Association of STOX1 Maternal and Fetal Polymorphisms with Hypertensive Disorders of Pregnancy: Preliminary Evidence for a Parent-of-Origin Effect and Maternal-Fetal Genotypic Interaction

Objective: Preeclampsia (PE) is a serious pregnancy-related condition that accounts for a high proportion of maternal and fetal morbidity and mortality and falls under the category of hypertensive disorders of pregnancy (HDP). STOX1 has been identified as a potential paternally imprinted (maternally expressed) gene that influences placental development. Study design: We examined three STOX1 polymorphisms in two case-control studies, including rs10509305, rs1341667, and rs1694505. The first study included predominantly Latina women with HDP and the second included predominantly Caucasian women with severe preeclampsia (sPE) and/or HELLP Syndrome. The HDP cohort included 142 cases and 169 controls (mother-baby dyads) recruited at the Los Angeles County Women’s and Children’s Hospital, while the sPE/HELLP cohort included 178 cases and 33 controls (mother-baby-father triads) recruited through HELLP syndrome-focused social media platforms. Linkage disequilibrium (LD), single-SNP, haplotype association, and parent-of-origin (PoO) analyses were conducted using log-linear regression models in Haplin (R) (Version 4.4.1). Results: No significant associations were observed between STOX1 SNPs and HDP. In contrast, maternal carriage of the variant allele was significantly associated with increased risk of sPE/HELLP at rs10509305 for a heterozygous T allele (RR=1.96, p=0.002) and rs1341667 for a heterozygous C allele (RR=3.63, p< 0.001). Similar associations were observed in infants, where rs10509305 heterozygous T allele (RR=2.50, p< 0.001) and rs1341667 heterozygous C allele carriers (RR=3.93, p0.05). In the HDP cohort, no haplotype was identified as a risk factor for disease. In sPE/HELLP cohort, maternal heterozygous c-g-C (RR=2.25, p=0.004), heterozygous T-A-t (RR=4.29, p< 0.001), and homozygous T-g-t (RR=6.61, p=0.004) haplotypes were linked to increased risk. Infants carrying a heterozygous c-g-C (RR=2.30, p=0.003), heterozygous T-A-t (RR=5.71, p< 0.001) showed a significant increase in risk of sPE/HELLP. PoO analysis suggested risk of the mother developing sPE/HELLP associated with the fetal genotype when the child carries a paternally-inherited copy of the variant allele and decreased risk when the child inherits the variant allele from their mother for both rs10509305 and rs1341667 (RRR=0.07, p< 0.001 and RRR=0.02, p< 0.001, respectively). Conclusion: Maternal and fetal STOX1 polymorphisms may contribute to sPE/HELLP risk but not risk of less severe HDP. Significant PoO effects were noted, whereby paternally-derived alleles increase risk of sPE/HELLP while maternally inherited alleles decrease risk, highlighting a possible maternal-fetal genetic incompatibility pathway underlying sPE/HELLP.