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

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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.

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Acknowledgments

This work was supported by Grants from the March of Dimes (LJM and JCM) and NIH (T32 GM07347 to JJM; R01 HD52953 to JCM; and T32 HD068256 to CEG).

Conflict of interest

The authors declare that they have no conflict of interest

Author information

Authors and Affiliations

  1. Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA

    Jude J. McElroy & Christian M. Shaffer

  2. Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN, USA

    Jude J. McElroy

  3. Division of Neonatology, Vanderbilt University School of Medicine and Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN, USA

    Courtney E. Gutman

  4. Genome Technology Core, Vanderbilt University, Nashville, TN, USA

    Christian M. Shaffer

  5. Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa, IA, USA

    Tamara D. Busch & Jeffrey C. Murray

  6. Department of Obstetrics and Gynecology, University Central Hospital, Helsinki, Finland

    Hilkka Puttonen & Kari Teramo

  7. Department of Pediatrics, Institute of Clinical Medicine, University of Oulu, Oulu, Finland

    Mikko Hallman

  8. Center for Prevention of Preterm Birth, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave. MLC 7009, Cincinnati, OH, 45229, USA

    Louis J. Muglia

  9. Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Louis J. Muglia

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  1. Jude J. McElroy
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Correspondence to Jude J. McElroy.

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Supplementary material 1 (PDF 389 kb)

Supplemental Table 1. VAAST genes with most significant p values in family 1168 sorted by rank

Supplemental Table 2. VAAST genes with most significant p values in family 1281 sorted by rank

Supplemental Table 3. KEGG pathways with more than three genes from the list of the most significant p value genes for family 1168

Supplemental Table 4. KEGG pathways that contained more than three genes from the most significant p value genes for family 1281

Supplemental Table 5. Novel missense variants in the six other exomes for the six complement and coagulation cascade genes identified by VAAST (for the PolyPhen-2 prediction the HumDiv algorithm was used).

Supplemental Table 6. Complete unadjusted and adjusted additive logistic regression association results for Finnish mothers’ complement and coagulation factor exome SNPs on Illumina arrays sorted by adjusted p value. The gene listed is that in which the SNP is located and in parentheses is the VAAST gene; the SNP was selected to interrogate within the 10 kb 5′ and 3′ buffer.

Supplemental Table 7. Complete unadjusted additive logistic association results for Finnish mothers’ Affymetrix 6.0 SNP arrays sorted by p value. The gene listed is that in which the SNP is located and in parentheses is the VAAST gene the SNP was selected to interrogate within the 10 kb 5′ and 3′ buffer.

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McElroy, J.J., Gutman, C.E., Shaffer, C.M. et al. Maternal coding variants in complement receptor 1 and spontaneous idiopathic preterm birth. Hum Genet 132, 935–942 (2013). https://doi.org/10.1007/s00439-013-1304-5

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