Abstract
Aims
To estimate genetically predicted causal associations of general and central obesity
with GDM, and to determine the mediating role of circulating lipids.
Methods
Summary-level data was obtained from the largest available genome-wide association
studies of five obesity traits, five lipid traits and GDM. Two-sample univariate Mendelian
randomization (MR), multivariate MR, and MR-based mediation analysis was applied to
determine the total effect, direct effect and the mediating effect, respectively.
Results
Univariate MR showed that the odds of GDM increased per 1-SD increase in body mass
index (BMI) (OR = 1.64, P = 5.05 × 10−17), waist-to-hip ratio (WHR) (OR = 1.57, P = 2.27 × 10−14) and WHR adjusted for BMI (OR = 1.42, P = 6.11 × 10−15). The heterogeneous associations of waist circumference (OR = 1.64, P = 5.57 × 10−14) and hip circumference (OR = 1.20, P = 0.002) on GDM further reflected that body fat distribution could influence GDM
risk. Mediation analysis suggested that triglycerides, high-density lipoprotein-cholesterol
and apolipoprotein A-I each mediated between 5% and 10% of the association between
obesity and GDM.
Conclusion
Our findings supported a deleterious causal effect of obesity on GDM risk, where lipid
metabolism acted as potential drivers of the relationships between both general and
central obesity and GDM.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Diabetes Research and Clinical PracticeAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Increasing prevalence of gestational diabetes mellitus: a public health perspective.Diabetes Care. 2007; 30: S141-S146
- Gestational diabetes: new criteria may triple the prevalence but effect on outcomes is unclear.BMJ. 2014; 348g1567
- Pre-pregnancy body mass index and risk of macrosomia and large for gestational age births with gestational diabetes mellitus as a mediator: a prospective cohort study in Central China.Nutrients. 2022; 14
- Effects of maternal obesity on fetal growth and body composition: implications for programming and future health.Semin Fetal Neonatal Med. 2010; 15: 113-118
- High birth weight and obesity--a vicious circle across generations.Int J Obes (Lond). 2012; 36: 1320-1324
- Body-mass index and obesity in urban and rural China: findings from consecutive nationally representative surveys during 2004-18.Lancet. 2021; 398: 53-63
- Maternal obesity and risk of gestational diabetes mellitus.Diabetes Care. 2007; 30: 2070-2076
- Health effects of overweight and obesity in 195 countries over 25 years.N Engl J Med. 2017; 377: 13-27
- Mechanisms, pathophysiology, and Management of Obesity.N Engl J Med. 2017; 376: 1492
- The association of general obesity, central obesity and visceral body fat with the risk of gestational diabetes mellitus: evidence from a systematic review and meta-analysis.Obes Res Clin Pract. 2021; 15: 425-430
- Adipose tissue dysfunction and hypertriglyceridemia: mechanisms and management.Obes Rev. 2011; 12: 829-840
- Gestational diabetes, pregnancy hypertension, and late vascular disease.Diabetes Care. 2007; 30: S246-S250
- Lipid changes throughout pregnancy according to pre-pregnancy BMI: results from a prospective cohort.BJOG. 2016; 123: 570-578
- Altered triglyceride and phospholipid metabolism predates the diagnosis of gestational diabetes in obese pregnancy.Mol Omics. 2019; 15: 420-430
- Maternal lipid levels during pregnancy and gestational diabetes: a systematic review and meta-analysis.BJOG. 2015; 122: 643-651
- BMI and lipidomic biomarkers with risk of gestational diabetes in pregnant women.Obesity (Silver Spring). 2022; 30: 2044-2054
- Correlation between body mass index and central adiposity with pregnancy complications in pregnant women.Health Promot Perspect. 2013; 3: 73-79
- A pilot study on the usefulness of body mass index and waist hip ratio as a predictive tool for gestational diabetes in Asian Indians.Gynecol Endocrinol. 2008; 24: 701-707
- Mendelian randomization: genetic anchors for causal inference in epidemiological studies.Hum Mol Genet. 2014; 23: R89-R98
- Mendelian randomization: using genes as instruments for making causal inferences in epidemiology.Stat Med. 2008; 27: 1133-1163
- Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE-MR statement.JAMA. 2021; 326: 1614-1621
- ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease?.Int J Epidemiol. 2003; 32: 1-22
- Mendelian randomization.JAMA. 2017; 318: 1925-1926
- Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-egger regression: the role of the I2 statistic.Int J Epidemiol. 2016; 45: 1961-1974
- Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians.BMJ. 2018; 362k601
- Vitamin D levels and risk of type 1 diabetes: a Mendelian randomization study.. 2021; 18e1003536
- Calculating statistical power in Mendelian randomization studies.Int J Epidemiol. 2013; 42: 1497-1501
- Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry.Hum Mol Genet. 2019; 28: 166-174
- 1: The MRC IEU OpenGWAS data infrastructure. bioRxiv. 2020 Aug 10https://doi.org/10.1101/2020.08.10.244293 (1)
- Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis.PLoS Med. 2020; 17e1003062
- The UK biobank sample handling and storage protocol for the collection, processing and archiving of human blood and urine.Int J Epidemiol. 2008; 37: 234-244
- FinnGen documentation of R7 release.(Accessed July 1, 2022)
- Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants.Epidemiology. 2017; 28: 30-42
- Mendelian randomization with invalid instruments: effect estimation and bias detection through egger regression.Int J Epidemiol. 2015; 44: 512-525
- Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator.Genet Epidemiol. 2016; 40: 304-314
- Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption.Int J Epidemiol. 2017; 46: 1985-1998
- Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption.Int J Epidemiol. 2019; 48: 728-742
- A framework for the investigation of pleiotropy in two-sample summary data Mendelian randomization.Stat Med. 2017; 36: 1783-1802
- Orienting the causal relationship between imprecisely measured traits using GWAS summary data.PLoS Genet. 2017; 13e1007081
- An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings.Int J Epidemiol. 2019; 48: 713-727
- Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects.Am J Epidemiol. 2015; 181: 251-260
- Testing and correcting for weak and pleiotropic instruments in two-sample multivariable Mendelian randomization.Stat Med. 2021; 10: 5434-5452
- Dissecting causal pathways using Mendelian randomization with summarized genetic data: application to age at menarche and risk of breast cancer.Genetics. 2017; 207: 481-487
- Two-step epigenetic Mendelian randomization: a strategy for establishing the causal role of epigenetic processes in pathways to disease.Int J Epidemiol. 2012; 41: 161-176
- Mendelian randomisation for mediation analysis: current methods and challenges for implementation.Eur J Epidemiol. 2021; 36: 465-478
- The MR-base platform supports systematic causal inference across the human phenome.2018: 7
- Genetic analyses identify widespread sex-differential participation bias.Nat Genet. 2021; 53: 663-671
- Genetic studies of body mass index yield new insights for obesity biology.Nature. 2015; 518: 197-206
- New genetic loci link adipose and insulin biology to body fat distribution.Nature. 2015; 518: 187-196
- A robust example of collider bias in a genetic association study.Am J Hum Genet. 2016; 98: 392-393
- Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations.Int J Epidemiol. 2021; 20: 1639-1650
- Quantifying heterogeneity in a meta-analysis.Stat Med. 2002; 21: 1539-1558
- Relationship of early pregnancy waist-to-hip ratio versus body mass index with gestational diabetes mellitus and insulin resistance.Am J Perinatol. 2016; 33: 114-121
- Relation of central adiposity and body mass index to the development of diabetes in the diabetes prevention program.Am J Clin Nutr. 2008; 87: 1212-1218
- Differential effects of BMI on diabetes risk among black and white Americans.Diabetes Care. 1998; 21: 1828-1835
- ApoB versus non-HDL-C: what to do when they disagree.Curr Atheroscler Rep. 2009; 11: 358-363
- Apolipoprotein A-I protects against pregnancy-induced insulin resistance in rats.Arterioscler Thromb Vasc Biol. 2019; 39: 1160-1171
- Zitman-gal T: gestational diabetes type 2: variation in high-density lipoproteins composition and function.Int J Mol Sci. 2020; 21
- Disturbances in lipid metabolism in diabetic pregnancy - are these the cause of the problem?.Best Pract Res Clin Endocrinol Metab. 2010; 24: 515-525
- Systemic inflammation, adipose tissue tumor necrosis factor, and leptin expression.Obes Res. 2003; 11: 525-531
- Interpretation and potential biases of Mendelian randomization estimates with time-varying exposures.Am J Epidemiol. 2019; 188: 231-238
Article info
Publication history
Published online: February 02, 2023
Accepted:
January 30,
2023
Received in revised form:
December 29,
2022
Received:
August 8,
2022
Identification
Copyright
© 2023 Elsevier B.V. All rights reserved.
