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Association of BMAL1 and CLOCK Gene Polymorphisms with Preeclampsia Risk with Subtype Analysis
Fan Xia1, Peiwen Wang1, Ziye Li1
1Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, No. 172 Tongzipo Road, Yuelu District, Changsha 410013, China.
Insights
Genetic variations in the BMAL1 gene may protect against preeclampsia (PE), particularly early-onset PE. A specific BMAL1 single nucleotide polymorphism (SNP) was linked to reduced PE risk and altered BMAL1 gene expression.
Area of Science:
- Genetics
- Obstetrics
- Molecular Biology
Background:
- Preeclampsia (PE) is a serious hypertensive disorder of pregnancy with unclear causes.
- Circadian gene dysregulation, including BMAL1 and CLOCK, is suspected in PE pathogenesis.
- The role of genetic variations in BMAL1 and CLOCK in PE susceptibility is not well understood.
Purpose of the Study:
- To investigate the association between genetic polymorphisms in BMAL1 and CLOCK genes and preeclampsia risk.
- To explore the impact of these polymorphisms on BMAL1 mRNA expression and protein interactions.
Main Methods:
- Case-control study involving 202 PE patients and 400 controls.
- Genotyping of BMAL1 and CLOCK single nucleotide polymorphisms (SNPs) using MassARRAY.
- Linkage disequilibrium pruning to select tag SNPs for association analysis.
- Expression quantitative trait locus (eQTL) and protein-protein interaction analyses.
Main Results:
- No significant association was found for CLOCK gene variants with PE.
- The BMAL1 rs11022780 variant showed a significant protective effect against PE, especially in early-onset PE (eoPE).
- eQTL analysis confirmed that rs11022780 influences BMAL1 mRNA levels in whole blood.
Conclusions:
- Genetic variations in BMAL1, specifically the rs11022780 SNP, may offer a protective mechanism against preeclampsia.
- BMAL1's role in circadian networks suggests a genetically regulated pathway influencing PE development.
- Further research into BMAL1's function could reveal novel therapeutic targets for PE.
Abstract:
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 (BMAL1; also termed ARNTL) and circadian locomotor output cycles kaput (CLOCK) has been implicated in PE, the contribution of their genetic polymorphisms to PE remains unclear. In this case-control study, polymorphisms in BMAL1 and CLOCK 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 (r2 > 0.8) to retain representative tag SNPs, the final set for association analysis comprised three non-redundant BMAL1 SNPs (rs4757144, rs11022780, rs969485) and one CLOCK SNP (rs1048004). After confounder adjustment, no significant associations were detected for CLOCK variants, whereas the BMAL1 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 BMAL1 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 BMAL1 expression.
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