Association of BMAL1 and CLOCK Gene Polymorphisms with Preeclampsia Risk with Subtype Analysis

Preeclampsia (PE), a major cause of maternal and perinatal morbidity, is a hypertensive pregnancy disorder with poorly defined pathogenesis. While dysregulation of core circadian genes including brain and muscle ARNT-like 1 (<i>BMAL1</i>; also termed <i>ARNTL</i>) and circadian locomotor output cycles kaput (<i>CLOCK</i>) has been implicated in PE, the contribution of their genetic polymorphisms to PE remains unclear. In this case-control study, polymorphisms in <i>BMAL1</i> and <i>CLOCK</i> were genotyped using MassARRAY in 202 PE patients (97 early-onset [eoPE], 105 late-onset [loPE]) and 400 controls. Following genotyping and linkage disequilibrium-pruning (<i>r</i>² > 0.8) to retain representative tag SNPs, the final set for association analysis comprised three non-redundant <i>BMAL1</i> SNPs (rs4757144, rs11022780, rs969485) and one <i>CLOCK</i> SNP (rs1048004). After confounder adjustment, no significant associations were detected for <i>CLOCK</i> variants, whereas the <i>BMAL1</i> rs11022780 variant demonstrated a significant protective effect against PE (TT vs. CC: OR = 0.26 [95% CI 0.09-0.78]; recessive model: OR = 0.25 [95% CI 0.09-0.74]), particularly in the eoPE subgroup. Expression quantitative trait locus (eQTL) analysis confirmed that this SNP correlated with <i>BMAL1</i> mRNA expression in whole blood, and protein-protein interaction analysis highlighted BMAL1's central role in circadian networks, implying a genetically influenced regulatory mechanism of PE through <i>BMAL1</i> expression.