Candidate gene linkage approach to Identify DNA variants that predispose to preterm birth

Department of Pediatrics, University of Iowa, Iowa City, IA.
Pediatric Research (Impact Factor: 2.31). 11/2012; 73(2). DOI: 10.1038/pr.2012.166
Source: PubMed


To identify genetic variants contributing to preterm birth using a linkage candidate gene approach.

We studied 99 single nucleotide polymorphisms for 33 genes in 257 families with preterm births segregating. Nonparametric and parametric analyses were used. Premature infants and mothers of premature infants were defined as affected cases in independent analyses.

Analyses with the infant as the case identified two genes with evidence of linkage: CRHR1 (p=0.0012) and CYP2E1 (p=0.0011). Analyses with the mother as the case identified four genes with evidence of linkage: ENPP1 (p=0.003), IGFBP3 (p=0.006), DHCR7 (p=0.009), and TRAF2 (p=0.01). DNA sequence analysis of the coding exons and splice sites for CRHR1 and TRAF2 identified no new likely etiologic variants.

These findings suggest the involvement of six genes acting through the infant and/or the mother in the etiology of preterm birth.

Download full-text


Available from: John M Dagle, Feb 11, 2014
28 Reads
  • Source
    • "So far, the analysis of rare variants associated with preterm birth has been limited. In one study exploiting candidate gene linkage for 33 genes in 257 families, nonparametric and parametric analyses performed on 99 SNPs in premature infants and mothers of premature infants resulted in the identification of a moderate association with preterm birth of corticotropin releasing hormone receptor 1 (CRHR1) and cytochrome P450 2E1 (CYP2E1) in affected infants, and with ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), insulin-like growth factor binding protein 3 (IGFBP3), TNF receptor-associated factor 2 (TRAF2) and 7-dehydrocholesterol reductase (DHCR7) in mothers [61]. DNA sequence analysis was performed for CRHR1 and TRAF2 to detect novel potentially causative mutations, but no new variants were detected [61]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Preterm birth (delivery at less than 37 weeks of gestation) is the leading cause of infant mortality worldwide. So far, the application of animal models to understand human birth timing has not substantially revealed mechanisms that could be used to prevent prematurity. However, with amassing data implicating an important role for genetics in the timing of the onset of human labor, the use of modern genomic approaches, such as genome-wide association studies, rare variant analyses using whole-exome or genome sequencing, and family-based designs, holds enormous potential. Although some progress has been made in the search for causative genes and variants associated with preterm birth, the major genetic determinants remain to be identified. Here, we review insights from and limitations of animal models for understanding the physiology of parturition, recent human genetic and genomic studies to identify genes involved in preterm birth, and emerging areas that are likely to be informative in future investigations. Further advances in understanding fundamental mechanisms, and the development of preventative measures, will depend upon the acquisition of greater numbers of carefully phenotyped pregnancies, large-scale informatics approaches combining genomic information with information on environmental exposures, and new conceptual models for studying the interaction between the maternal and fetal genomes to personalize therapies for mothers and infants. Information emerging from these advances will help us to identify new biomarkers for earlier detection of preterm labor, develop more effective therapeutic agents, and/or promote prophylactic measures even before conception.
    Genome Medicine 04/2013; 5(4):34. DOI:10.1186/gm438 · 5.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We investigated the housekeeping cytochrome P450 CYP51A1 encoding lanosterol 14α-demethylase from cholesterol synthesis that was so far not directly linked to human disorders. By direct sequencing of CYP51A1 in 188 women with spontaneous preterm delivery and 188 unrelated preterm infants (gestational age <37 weeks) we identified 22 variants where 10 are novel and rare. In infants there were two novel CYP51A1 variants where damaging effects of p.Tyr145Asp from the substrate recognition region, but not p.Asn193Asp, were predicted by PolyPhen2 and SIFT. This was confirmed by molecular modeling showing that Tyr145Asp substitution results in changed electrostatic potential of the CYP51 protein surface and lengthened distance to the heme which prevents hydrogen bonding. The CYP51 Tyr145Asp mutation is rare and thus very interesting for further structure/function relationship studies. From the 12 identified known variants rs6465348 was chosen for family based association studies due to its high minor allele frequency. Interestingly, this CYP51A1 common variant associates with small for gestational age weight in newborns (p = 0.028) and lower blood total cholesterol and low density lipoprotein cholesterol levels in mothers in 2nd trimester of pregnancy (p = 0.042 and p = 0.046 respectively). Our results indicate a new link between a cholesterol synthesis gene CYP51A1 and pregnancy pathologies.
    PLoS ONE 12/2013; 8(12):e82554. DOI:10.1371/journal.pone.0082554 · 3.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Recent evidence suggests that prolonged pregnancies beyond 42 weeks of gestation (post-term births) are associated with long-term adverse health outcomes in the offspring. Discussion There is evidence that post-term birth has not only environmental causes, but also significant heritability, suggesting genetic and/or epigenetic influences interact with environmental cues to affect gestational length. Summary As prolonged gestation is associated with adverse short- and long-term outcomes in the offspring, further research into the underlying genetic and epigenetic causes of post-term birth could be of importance for improving obstetric management.
    BMC Research Notes 10/2014; 7(1):720. DOI:10.1186/1756-0500-7-720
Show more