Understanding rare genetic variants within the terminal pathway of complement system in preeclampsia

Abstract

Preeclampsia is a common multifactorial disease of pregnancy. Dysregulation of complement activation is among emerging candidates responsible for disease pathogenesis. In a targeted exomic sequencing study of 609 women with preeclampsia and 2092 non-preeclamptic controls, we identified 14 variants within nine genes coding for components of the membrane attack complex (MAC, C5b-9) that are associated with preeclampsia. We found two rare missense variants in the C5 gene that predispose to preeclampsia (rs200674959: I1296V, OR (CI95) = 24.13 (1.25-467.43), p value = 0.01 and rs147430470: I330T, OR (CI95) = 22.75 (1.17-440.78), p value = 0.01). In addition, one predisposing rare variant and one protective rare variant were discovered in C6 (rs41271067: D396G, OR (CI95) = 2.93 (1.18-7.10), p value = 0.01 and rs114609505: T190I, 0.02 OR (CI95) = 0.47 (0.22-0.92), p value = 0.02). The results suggest that variants in the terminal complement pathway predispose to preeclampsia.

Fig. 1. The structure of C5 and C6 proteins.

A The domain structure of C5b (top) and C6 (bottom) with PE associating variants indicated. The C5 variants are located in exon 31/41 (I330) coding the Immunoglobulin-like domain 3 (MG3) and in exon 9/41 (I1296) coding the conserved complement-activating CUB (complement C1r/C1s, Uegf, Bmp1) domain Both C6 variants in exons 6/16 (T190) and 12/16 (D396) are located in the membrane attack complex/perforin domain (MACPF). B The protein structure of C6 (orange) in complex with C5b (green) with the PE-associating amino acids’ positions indicated. The D396 is located directly in the interaction site between the two molecules. The structural model is based on construct 4A5W [37].