Human Genetics

, Volume 132, Issue 8, pp 935–942 | Cite as

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

  • Jude J. McElroy
  • Courtney E. Gutman
  • Christian M. Shaffer
  • Tamara D. Busch
  • Hilkka Puttonen
  • Kari Teramo
  • Jeffrey C. Murray
  • Mikko Hallman
  • Louis J. Muglia
Original Investigation


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.

Supplementary material

439_2013_1304_MOESM1_ESM.pdf (390 kb)
Supplementary material 1 (PDF 389 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Jude J. McElroy
    • 1
    • 2
  • Courtney E. Gutman
    • 3
  • Christian M. Shaffer
    • 1
    • 4
  • Tamara D. Busch
    • 5
  • Hilkka Puttonen
    • 6
  • Kari Teramo
    • 6
  • Jeffrey C. Murray
    • 5
  • Mikko Hallman
    • 7
  • Louis J. Muglia
    • 8
    • 9
  1. 1.Center for Human Genetics ResearchVanderbilt UniversityNashvilleUSA
  2. 2.Medical Scientist Training ProgramVanderbilt University School of MedicineNashvilleUSA
  3. 3.Division of NeonatologyVanderbilt University School of Medicine and Monroe Carell Jr. Children’s Hospital at VanderbiltNashvilleUSA
  4. 4.Genome Technology CoreVanderbilt UniversityNashvilleUSA
  5. 5.Department of PediatricsUniversity of Iowa Carver College of MedicineIowaUSA
  6. 6.Department of Obstetrics and GynecologyUniversity Central HospitalHelsinkiFinland
  7. 7.Department of Pediatrics, Institute of Clinical MedicineUniversity of OuluOuluFinland
  8. 8.Center for Prevention of Preterm BirthCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  9. 9.Perinatal InstituteCincinnati Children’s Hospital Medical CenterCincinnatiUSA

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