A functional SNP in the promoter of the SERPINH1 gene increases risk of preterm premature rupture of membranes in African Americans
- Hongyan Wang*,
- Samuel Parry*,
- George Macones*,
- Mary D. Sammel†,
- Helena Kuivaniemi‡,
- Gerard Tromp‡,
- George Argyropoulos§,
- Indrani Halder¶,
- Mark D. Shriver¶,
- Roberto Romero‖, and
- Jerome F. Strauss III*,**,††
- *Center for Research on Reproduction and Women's Health and
- †Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA 19104;
- ‡Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201;
- §Pennington Center for Biomedical Research, Baton Rouge, LA 70808;
- ‖Perinatology Research Branch, National Institute of Child Health and Human Development, Hutzel Hospital, Detroit, MI 48201;
- ¶Department of Anthropology, Pennsylvania State University, University Park, PA 16802; and
- **Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA 23298
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Edited by R. Michael Roberts, University of Missouri, Columbia, MO, and approved July 11, 2006 (received for review May 5, 2006)
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 (12.4% 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.
Footnotes
- ††To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Virginia Commonwealth University, Sanger Hall, First Floor, Room 1071, 1101 East Marshall Street, P.O. Box 980565, Richmond, VA 23298. E-mail: jfstrauss{at}vcu.edu
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Author contributions: H.W., M. D. Shriver, R.R., and J.F.S. designed research; H.W., S.P., G.M., H.K., and G.T. performed research; G.A. contributed new reagents/analytic tools; H.W., M. D. Sammel, I.H., M. D. Shriver, and J.F.S. analyzed and interpreted data; H.W., M. D. Shriver, R.R., and J.F.S. wrote the paper; S.P, G.M., H.K., G.T., and G.A. acquired data; M. D. Sammel, I.H., and M. D. Shriver, performed statistical analysis; J.F.S. and M. D. Shriver obtained funding; and R.R. and J.F.S. supervised the study.
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Conflict of interest statement: No conflicts declared.
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This paper was submitted directly (Track II) to the PNAS office.
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See Commentary on page 13267.
- Abbreviations:
- PPROM,
- preterm premature rupture of membranes;
- Hsp47,
- heat-shock protein 47;
- CI,
- confidence interval
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Freely available online through the PNAS open access option.
- © 2006 by The National Academy of Sciences of the USA
