Maternal coding variants in complement receptor 1 and spontaneous idiopathic preterm birth.
Jude J McElroy1, Courtney E Gutman, Christian M Shaffer
1Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA. jude.j.mcelroy@Vanderbilt.edu
Human Genetics
|April 18, 2013
Summary
Rare genetic variants in the complement and coagulation cascades are linked to spontaneous preterm birth (PTB). This finding offers new avenues for preventing prematurity by targeting these pathways.
Area of Science:
- Genetics
- Reproductive Medicine
- Immunology
Background:
- Spontaneous idiopathic preterm birth (PTB) is a significant global health issue with poorly understood causes.
- Identifying genetic factors contributing to PTB risk is crucial for developing preventative strategies.
- Previous research has not fully elucidated the role of rare genetic variants in PTB pathophysiology.
Purpose of the Study:
- To investigate the hypothesis that rare genetic variants in specific genes and pathways contribute to PTB risk.
- To identify novel variants and pathways associated with PTB in families with multiple affected individuals.
- To assess the role of the complement and coagulation cascades in the pathophysiology of spontaneous PTB.
Main Methods:
- Whole-exome sequencing was performed on 10 mothers with PTB from densely affected families.
- Variant analysis was compared against the 1000 Genomes Project database to identify novel variants.
- Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was used to identify enriched pathways.
- Association analysis of candidate genes was conducted in a larger cohort of Finnish nuclear families (237 cases, 328 controls).
Main Results:
- The complement and coagulation cascade pathway was significantly enriched in PTB mothers.
- Six genes within this pathway (CFH, CR1, F13B, F5, CR2, C4BPA) were examined, with half of the exomes harboring at least one missense variant.
- Association analysis revealed statistically significant associations for three CR1 single nucleotide polymorphisms (SNPs) in Finnish families, notably an exonic missense SNP (rs6691117, p=6.91e-5, OR=1.71).
Conclusions:
- The study highlights the critical role of the complement and coagulation cascades in the pathophysiology of spontaneous preterm birth.
- Genetic variants within these cascades represent potential risk factors for PTB.
- These findings suggest that targeting the complement and coagulation pathways may offer novel screening and intervention strategies for preventing prematurity.
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