title: A functional SNP in the promoter of the SERPINH1 gene increases risk of preterm premature rupture of membranes in African Americans.
abstract: Prematurity is more prevalent in African Americans than in European Americans. We investigated the contribution of a functional SNP in the promoter of the SERPINH1 gene, enriched among those of African ancestry, to preterm premature rupture of membranes (PPROM), the leading identifiable cause of preterm birth. SERPINH1 encodes heat-shock protein 47, a chaperone essential for collagen synthesis. The SERPINH1 -656 minor T allele had a greater frequency in African populations and African Americans than in European Americans (7.4% [corrected] vs. 4.1%). The -656 T allele displayed significantly reduced promoter activity compared to the major -656 C allele in amnion fibroblasts, which lay down the fibrillar collagen that gives tensile strength to the amnion. An initial case-control study demonstrated that the -656 T allele is significantly more frequent in African-American neonates (P < 0.0009) born from pregnancies complicated by PPROM compared with controls (odds ratio of 3.22, 95% confidence interval 1.50, 7.22). There was no significant difference in ancestry among cases and controls using a dihybrid model based on 29 ancestry-informative markers. Adjusting the results of the case-control study for admixture still yielded a statistically significant association between the -656 T allele and PPROM (P < 0.002). A follow-up case-control study gave similar results. The combined case-control findings showed a highly significant (P < 0.0000045) association between the -656 T allele and PPROM. The SERPINH1 -656 T allele is the first example of an ancestry-informative marker associated with preterm birth in African Americans.
authors.affiliation: Center for Research on Reproduction and Women's Health and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Wang
authors.forename: Samuel
authors.initials: S
authors.lastname: Parry
authors.forename: George
authors.initials: G
authors.lastname: Macones
authors.forename: Mary D
authors.initials: MD
authors.lastname: Sammel
authors.forename: Helena
authors.initials: H
authors.lastname: Kuivaniemi
authors.forename: Gerard
authors.initials: G
authors.lastname: Tromp
authors.forename: George
authors.initials: G
authors.lastname: Argyropoulos
authors.forename: Indrani
authors.initials: I
authors.lastname: Halder
authors.forename: Mark D
authors.initials: MD
authors.lastname: Shriver
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Strauss
mesh_terms: D001741:Black or African American; D000483:Alleles; D001724:Birth Weight; D044383:Black People / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005322:Premature Rupture of Fetal Membranes / Q000208:ethnology / Q000235:genetics*; D015870:Gene Expression; D005787:Gene Frequency; D005865:Gestational Age; D050958:HSP47 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012307:Risk Factors
chemical_list: D050958:HSP47 Heat-Shock Proteins; C494660:SERPINH1 protein, human