Maternal coding variants in complement receptor 1 and spontaneous idiopathic preterm birth

Abstract

Preterm birth (PTB) is a major global public health concern. However, little is known about the pathophysiology of spontaneous idiopathic PTB. We tested the hypothesis that rare variants in families would target specific genes and pathways that contribute to PTB risk in the general population. Whole-exome sequencing was performed on 10 PTB mothers from densely affected families including two mother-daughter pairs. We identified novel variants shared between the two mother-daughter pairs when compared to a 1000 Genomes Project background exome file and investigated these genes for pathway aggregation using the Kyoto Encyclopedia of Genes and Genomes (KEGG). Genes in enriched pathways were then surveyed in the other six PTB exomes and tested for association in a larger number of nuclear families. The KEGG complement and coagulation cascade was one of the most enriched pathways in our two mother-daughter pairs. When the six genes found in this pathway (CFH, CR1, F13B, F5, CR2, and C4BPA) were examined for novel missense variants, half of all the exomes harbored at least one. Association analysis of variants in these six gene regions in nuclear families from Finland (237 cases and 328 controls) found statistically significant associations after multiple test corrections in three CR1 SNPs; the strongest in an exonic missense SNP, rs6691117, p-value = 6.91e-5, OR = 1.71. Our results demonstrate the importance of the complement and coagulation cascades in the pathophysiology of PTB, and suggest potential screening and intervention approaches to prevent prematurity that target this pathway.

Innate Immune System at the Maternal–Fetal Interface: Mechanisms of Disease and Targets of Therapy in Pregnancy Syndromes

“…42,43 Interestingly, maternal coding variants of CR1 were reported to be significantly associated with spontaneous idiopathic preterm birth. 44 The lower expression of CR2 on peripheral memory B cells has a similar effect to CR1, as it elevates the activation threshold of effector memory B cells. 45,46 In this view, elevated serum levels of IgG and reduced C4 complement component in PE women can be considered as immunological markers suggesting that elevated autoimmune reactivity contributes to the onset of disease.…”

Prevention of preterm birth: Harnessing science to address the global epidemic

“…These loci were further evaluated in nuclear families from Finland, where similar associations with common variants were found (17,18). More recently, families with highly penetrant spontaneous PTB phenotypes from Finland were subjected to whole-exome sequencing analysis and found to have an overrepresentation of rare variants in genes in the complement and coagulation cascade pathways (19). An extension of this analysis to nuclear families in Finland demonstrated an association of the complement receptor 1 (CR1) locus with PTB risk (19).…”

“…More recently, families with highly penetrant spontaneous PTB phenotypes from Finland were subjected to whole-exome sequencing analysis and found to have an overrepresentation of rare variants in genes in the complement and coagulation cascade pathways (19). An extension of this analysis to nuclear families in Finland demonstrated an association of the complement receptor 1 (CR1) locus with PTB risk (19). The continued acquisition of wellphenotyped families for genome-wide studies to identify associations with common gene variants and enable sequencing for rare variants holds substantial promise for revealing fundamental mechanistic pathways in PTB.…”

Is parturition-timing machinery related to the number of inhibitor CD94/NKG2A positive uterine natural killer cells?

“…However, there is another event occurring in the last days of pregnancy, and increasing evidence supports human parturition representing an inflammatory response [5,6]. & A. Yildiran yildiran@omu.edu.tr 1 In this context, there is the necessity for a human model that could be used to search for the parturition-timing machinery. For this purpose, the human placenta could easily represent an obtainable source of decidual cells [7], and if this decidua is obtained during an elective cesarean section (C/S), it can be assumed that it reflects ongoing gestation.…”

“…This is because preterm birth, defined as a live birth before 37 weeks of completed gestation, is the leading cause of infant mortality worldwide [1]. Therefore, the way that the parturition-timing machinery initiates birth needs to be understood.…”