS</p> <p>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. </p>

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

PLoS Medicine ◽  
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.

scholarly journals Association of genetically predicted blood sucrose with coronary heart disease and its risk factors in Mendelian randomization

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ting Zhang ◽  
Shiu Lun Au Yeung ◽  
C. Mary Schooling
Keyword(s):  
Risk Factors ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Dental Caries ◽  
Multiple Testing ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Standard Deviation Increase

AbstractWe assessed the associations of genetically instrumented blood sucrose with risk of coronary heart disease (CHD) and its risk factors (i.e., type 2 diabetes, adiposity, blood pressure, lipids, and glycaemic traits), using two-sample Mendelian randomization. We used blood fructose as a validation exposure. Dental caries was a positive control outcome. We selected genetic variants strongly (P < 5 × 10–6) associated with blood sucrose or fructose as instrumental variables and applied them to summary statistics from the largest available genome-wide association studies of the outcomes. Inverse-variance weighting was used as main analysis. Sensitivity analyses included weighted median, MR-Egger and MR-PRESSO. Genetically higher blood sucrose was positively associated with the control outcome, dental caries (odds ratio [OR] 1.04 per log10 transformed effect size [median-normalized standard deviation] increase, 95% confidence interval [CI] 1.002–1.08, P = 0.04), but this association did not withstand allowing for multiple testing. The estimate for blood fructose was in the same direction. Genetically instrumented blood sucrose was not clearly associated with CHD (OR 1.01, 95% CI 0.997–1.02, P = 0.14), nor with its risk factors. Findings were similar for blood fructose. Our study found some evidence of the expected detrimental effect of sucrose on dental caries but no effect on CHD. Given a small effect on CHD cannot be excluded, further investigation with stronger genetic predictors is required.

scholarly journals Rheumatoid arthritis decreases risk for Parkinson’s disease: a Mendelian randomization study

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
ChunYu Li ◽  
RuWei Ou ◽  
HuiFang Shang
Keyword(s):  
Rheumatoid Arthritis ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Correlation ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Standard Deviation Increase ◽  
Rheumatoid Arthritis Risk

AbstractEpidemiological and clinical studies have suggested comorbidity between rheumatoid arthritis and Parkinson’s disease (PD), but whether there exists a causal association and the effect direction of rheumatoid arthritis on PD is controversial and elusive. To evaluate the causal relationship, we first estimated the genetic correlation between rheumatoid arthritis and PD, and then performed a two-sample Mendelian randomization analysis based on summary statistics from large genome-wide association studies of rheumatoid arthritis (N = 47,580) and PD (N = 482,703). We identified negative and significant correlation between rheumatoid arthritis and PD (genetic correlation: −0.10, P = 0.0033). Meanwhile, one standard deviation increase in rheumatoid arthritis risk was associated with a lower risk of PD (OR: 0.904, 95% CI: 0.866–0.943, P: 2.95E–06). The result was robust under all sensitivity analyses. Our results provide evidence supporting a protective role of rheumatoid arthritis on PD. A deeper understanding of the inflammation and immune response is likely to elucidate the potential pathogenesis of PD and identify therapeutic targets for PD.

scholarly journals Educational Attainment Decreases the Risk of COVID-19 Severity in the European Population: A Two-Sample Mendelian Randomization Study

2021 ◽  
Vol 9 ◽  
Author(s):  
Masahiro Yoshikawa ◽  
Kensuke Asaba
Keyword(s):  
Educational Attainment ◽  
Lower Risk ◽  
Mendelian Randomization ◽  
European Population ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Standard Deviation Increase ◽  
Summary Data ◽  
Years Of Schooling

Observational studies have reported that the severity of COVID-19 depends not only on physical conditions but also on socioeconomic status, including educational level. Because educational attainment (EA), which measures the number of years of schooling, is moderately heritable, we investigated the causal association of EA on the risk of COVID-19 severity using the Mendelian randomization (MR) approach. A two-sample MR analysis was performed using publicly available summary-level data sets of genome-wide association studies (GWASs). A total of 235 single-nucleotide polymorphisms (SNPs) were extracted as instrumental variables for the exposure of EA from the Social Science Genetic Association Consortium GWAS summary data of 766,345 participants of European ancestry. The effect of each SNP on the outcome of COVID-19 severity risk was obtained from the GWAS summary data of 1,059,456 participants of European ancestry gathered from the COVID-19 Host Genetics Initiative. Using inverse variance weighted method, our MR study shows that EA was significantly associated with a lower risk of COVID-19 severity (odds ratio per one standard deviation increase in years of schooling, 0.540; 95% confidence interval, 0.376–0.777, P = 0.0009). A series of sensitivity analyses showed little evidence of bias. In conclusion, we show for the first time using a two-sample MR approach the associations between higher EA and the lower risk of COVID-19 severity in the European population. However, the genetic or epidemiological mechanisms underlying the association between EA and the risk of COVID-19 severity remain unknown, and further studies are warranted to validate the MR findings and investigate underlying mechanisms.

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

Diabetes Care ◽  
2021 ◽  
pp. dc211049
Author(s):  
Nahid Yazdanpanah ◽  
Mojgan Yazdanpanah ◽  
Ye Wang ◽  
Vincenzo Forgetta ◽  
Michael Pollak ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Mendelian Randomization ◽  
Protein Biomarkers

Immunization profiles and progression of islet autoimmunity in children at type 1 diabetes risk

2012 ◽  
Vol 7 (S 01) ◽  
Author(s):  
R Chmiel ◽  
S Krause ◽  
A Knopff ◽  
C Matzke ◽  
D Höfelmann ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Diabetes Risk ◽  
Islet Autoimmunity

scholarly journals Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations

2021 ◽  
Author(s):  
Fernando Pires Hartwig ◽  
Kate Tilling ◽  
George Davey Smith ◽  
Deborah A Lawlor ◽  
Maria Carolina Borges
Keyword(s):  
Waist Circumference ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Real Data ◽  
Sensitivity Analyses ◽  
Effect Estimate ◽  
Genome Wide Association Studies ◽  
Residual Confounding

Abstract Background Two-sample Mendelian randomization (MR) allows the use of freely accessible summary association results from genome-wide association studies (GWAS) to estimate causal effects of modifiable exposures on outcomes. Some GWAS adjust for heritable covariables in an attempt to estimate direct effects of genetic variants on the trait of interest. One, both or neither of the exposure GWAS and outcome GWAS may have been adjusted for covariables. Methods We performed a simulation study comprising different scenarios that could motivate covariable adjustment in a GWAS and analysed real data to assess the influence of using covariable-adjusted summary association results in two-sample MR. Results In the absence of residual confounding between exposure and covariable, between exposure and outcome, and between covariable and outcome, using covariable-adjusted summary associations for two-sample MR eliminated bias due to horizontal pleiotropy. However, covariable adjustment led to bias in the presence of residual confounding (especially between the covariable and the outcome), even in the absence of horizontal pleiotropy (when the genetic variants would be valid instruments without covariable adjustment). In an analysis using real data from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and UK Biobank, the causal effect estimate of waist circumference on blood pressure changed direction upon adjustment of waist circumference for body mass index. Conclusions Our findings indicate that using covariable-adjusted summary associations in MR should generally be avoided. When that is not possible, careful consideration of the causal relationships underlying the data (including potentially unmeasured confounders) is required to direct sensitivity analyses and interpret results with appropriate caution.

scholarly journals Evaluation of glycemic traits in susceptibility to COVID-19 risk: a Mendelian randomization study

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Shiu Lun Au Yeung ◽  
Jie V Zhao ◽  
C Mary Schooling
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Predisposition ◽  
Mendelian Randomization ◽  
Fasting Glucose ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Inverse Association ◽  
Wide Confidence Interval

Abstract Background Observational studies suggest poorer glycemic traits and type 2 diabetes associated with coronavirus disease 2019 (COVID-19) risk although these findings could be confounded by socioeconomic position. We conducted a two-sample Mendelian randomization to clarify their role in COVID-19 risk and specific COVID-19 phenotypes (hospitalized and severe cases). Method We identified genetic instruments for fasting glucose (n = 133,010), 2 h glucose (n = 42,854), glycated hemoglobin (n = 123,665), and type 2 diabetes (74,124 cases and 824,006 controls) from genome wide association studies and applied them to COVID-19 Host Genetics Initiative summary statistics (17,965 COVID-19 cases and 1,370,547 population controls). We used inverse variance weighting to obtain the causal estimates of glycemic traits and genetic predisposition to type 2 diabetes in COVID-19 risk. Sensitivity analyses included MR-Egger and weighted median method. Results We found genetic predisposition to type 2 diabetes was not associated with any COVID-19 phenotype (OR: 1.00 per unit increase in log odds of having diabetes, 95%CI 0.97 to 1.04 for overall COVID-19; OR: 1.02, 95%CI 0.95 to 1.09 for hospitalized COVID-19; and OR: 1.00, 95%CI 0.93 to 1.08 for severe COVID-19). There were no strong evidence for an association of glycemic traits in COVID-19 phenotypes, apart from a potential inverse association for fasting glucose albeit with wide confidence interval. Conclusion We provide some genetic evidence that poorer glycemic traits and predisposition to type 2 diabetes unlikely increase the risk of COVID-19. Although our study did not indicate glycemic traits increase severity of COVID-19, additional studies are needed to verify our findings.

scholarly journals Using genetic variants to evaluate the causal effect of serum vitamin D concentration on COVID-19 susceptibility, severity and hospitalization traits: a Mendelian randomization study

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Zhiyong Cui ◽  
Yun Tian
Keyword(s):  
Vitamin D ◽  
Fixed Effects ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Serum Vitamin ◽  
Vitamin D Supplementation ◽  
Sensitivity Analyses ◽  
Global Test ◽  
Serum Vitamin D

Abstract Background The coronavirus disease 2019 (COVID-19) pandemic has struck globally and is exerting a devastating toll on humans. The pandemic has led to calls for widespread vitamin D supplementation in public. However, evidence supporting the role of vitamin D in the COVID-19 pandemic remains controversial. Methods We performed a two-sample Mendelian randomization (MR) analysis to analyze the causal effect of the 25-hydroxyvitamin D [25(OH)D] concentration on COVID-19 susceptibility, severity and hospitalization traits by using summary-level GWAS data. The causal associations were estimated with inverse variance weighted (IVW) with fixed effects (IVW-fixed) and random effects (IVW-random), MR-Egger, weighted edian and MR Robust Adjusted Profile Score (MR.RAPS) methods. We further applied the MR Steiger filtering method, MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global test and PhenoScanner tool to check and remove single nucleotide polymorphisms (SNPs) that were horizontally pleiotropic. Results We found no evidence to support the causal associations between the serum 25(OH)D concentration and the risk of COVID-19 susceptibility [IVW-fixed: odds ratio (OR) = 0.9049, 95% confidence interval (CI) 0.8197–0.9988, p = 0.0473], severity (IVW-fixed: OR = 1.0298, 95% CI 0.7699–1.3775, p = 0.8432) and hospitalized traits (IVW-fixed: OR = 1.0713, 95% CI 0.8819–1.3013, p = 0.4878) using outlier removed sets at a Bonferroni-corrected p threshold of 0.0167. Sensitivity analyses did not reveal any sign of horizontal pleiotropy. Conclusions Our MR analysis provided precise evidence that genetically lowered serum 25(OH)D concentrations were not causally associated with COVID-19 susceptibility, severity or hospitalized traits. Our study did not provide evidence assessing the role of vitamin D supplementation during the COVID-19 pandemic. High-quality randomized controlled trials are necessary to explore and define the role of vitamin D supplementation in the prevention and treatment of COVID-19.

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