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Abstract

  1. Top of page
  2. Abstract
  3. Evidence supporting a genetic predisposition to preterm delivery (PTD)
  4. Molecular methods for studying PTD
  5. Plausible candidate genes
  6. Conclusions
  7. References

Preterm delivery (PTD) complicates as many as 10% of pregnancies in the United States. Moreover, prematurity accounts for more than 70% of the consequent neonatal and infantile morbidity and mortality. Serious long-term complications include cerebral palsy, respiratory disease, blindness and deafness. Despite substantial basic scientific, translational and clinical investigation in recent years, the PTD rate (10%) and the low birthweight rate (7%) remain largely unchanged. Indeed, the very aetiology and pathophysiology of PTD remain unknown in most cases. In short, PTD continues to constitute a major clinical and public health challenge of the highest order, a circumstance further compounded by the controversy surrounding the efficacy of current therapeutic regimens. In an effort to address the relevant knowledge gap, we put forth the hypothesis that PTD results, at least in part, from a genetic predisposition. Evidence supporting the hypothesis that certain women have a genetic predisposition to deliver preterm is growing. Moreover, the discovery of a gene mutation predisposing to PTD would constitute a major breakthrough for future research into the biology, prediction, and therapy of preterm labour. Presented here is a discussion of the evidence to support a genetic predisposition to PTD, molecular techniques proposed to study the genetics of preterm labour, and plausible candidate genes that warrant further investigation.


Evidence supporting a genetic predisposition to preterm delivery (PTD)

  1. Top of page
  2. Abstract
  3. Evidence supporting a genetic predisposition to preterm delivery (PTD)
  4. Molecular methods for studying PTD
  5. Plausible candidate genes
  6. Conclusions
  7. References

Studies of the genetics of PTD are limited. This paucity of information may reflect the fact that until recently, the high mortality rate of infants delivered preterm meant that few survived to pass on a possible genetic trait predisposing to preterm birth. The past two decades have witnessed major advances in neonatal care, and women who themselves were delivered preterm are now in their reproductive years.1[2]–3 The existence of this population of prematurely born women, along with the availability of modern DNA analytical techniques, afford a unique opportunity to study the genetics of PTD.

Several arguments can be advanced to postulate a genetic basis for PTD. First and foremost, a leading risk factor for PTD is a prior pregnancy resulting in PTD. Women with a history of prior PTD are at risk for delivering another preterm baby in 15–80% of subsequent pregnancies, depending on the population studied.4[5]–6 A longitudinal study conducted in Norway disclosed that the likelihood of spontaneous PTD increased with the number of prior PTDs, the most recent birth being the most predictive.6 The risk for subsequent PTD increases significantly with two or more prior PTDs. A tendency for repeat PTD occurring at the same gestational age has also been observed.7 Second, certain single gene disorders have been associated with aberrant timing of the onset of labour.8,9 Third, racial predisposition to PTD has been described. African-American women suffer twice the rate of PTD compared with Caucasians even when confounding social and economic variables are controlled for.10 Finally, recent studies carried out at the University of Utah Health Sciences Center, provide independent support for a genetic basis for PTD.11 Intergenerational data were collected from a linked data base of birth certificates composed of two different generational cohorts: a parental cohort of women born between 1947 and 1957, and their offspring born between 1970 and 1992. ‘Preterm mothers’ were defined as those women in the parental cohort who themselves were born leqslant R: less-than-or-eq, slant 37 weeks of gestation. ‘Term mothers’ were defined as women in the parental cohort born geqslant R: gt-or-equal, slanted 38 weeks of gestation. By using multiple logistic regression analysis to assess the interaction of concomitant variables and the risk of PTD for the two cohorts, the risk of PTD proved significantly higher for ‘preterm mothers’ than for ‘term mothers’ (Odds Ratio [OR] 1.18; 95% confidence interval [CI] 1.02, 1.37). This risk increased as the mother’s own birth gestational age decreased (< 30 weeks: OR 2.38; 95% CI 1.37,4.16).

Molecular methods for studying PTD

  1. Top of page
  2. Abstract
  3. Evidence supporting a genetic predisposition to preterm delivery (PTD)
  4. Molecular methods for studying PTD
  5. Plausible candidate genes
  6. Conclusions
  7. References

When studying PTD as a genetic disease one must recall several basic concepts. First, PTD is a heterogeneous disease presenting phenotypically with varying time of onset and severity of disease. Therefore, PTD is probably not the result of a single gene disorder, but rather gene/gene interactions or gene/environment interactions. Furthermore, as PTD is probably a complex trait, genetic phenomena such as incomplete penetrance and variable expressivity must also be taken into consideration when studying PTD as a genetic predisposition. Second, investigations have focused on maternal candidate genes. Because of the accessibility of tissues and blood samples for study, many researchers have studied maternal serum markers. However paternal, fetal and placental proteins have been relatively understudied. Third, and more recently, investigations have been directed towards early human fetal placentation. Knowledge of gene expression at the maternal–fetal interface during early human development seems critical to a better understanding of disease pathophysiology. Therefore, we should best devote our investigations into a comprehensive study of maternal, fetal and placental genes.

Several molecular methods used to investigate the genetics of PTD include the study of functional variants of candidate genes (case-control studies), positional cloning (linkage analysis), and subtractive complementary DNA (cDNA) libraries. Once a gene has been cloned, sequenced and localised and functional variants have been identified, a comparison of allele frequencies and carrier rates for the variant in populations with disease compared with controls may be done. Examples of functional variants of candidate genes that have been studied include the tumour necrosis factor (TNF) T1 variant of the TNF-α gene. A major advantage of this methodology is the use of straightforward standardised DNA techniques such as polymerase chain reaction followed by allele-specific mutation detection. Strict disease definition for both cases and controls should be adhered to. In addition, cases should be matched for ethnicity as different ethnic groups will carry alleles with different frequencies. A major limitation is that these type of studies are restricted to previously identified genes and functional variants.

Second, positional cloning, the isolation of a gene based solely on its chromosomal location without regard to biochemical function, has been another method used to discover novel genes responsible for PTD.12,13 Highly polymorphic genetic markers, such as short tandem repeat sequences are used allowing inheritance of disease-linked markers to be traced in existing human pedigrees. The advantage of this methodology is the identification of novel, previously unidentified genes contributing to PTD. The disadvantage is the challenge of identifying the cohort to be studied. These individuals must be related and exhibit a similar disease phenotype (i.e. PTD at a similar gestational age). Furthermore, it is also important to use the STR polymorphic markers with individuals of the same ethnicity as the one from which their allele frequencies have been calculated.

The synthesis of subtractive cDNA libraries and the use of cDNA chip microarrays are other powerful techniques used for gene identification. By subtracting genes expressed by normal tissues from genes expressed by disease tissues, novel genes unique to a certain disease process such as PTD can be isolated.14[15]–16 With the use of this technique our laboratory is currently studying gene expression unique to first trimester human development. With widespread use of molecular techniques, we are able to study the genetic origins of PTD at greater depth.

Plausible candidate genes

  1. Top of page
  2. Abstract
  3. Evidence supporting a genetic predisposition to preterm delivery (PTD)
  4. Molecular methods for studying PTD
  5. Plausible candidate genes
  6. Conclusions
  7. References

Preterm labour with subsequent PTD is a heterogeneous disease, and may result from different pathogenic processes. Potential processes include intrauterine infection, uteroplacental insufficiency, and thrombotic vasulopathy. Therefore, PTD is probably not the result of a single gene perturbation. The possibility exists that potential candidate genes are in fact epiphenomena, i.e. they or their proteins translated could be perturbed, but only after another factor (e.g. infection) has already set into motion the cascade of events leading to PTD. Disease definition is critical to the study of a genetic predisposition to PTD. It is of importance to distinguish preterm contractions, preterm labour and PTD. Most gravid women experi­encing preterm contractions will not go on to deliver preterm. Furthermore, preterm rupture of membranes (PROM) should be considered as a distinct entity because of the possibility of other distinct candidate genes being responsible for PROM rather than PTD of an idiopathic origin. For example, genes related to inadequate or defective collagen synthesis may predispose to PTD through PROM, whereas genes encoding oxytocin or its receptor may be associated with idiopathic PTD.

Evidence supporting PTD as an intrauterine inflammatory response syndrome

Romero and colleagues17 have described the ‘preterm labour syndrome’ according to which PTD may be preceded by either an infectious or ischaemic insult at the maternal-fetal interface. This insult, in turn, is predicted to promote the elaboration of cytokines and other inflammatory mediators thereby resulting in the stimulation of prostaglandin biosynthesis, the propagation of myometrial contractility and the initiation of preterm labour and birth. It has been proposed that genetic predisposition to immune hyper-responsiveness to an infectious insult may result in overproduction of cytokines such as TNF-α and interleukin-1 (IL-1).18 We speculate that common organisms colonising the vagina, such as group B streptococcus and bacterial vaginosis, may serve as one such insult and thus result in PTD in individuals genetically predisposed to immune hyper-responsiveness. This genetic predisposition to cytokine over-expression may manifest itself on either the maternal, fetal, or both sides of the maternal-fetal interface.

Pro-inflammatory cytokines

Human gestational tissues constitute a rich source of inflammatory cytokines as documented by both in vivo and in vitro studies. The fetal membranes and the maternal decidua produce cytokines, including TNF-α, IL-1, interleukin-6 (IL-6) and interleukin-10 (IL-10) in response to a variety of inflammatory or ischaemic insults. Elevated concentrations of pro-inflammatory cytokines can be detected in both the amniotic fluid and plasma compartments of women whose pregnancy was complicated by PTD. Indeed, elevated concentrations of both TNF-α and IL-1 can be found in the amniotic fluid of women experiencing preterm labour. Romero and colleagues19 documented a strong correlation between the concentration of IL-1β and prostaglandin production. Amniotic fluid levels of TNF-α were also noted to be elevated in women with PROM, preterm labour, and positive amniotic fluid cultures.20 The maternal decidua has been shown to produce both TNF-α and IL-1.21 Cultured decidual cells and decidual explants stimulated with lipopolysaccharide (LPS) have been shown to produce both cytokines.20,21 Vince et al.22 observed TNF-α to localise to decidual macrophages during the first trimester and then later, in the third trimester, to be expressed by both decidual macrophages and the chorionic villous trophoblast. These findings were confirmed by others.23,24 Using immunocytochemical techniques, Baergen et al.25 documented IL-1 in the fetal amnion, trophoblast, and decidua. Increased elaboration of IL-1β from placental cell cultures in women delivering preterm (as compared with term) has been reported by Steinborn and colleagues.26 Furthermore, IL-1β has been shown to be distributed throughout the decidua, chorion, and amnion in preterm and term labour.24

IL-6 is probably the best studied of all cytokines during pregnancy. IL-6 has been found to be elevated in the amniotic fluid in association with ‘idiopathic’ preterm labour as well as infection-associated preterm labour in a number of studies.27 Romero and colleagues first reported28,29 that elevated concentrations of amni­otic fluid IL-6 characterised pregnancies complicated with infection-associated preterm labour. Furthermore, measurement of IL-6 proved to be among the most sensitive and specific indicators of infection-associated preterm labour. Human gestational tissues have been shown to constitute potential sources for IL-6. Decidual explants have been shown to produce IL-6 after incubation with LPS.27 Regulation of IL-6 by IL-1β and TNF-α, has been demonstrated in cultured monolayers of human decidua and chorion cells.30,31

IL-10 is a major inhibitor of cytokine synthesis. Heyborne et al.32 noted that elevated concentrations of IL-10 in the amniotic fluid of women at the time of second trimester genetic amniocentesis could predict the development of small-for-gestational age infants and reflect generalised dysregulated immune activation during pregnancy. In the setting of preterm labour, several investigators have reported elevated concentrations of IL-10 in the amniotic fluid associated with clinically evident chorioamnionitis.33 IL-10 appears to be predominantly elaborated by trophoblast cells. It has thus been hypothesised that IL-10 production may be important in maintaining the maternal tolerance of the allogeneic fetus.34,35 IL-10 production by cultured human decidual cells occurs after stimulation with IL-1β and LPS.36 It has also been shown to regulate IL-6 production at the transcriptional level in human amniochorionic membrane explants.37

The potential relevance of host immune hyper-responsiveness to PTD

The biosynthesis of all proinflammatory cytokines is under tight genetic control. Genes encoding TNF-α, IL-1, IL-6, and IL-10 have been cloned and sequenced. Importantly in vitro experiments have uncovered genetic ‘polymorphisms’ associated with increased transcriptional activity. Thus, gain of function mutations in effect result in increased levels of clinically detectable cytokines (Table 1). Carriers of these genetic polymorphisms, both in the heterozygous and homozygous states, have been shown to suffer from increased susceptibility to disease.

Table 1.  Previously published allele frequencies cytokine polymorphisms to be studied Thumbnail image of

This group was the first to propose that genetic predisposition to host immune hyper-responsiveness may lead to PTD.38 Our initial study did not reveal significant association between PTD and a mutation in the promoter of the TNF-α gene. The study in question was limited for several reasons. Although medically indicated deliveries were excluded, the group studied was heterogeneous. Infectious and non-infectious aetiologies were not distinguished. PROM was not evaluated separately. When we corrected for these relative shortcomings and performed a re-evaluation of the data, a trend towards significance was noted for an association between a gain of function mutation in the TNF-α promoter and infection-prompted PTD as compared with term delivery.39

Recently, Roberts et al.40 reported on studies of the same mutation in the TNF-α promoter in women whose pregnancy was complicated by PROM and subsequent PTD, the control group consisting of women delivering preterm. The results established a statistically significant association between the gain of function mutation of the TNF-α promoter and PTD related to PROM. This study emphasised the need for further investigation of functional variants of cytokine genes and PTD.

TNF-α gene

Two functional polymorphisms have been identified in the promoter region of the TNF-α gene. The first is a G [RIGHTWARDS ARROW] A transition at position –308.41,42 This mutation is associated with higher constitutive and inducible levels of transcription of the gene.42 Increased levels of TNF-α protein have been confirmed clinically.43 This polymorphism can be detected by enzymatic digestion with Nco1. Following enzymatic digestion, the resultant alleles are referred to as either TNF T1 or TNF T2. With the use of chloramphenicol acetyltransferase reporter gene assays, the TNF T2 allele has been shown to result in elevated levels of the TNF-α protein.42 The second mutation occurs at position –238 in the promoter region of the TNF-α gene.44 This is another G [RIGHTWARDS ARROW] A transition designated as the TNFA-A allele, which has been associated with genetic susceptibility to pulmonary tuberculosis, liver disease, and insulin resistance.

IL-6 gene

A novel polymorphism in the IL-6 gene has been associated with increased transcription and plasma levels of IL-6. Clinically, an association of this polymorphism with juvenile onset chronic arthritis has been established.45 The polymorphism to be studied is a G [RIGHTWARDS ARROW] C transition at position –174 in the promoter region of the IL-6 gene.

IL-10 gene

IL-10 has been shown to inhibit the secretion of a variety of cytokines including TNF-α, IL-6, IL-8 and IL-12 from monocytes/macrophages and interferon-γ, and IL-2 from T cells. The gene encoding IL-10 has been cloned, sequenced, and localised to chromosome 1. Three polymorphisms in the promoter region of the IL-10 gene occur at positions –1082, –819, and –592 relative to the transcriptional start site. A G [RIGHTWARDS ARROW] A polymorphism at –1082 has been shown to be associated with increased inducible levels of IL-10. The A allele is associated with an increase in inducible IL-10 production.46

Conclusions

  1. Top of page
  2. Abstract
  3. Evidence supporting a genetic predisposition to preterm delivery (PTD)
  4. Molecular methods for studying PTD
  5. Plausible candidate genes
  6. Conclusions
  7. References

PTD can be a devastating event with long-term complications for the offspring. Furthermore, prematurity and low birthweight place a significant psychological and economic impact upon affected individuals, their families, and society. The USA’s health care delivery system is responsible for the expenditure of millions of dollars for the medical care of the premature infant. If a gene or genes are identified as being associated with PTD, then this may be used as a screening test in the general obstetric population during routine prenatal laboratory evaluation. Furthermore, we speculate that an individual identified as having a genetic predisposition to elevated cytokine levels may benefit from early screening and treatment of common vaginal organisms such as group B streptococcus and bacterial vaginosis.

If an association of a functional variant of a cytokine gene with PTD is observed, then future studies may emphasise prospective randomised clinical studies in women identified as carriers. One might propose a genetic screening test for a cytokine mutation at the time of their routine prenatal laboratory evaluation. If an individual is identified as being a carrier, then she could be assigned to earlier than customary screening and treatment for group B streptococcus and bacterial vaginosis vs. standard routine evaluation.

References

  1. Top of page
  2. Abstract
  3. Evidence supporting a genetic predisposition to preterm delivery (PTD)
  4. Molecular methods for studying PTD
  5. Plausible candidate genes
  6. Conclusions
  7. References
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