ABSTRACT
BACKGROUND: The aim of this study was to identify genetic variants contributing to preterm birth (PTB) using a linkage candidate gene approach. METHODS: We studied 99 single-nucleotide polymorphisms (SNPs) for 33 genes in 257 families with PTBs segregating. Nonparametric and parametric analyses were used. Premature infants and mothers of premature infants were defined as affected cases in independent analyses. RESULTS: 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. CONCLUSION: These findings suggest the involvement of six genes acting through the infant and/or the mother in the etiology of PTB.
Subject(s)
Infant, Premature , Polymorphism, Single Nucleotide , Premature Birth/genetics , Cytochrome P-450 CYP2E1/genetics , Denmark , Genetic Association Studies , Genetic Linkage , Genetic Predisposition to Disease , Gestational Age , Humans , Infant, Newborn , Insulin-Like Growth Factor Binding Protein 3/genetics , Oxidoreductases Acting on CH-CH Group Donors/genetics , Phenotype , Phosphoric Diester Hydrolases/genetics , Pyrophosphatases/genetics , Receptors, Corticotropin-Releasing Hormone/genetics , Risk Assessment , Risk Factors , TNF Receptor-Associated Factor 2/genetics , United StatesABSTRACT
OBJECTIVE: To examine associations between rs9883204 in ADCY5 and rs900400 near LEKR1 and CCNL1 with birth weight in a preterm population. Both markers were associated with birth weight in a term population in a recent genome-wide association study of Freathy et al. STUDY DESIGN: A meta-analysis of mother and infant samples was performed for associations of rs900400 and rs9883204 with birth weight in 393 families from the US, 265 families from Argentina, and 735 mother-infant pairs from Denmark. Z-scores adjusted for infant sex and gestational age were generated for each population separately and regressed on allele counts. Association evidence was combined across sites by inverse-variance weighted meta-analysis. RESULTS: Each additional C allele of rs900400 (LEKR1/CCNL1) in infants was marginally associated with a 0.069 SD lower birth weight (95% CI, -0.159 to 0.022; P = .068). This result was slightly more pronounced after adjusting for smoking (P = .036). No significant associations were identified with rs9883204 or in maternal samples. CONCLUSIONS: These results indicate the potential importance of this marker on birth weight regardless of gestational age.
