313: Quantitative functional alterations in complement alternative pathway and related genetic analysis in severe phenotype preeclampsia and HELLP syndrome

Abstract

Preeclampsia and HELLP syndrome share many clinical and biologic features with thrombotic microangiopathy syndromes caused by abnormalities in complement pathways. It is unclear whether functional and genetic alterations in the complement alternative pathway (CAP) are associated with preeclampsia and HELLP syndrome. We used prospectively collected blood samples (2012 to 2016) from cases of severe phenotype preeclampsia, defined as delivery <34 weeks, HELLP syndrome and eclampsia, and matched normotensive controls (n=25 in each arm). Quantitative and functional analysis of 15 CAP components and activation fragments was conducted using clinically available immunoassays. Whole exome sequencing was performed on study group to interrogate 36 genes encoding CAP factors for coding non-synonymous sequence variants with a population allele frequency of <5%. Study and control groups were similar in age, gravidity, parity, marital status and race. However, the study group had a higher BMI (mean±SD; 32±8 vs 25±4 kg/m2; p=0.002) and earlier gestational age at delivery (32.5±3.6 vs 40.3±1 weeks; p<0.001). Serological studies in cases compared with controls demonstrated elevated Bb subunit (median [range]; 1.2 [0.5-4.3] vs 0.6 [0.5-1] mcg/mL; p<0.001), C5 concentrations (28 [18-33] vs 24 [15-34] mg/dL; p=0.03) and sMAC (371 [167-761] vs 184 [112-249] ng/mL; p<0.001) levels. Of 25 cases, 17 (68%) had at least 1 sequence variant in CAP genes (5 x CFB, 2 x CFI, 3 x CFH, 5 x CFHR, 1 x MCP, 5 x C2, 3 x C3, 1 x C3R, 1x C5, 5 x C7, 5 x C8, 1x C9). Specific listings are found in Figure. Patients with severe phenotype preeclampsia manifest functional alterations in complement alternative pathway activation, as evident by elevated levels of Bb, C5 and sMAC. Associated genetic sequence variants in complement pathway genes are also more common than expected, some of which are potentially pathogenic, suggesting shared genetic pathogenesis. Genetic screening and complement-targeted treatment may be useful in risk stratification and novel therapeutic approaches.