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

Autor: Roberto Romero, Timothy P. York, Hardik I. Parikh, Rewa Kulkarni, Bhavi P. Modi, Jerome F. Strauss, Jiang Liyu, Maria E. Teves
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Candidate gene
Fetal Membranes
Premature Rupture
beta-Defensins
Defensin β1
Gene Expression
Genome-wide association study
Bioinformatics
0302 clinical medicine
Gene Frequency
Pregnancy
Genetics (clinical)
Exome sequencing
030219 obstetrics & reproductive medicine
3. Good health
Technical Advance
Codon
Nonsense
Methyltransferase like 7B
Premature Birth
Female
Infant
Premature
Adult
lcsh:Internal medicine
lcsh:QH426-470
Black People
Biology
Mannose-Binding Lectin
Polymorphism
Single Nucleotide
03 medical and health sciences
Fetus
Preterm premature rupture of membranes
Exome Sequencing
Genetics
medicine
Humans
Genetic Predisposition to Disease
lcsh:RC31-1245
Allele frequency
Alleles
Genetic association
Whole genome sequencing
Genome
Human
Whole exome sequencing
Infant
Newborn
medicine.disease
Human genetics
Mannose binding lectin-2
lcsh:Genetics
030104 developmental biology
Case-Control Studies
Carrier Proteins
Premature rupture of membranes
Zdroj: BMC Medical Genetics
BMC Medical Genetics, Vol 19, Iss 1, Pp 1-13 (2018)
ISSN: 1471-2350
Popis: 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. Electronic supplementary material The online version of this article (10.1186/s12881-018-0696-4) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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