Editorial - University of Alberta

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Craig Pennell, Scott M. Williams, for the Preterm Birth Genome Project. Despite enormous efforts, preterm birth (PTB) (37 weeks' gestational age) remains the ...
Editorial

www. AJOG.org

A call for an international consortium on the genetics of preterm birth Joseph Biggio, Inge Christiaens, Michael Katz, Ramkumar Menon, Mario Merialdi, Nils-Halvdan Morken, Craig Pennell, Scott M. Williams, for the Preterm Birth Genome Project

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espite enormous efforts, preterm birth (PTB) (⬍37 weeks’ gestational age) remains the leading cause of neonatal morbidity and mortality.1 In addition, there is increasing evidence that it has long-term sequelae, including behavioral and learning problems, developmental delays, and adult diseases, such as diabetes and cardiovascular disease.2-5 These complications of PTB are associated with an estimated annual costs of $26 billion in the United States.6 The PTB rate continues to increase, with the most recent rise being in the United States of 12.5%. Other countries, both industrialized and developing, have shown similar increases in PTB rates. Some explanations for the rising PTB rates include increasing multiple births, advanced maternal age (ⱖ35 years), and the use of assisted reproductive technologies, such as in vitro fertilization. However, these factors alone do not account for the largest proportion of this trend,7-11 and the majority of preterm deliveries are still unexplained.8 Pregnancy and parturition involve complex molecular and physiologic pathways in both the mother and the fetus that are not well understood, but include stress, inflammation, hemorrhage, and pathologic uterine distension.6,12 These pathways can function independently, but usually act in concert in various combinations, adding to the complexity of the phenotype. Experimental approach to the myriad of possible pathways and their interactions physiologically is a truly daunting task. An alternative to this effort is an examination of static markers, such as genetic variants. These can help to define a priori the most probable interactions among pathways.13-18 From a clinical perspective, the primary objective is to predict and prevent PTB. Although several biomarkers of PTB

From the Department of Obstetrics and Gynecology and the Department of Genetics, University of Alabama at Birmingham, Birmingham, AL; the Perinatal Research Centre, University of Alberta, Alberta, Canada; the March of Dimes Foundation, New York, NY; the Perinatal Research Center, Nashville, TN; the World Health Organization; the School of Women’s and Infants’ Health, The University of Western Australia; and the Department of Medicine, Vanderbilt University, Nashville, TN Received April 18, 2008; accepted June 3, 2008. Reprints not available from the authors. Address correspondence to Ramkumar Menon, 2300 Patterson St, Nashville, TN 37203. [email protected] The order of authorship was determined alphabetically. 0002-9378/$34.00 © 2008 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2008.06.012

have been identified, they often present themselves too late for successful intervention.19 In contrast, static genetic markers can be used to predict outcome even before pregnancy. Genetic analysis can also be used to improve interventions by using phamacogenetic approaches. With the availability of highthroughput methods, genotyping of large numbers of samples and thousands of genes has become a faster and cheaper way to gain novel insights into the influence of genetic variations in PTB. Most reported investigations of the genetic contributions to PTB have been based on the candidate gene approach. However, there are a number of limitations to this method. Complex patterns of inheritance that are postulated to occur in PTB, arise from the accumulation of multiple common polymorphisms, each responsible for small effects.21-23 Limiting the investigation to just a few genes or polymorphisms restricts the information that can be gleaned to only a small portion of the pathways involved, and not the system as a whole. Therefore, candidate gene studies are likely to miss genes outside of the known pathways. Epistasis, or gene-gene interaction, also has a potentially profound role in multiple disease processes and biologic pathways.21-23 A candidate gene approach could easily fail to detect this potential effect because of the narrow focus of investigation.20 Because of these evident problems, a whole genome approach is needed to identify the unexpected variants that can contribute to PTB. In a whole-genome approach, a large set of sequence variants are used as markers to detect associations between a particular genomic region and a well-classified phenotype of interest.21-23 The variants themselves may or may not be functional or contributory to the phenotype, but instead they serve as a landmarks. Currently, it is feasible to genotype approximately 1 million genetic markers that enable finding an association with genetic markers within a susceptibility gene or regulatory element, or very close to it. The whole-genome association studies can be best appreciated as a first step of hypothesis testing for known candidates and also as hypothesis generating in novel pathways/genes. The sample size required for a whole-genome study is quite large because of the large number of comparisons, unless the effect size of the genotype is extraordinary, an event that is unlikely, given the putative multifactorial model of the genetics of PTB.21 Although studies of PTB will still need sample sizes larger than any published in candidate gene studies on PTB (thousands of cases and thousands of controls), these strategies, once considered a Herculean task, are now feasible. One way to assure that the numbers of samples are large enough to achieve sufficient power is to develop consortia that combine AUGUST 2008 American Journal of Obstetrics & Gynecology

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Editorial resources from multiple teams. This approach has been successful for studies of autism, multiple sclerosis, and several other diseases (Wellcome Trust Case Control Consortium [WTCCC]). We propose to apply it to the study of PTB. To coordinate multi-investigator and multisite large-scale genetic studies of PTB, it is essential to ensure that phenotype definitions are compatible. Here, we briefly review some basic phenotypic definitions. PTB has been defined by the World Health Organization (WHO) as a birth occurring before 37 completed weeks or 259 days of gestation.24 This definition has also been accepted by the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists.25 However, insofar as the subgroups of PTB are concerned, there is some ambiguity. This poses problems for assessing etiologic and presumably genetic heterogeneity.26 The subgrouping, based on clinical presentation, is the one most commonly used. It divides PTB into: preterm labor (PTL), preterm premature rupture of membranes (pPROM), and medically indicated (iatrogenic) PTB. Other subdivisions have been proposed27 and a recent article concluded that it is necessary to split and lump these categories when studying the cause of this complex trait.28 This may be appropriate for an epidemiologic survey of PTB; however, etiologic, pathologic, and physiologic heterogeneities will complicate the Genome-Wide Association (GWA) analysis, making any significant associations difficult to replicate. Such failure to replicate is not only a concern for PTB researchers but also for investigators in most other complex disease areas. Therefore, we argue that 1 of the reasons for these rather disappointing findings is the fact that previous studies of the genetic aspects of PTB have not devoted enough effort to defining the phenotype. PTB, in epidemiologic and biologic studies has been treated as a single dichotomous trait when in reality it is not. The reason to devote large-scale genotyping efforts to address the genetic basis of PTB is compelling. This will serve as a means of developing better predictive models and lead to a better understanding of disease pathophysiology. To assure adequate resources and the necessary number of samples, we require an assembly of investigators who have collected samples with appropriate phenotype data and are willing to join in a Preterm Birth Genome Project (PGP) consortium. This consortium has already been established at a meeting held at WHO headquarters in September 2007. The goal of the PGP is to pool resources with the intent of increasing sample sizes for both the initial GWA studies, as well as for the follow-up studies. This will be carried out as part of an international effort to define risk factors common to all populations and those that are unique for specific populations. Therefore, we invite all investigators who have DNA samples from studies of pregnancy outcome to join the PGP. The project will be coordinated by investigators at the WHO, Geneva, Switzerland, March of Dimes USA, and Preterm Birth International Collaborative (PREBIC). Michael Katz, MD, (Senior Vice President for Research and Global Programs, March of Dimes Birth Defect Foundation) is the director of the consortium. Those investigators who have a 96

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www.AJOG.org shared interest in identifying genetic risks for PTB risk should contact either Mario Merialdi ([email protected]), Project Chairman, Ramkumar Menon, Management committee ([email protected]), or Scott Williams, Scientific committee ([email protected]) with the subject heading “PGP Consortium.” The consortium has considered the rights of all investigators with respect to their intellectual property, the authorship of publications, and independence. These rules are available for perusal by all who express their interest in this important endeavor. We encourage them to contact us as soon as possible. f REFERENCES 1. Goldenberg RL, Rouse DJ. Prevention of premature birth. N Engl J Med 1998;339:313-20. 2. Barker DJ, Eriksson JG, Forsen T, Osmond C. Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol 2002;31:1235-39. 3. Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A. Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction: The Vermont Oxford Network. Am J Obstet Gynecol 2000;182:198-206. 4. Bhutta AT, Cleves MA, Casey PH, Cradock MM, Anand KJ. Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis. JAMA 2002;288:728-37. 5. Hack M, Klein NK, Taylor HG. Long-term developmental outcomes of low birth weight infants. Future Child 1995;5:176-96. 6. Berhman R, Butler A. Preterm birth: causes, consequences and prevention [video recording]. Institute of Medicine. 7-2-2006. 7. Dzakpasu S, Joseph KS, Rusen I. Health Canada Canadian Perinatal Report [videotape]. Ottawa, ON, Canada; 2000. 8. Green NS, Damus K, Simpson JL, Iams J, Reece EA, Hobel CJ, et al. Research agenda for preterm birth: recommendations from the March of Dimes. Am J Obstet Gynecol 2005;193:626-35. 9. Hanssens M, Devliger H, Martens GL, Keirse MJ. Changes in preterm delivery rates are not readily explained. J Soc Gynecol Investig 2005;12:2656A. 10. Langhoff-Roos J, Kesmodel U, Jacobsson B, Rasmussen S, Vogel I. Spontaneous preterm delivery in primiparous women at low risk in Denmark: population based study. BMJ 2006;332:937-9. 11. Slattery MM, Morrison JJ. Preterm delivery. Lancet 2002;360: 1489-97. 12. Lockwood CJ, Kuczynski E. Markers of risk for preterm delivery. J Perinat Med 1999;27:5-20. 13. Carr-Hill RA, Hall MH. The repetition of spontaneous preterm labour. BJOG 1985;92:921-8. 14. Clausson B, Lichtenstein P, Cnattingius S. Genetic influence on birthweight and gestational length determined by studies in offspring of twins. BJOG 2000;107:375-81. 15. Goldenberg RL, Cliver SP, Mulvihill FX, Hickey CA, Hoffman HJ, Klerman LV, et al. Medical, psychosocial, and behavioral risk factors do not explain the increased risk for low birth weight among black women. Am J Obstet Gynecol 1996;175:1317-24. 16. Porter TF, Fraser AM, Hunter CY, Ward RH, Varner MW. The risk of preterm birth across generations. Obstet Gynecol 1997;90:63-7. 17. Treloar SA, Macones GA, Mitchell LE, Martin NG. Genetic influences on premature parturition in an Australian twin sample. Twin Res 2000;3:80-2. 18. Ward K. Genetic factors in preterm birth. BJOG 2003;110(Suppl 20): 117. 19. Goldenberg RL, Goepfert AR, Ramsey PS. Biochemical markers for the prediction of preterm birth. Am J Obstet Gynecol 2005;192:S36-46.

www.AJOG.org 20. Williams SM, Haines JL, Moore JH. The use of animal models in the study of complex disease: all else is never equal or why do so many human studies fail to replicate animal findings? Bioessays 2004;26: 170-9. 21. Romero R, Kuivaniemi H, Tromp G, Olson J. The design, execution, and interpretation of genetic association studies to decipher complex diseases. Am J Obstet Gynecol 2002;187:1299-312. 22. Gibbs RA, Belmont JW, Hardenbol P, Willis TD, Yu FL, Yang HM, et al. The International HapMap Project. Nature 2003;426:789-96. 23. Romero R, Espinoza J, Gotsch F, Kusanovic JP, Friel LA, Erez O, et al. The use of high-dimensional biology (genomics, transcriptomics, proteomics, and metabolomics) to understand the preterm parturition syndrome. BJOG 2006;113(Suppl 3):118-35.

Editorial 24. World Health Organization. The prevention of perinatal morbidity and mortality report on a seminar, Tours 22-26 April 1969. Geneva: 1972. 25. American Academy of Pediatrics, American College of Obstetricians and Gynecologists. Guidelines for perinatal care. Elk Grove Village, IL: American Academy of Pediatrics; 2002. 26. Menon R, Fortunato SJ, Thorsen P, Williams SM. Genetic associations in preterm birth: a primer of marker selection, study design, and data analysis. J Soc Gynecol Investig 2006;13:531-41. 27. Klebanoff MA, Shiono PH. Top down, bottom up and inside out: reflections on preterm birth. Paediatr Perinat Epidemiol 1995;9:125-9. 28. Savitz DA, Dole N, Herring AH, Kaczor D, Murphy J, Siega-Riz AM, et al. Should spontaneous and medically indicated preterm births be separated for studying aetiology? Paediatr Perinat Epidemiol 2005;19:97-105.

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