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Investigating a possible causal relationship between maternal serum urate concentrations and offspring birthweight: a
Caitlin S Decina1,2,3, Rhian Hopkins1, Jack Bowden1
1Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.
Insights
Higher maternal urate levels are not a significant cause of lower offspring birthweight. Observational studies may be confounded, as Mendelian randomization analyses showed a minimal effect on birthweight.
Area of Science:
- Reproductive Health
- Metabolic Health
- Genetics
Background:
- Elevated urate levels correlate with higher systolic blood pressure (SBP) and lower birthweight.
- Mendelian randomization (MR) suggests urate causally impacts SBP, and maternal SBP impacts birthweight.
- Potential confounding of SBP's effect on birthweight by urate necessitates investigation.
Purpose of the Study:
- To investigate the causal effect of maternal urate levels on offspring birthweight.
- To determine if urate confounds the association between maternal SBP and birthweight.
Main Methods:
- Multivariable linear regression in the Exeter Family Study of Childhood Health (EFSOCH) and UK Biobank (UKB).
- Two-sample Mendelian randomization (MR) to assess the causal effect of maternal urate on offspring birthweight.
- One-sample MR in UKB women to evaluate the urate-SBP causal relationship.
Main Results:
- Higher maternal urate showed an association with lower offspring birthweight in observational analyses (EFSOCH: -22g, UKB: -28g per 1-SD increase).
- MR analysis indicated a smaller, non-significant causal effect of maternal urate on birthweight (-11g per 1-SD increase).
- Maternal urate was causally associated with higher SBP in women (1.7 mmHg per 1-SD increase).
Conclusions:
- The significant attenuation of the MR estimate suggests observational associations are likely confounded.
- The 95% confidence intervals for the MR result include the null, indicating a possible small effect.
- Maternal urate levels are unlikely to be a major determinant of offspring birthweight.
Background:
Higher urate levels are associated with higher systolic blood pressure (SBP) in adults, and in pregnancy with lower offspring birthweight. Mendelian randomization (MR) analyses suggest a causal effect of higher urate on higher SBP and of higher maternal SBP on lower offspring birthweight. If urate causally reduces birthweight, it might confound the effect of SBP on birthweight. We therefore tested for a causal effect of maternal urate on offspring birthweight.
Methods:
We tested the association between maternal urate levels and offspring birthweight using multivariable linear regression in the Exeter Family Study of Childhood Health (EFSOCH; n = 872) and UK Biobank (UKB; n = 133 187). We conducted two-sample MR to test for a causal effect of maternal urate [114 single-nucleotide polymorphisms (SNPs); n = 288 649 European ancestry] on offspring birthweight (n = 406 063 European ancestry; maternal SNP effect estimates adjusted for fetal effects). We assessed a causal relationship between urate and SBP using one-sample MR in UKB women (n = 199 768).
Results:
Higher maternal urate was associated with lower offspring birthweight with similar confounder-adjusted magnitudes in EFSOCH [22 g lower birthweight per 1-SD higher urate (95% CI: -50, 6); P = 0.13] and UKB [-28 g (95% CI: -31, -25); P = 1.8 × 10-75]. The MR causal effect estimate was directionally consistent, but smaller [-11 g (95% CI: -25, 3); PIVW = 0.11]. In women, higher urate was causally associated with higher SBP [1.7 mmHg higher SBP per 1-SD higher urate (95% CI: 1.4, 2.1); P = 7.8 × 10-22], consistent with that previously published in women and men.
Conclusion:
The marked attenuation of the MR result of maternal urate on offspring birthweight compared with the multivariable regression result suggests previous observational associations may be confounded. The 95% CIs of the MR result included the null but suggest a possible small effect on birthweight. Maternal urate levels are unlikely to be an important contributor to offspring birthweight.
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