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. 2018 Oct 5;19(1):181.
doi: 10.1186/s12881-018-0696-4.

Discovery of rare ancestry-specific variants in the fetal genome that confer risk of preterm premature rupture of membranes (PPROM) and preterm birth

Bhavi P Modi  1 , Hardik I Parikh  2 , Maria E Teves  3 , Rewa Kulkarni  1 , Jiang Liyu  3 , Roberto Romero  4   5 , Timothy P York  1   3 , Jerome F Strauss 3rd  6   7
Affiliations

Discovery of rare ancestry-specific variants in the fetal genome that confer risk of preterm premature rupture of membranes (PPROM) and preterm birth

Bhavi P Modi et al. BMC Med Genet. .

Abstract

Background: Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth, a complication that is more common in African Americans. Attempts to identify genetic loci associated with preterm birth using genome-wide association studies (GWAS) have only been successful with large numbers of cases and controls, and there has yet to be a convincing genetic association to explain racial/ethnic disparities. Indeed, the search for ancestry-specific variants associated with preterm birth has led to the conclusion that spontaneous preterm birth could be the consequence of multiple rare variants. The hypothesis that preterm birth is due to rare genetic variants that would go undetected in standard GWAS has been explored in the present study. The detection and validation of these rare variants present challenges because of the low allele frequency. However, some success in the identification of fetal loci/genes associated with preterm birth using whole genome sequencing and whole exome sequencing (WES) has recently been reported. While encouraging, this is currently an expensive technology, and methods to leverage the sequencing data to quickly identify and cost-effectively validate variants are needed.

Methods: We developed a WES data analysis strategy based on neonatal genomic DNA from PPROM cases and term controls that was unencumbered by preselection of candidate genes, and capable of identifying variants in African Americans worthy of focused evaluation to establish statistically significant associations.

Results: We describe this approach and the identification of damaging nonsense variants of African ancestry in the DEFB1 and MBL2 genes that encode anti-microbial proteins that presumably defend the fetal membranes from infectious agents. Our approach also enabled us to rule out a likely contribution of a predicted damaging nonsense variant in the METTL7B gene.

Conclusions: Our findings support the notion that multiple rare population-specific variants in the fetal genome contribute to preterm birth associated with PPROM.

Keywords: Defensin β1; Mannose binding lectin-2; Methyltransferase like 7B; Preterm premature rupture of membranes; Whole exome sequencing.

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Conflict of interest statement

Ethics approval and consent to participate

Subjects were self-reported African-American women and their neonates receiving obstetrical care at MCV Hospitals, Richmond, VA (all samples in the WES) and Hutzel Hospital in Detroit, MI. The study was approved by the Institutional Review Boards of MCV Hospitals, Richmond, VA (IRB Number: HM15009); Wayne State University (IRB Numbers: 103897MP2F (5R), 082403MP2F (5R), 110605MP4F, 103108MP2F, 052308MP2F) as well as NICHD (National Institute of Child Health and Human Development) (IRB Numbers: 0H97-CH-N065, OH98-CH-N001, OH97-CH-N067, OH99-CH-N056, OH09-CH-N014). Subjects from Hutzel Hospital, Detroit, MI were enrolled under both Wayne State University as well as NICHD protocols and thus respective IRB numbers for both institutes are provided. Written informed consent was obtained from mothers before sample collection.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

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