(201) Dyslipidemia and risk of hypertensive disorders of pregnancy: a multi-ancestry Mendelian Randomization study

Hypertensive disorders of pregnancy (HDP) remain a leading cause of maternal morbidity worldwide and across diverse populations. Dyslipidemia has been associated with HDP; however, observational studies are susceptible to residual confounding and few randomized controlled trials have been conducted. Mendelian randomization (MR) analyses use genetic variants as instrumental variables to create a pseudo-randomized experiment. In this study, we estimate the association between genetically predicted lipid values, their pharmacological targets, and the risk of HDP.

Study Design: We extracted uncorrelated (R² < 0.001) single-nucleotide polymorphisms (SNPs) strongly associated (p-value < 5e-8) with high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) from published genome-wide association studies of European, admixed African, Latino, and East Asian ancestry participants. Similar extraction was done for lipid-modifying drug targets among European participants. An inverse-variance weighted analysis was performed, and results were meta-analyzed across ancestry groups. Several sensitivity analyses were conducted to evaluate bias due to genetic pleiotropy.

Results: The meta-analysis across four ancestry groups included 1.5 million subjects with lipid measurements, 7,425 subjects with HDP and 239,290 without HDP. Lower genetically predicted HDL-C and higher genetically predicted TG were associated with increased risk of HDP, respectively (odds ratio [OR] 0.84; 95% CI 0.74-0.94; p=0.004, and OR 1.29; 95% CI 1.12-1.49; p< 0.001) (Figure 1). However, only the effect of HDL-C was consistent in the sensitivity analysis (data not shown). For the lipid-modifying genetic drug targets, only those targeting HDL-C were significant (Table 1).

Conclusion:

Robust MR analyses demonstrate a likely protective effect of elevated HDL-C on risk of HDP. This relationship was fairly consistent across different ancestry groups. These findings provide insight into a potentially new target for screening and intervention.