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Discovery of rare ancestry-specific variants in the fetal genome that confer risk of preterm premature rupture of membranes (PPROM) and preterm birth.
Modi, Bhavi P; Parikh, Hardik I; Teves, Maria E; Kulkarni, Rewa; Liyu, Jiang; Romero, Roberto; York, Timothy P; Strauss, Jerome F.
Afiliação
  • Modi BP; Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
  • Parikh HI; Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA.
  • Teves ME; Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine, Sanger Hall 11-029, 1101 East Marshall Street, Richmond, VA, 23298, USA.
  • Kulkarni R; Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
  • Liyu J; Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine, Sanger Hall 11-029, 1101 East Marshall Street, Richmond, VA, 23298, USA.
  • Romero R; Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.
  • York TP; Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Detroit, MI, USA.
  • Strauss JF; Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
BMC Med Genet ; 19(1): 181, 2018 10 05.
Article em En | MEDLINE | ID: mdl-30290772
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ruptura Prematura de Membranas Fetais / Códon sem Sentido / Predisposição Genética para Doença / Beta-Defensinas / Lectina de Ligação a Manose / População Negra / Nascimento Prematuro Tipo de estudo: Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Female / Humans / Newborn / Pregnancy Idioma: En Revista: BMC Med Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ruptura Prematura de Membranas Fetais / Códon sem Sentido / Predisposição Genética para Doença / Beta-Defensinas / Lectina de Ligação a Manose / População Negra / Nascimento Prematuro Tipo de estudo: Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Female / Humans / Newborn / Pregnancy Idioma: En Revista: BMC Med Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Reino Unido