MOUNT SINAI JOURNAL OF MEDICINE 77:160–165, 2010 160

Genetic andEnvironmental Contributions to

Racial Disparities in Preterm BirthSiobhan M. Dolan, MD, MPH

Department of Obstetrics and Gynecology and Women’s Health, Albert Einstein College of Medicine,Bronx, NY

OUTLINE

PRETERM BIRTH

GENETIC CONTRIBUTION TO

PRETERM BIRTH

GENE-ENVIRONMENT INTERACTIONS

PATHOPHYSIOLOGICAL PATHWAYS TO PRETERM BIRTH

InflammationMaternal/Fetal StressUterine DistensionDecidual HemorrhageMetabolic Enzymes

CONCLUSION

ABSTRACT

The preterm birth rate exceeds 12% in the UnitedStates, and preterm birth continues to be a clinicaland public health challenge globally. Even thoughpreterm birth is a major contributor to infantmortality and lifelong morbidity, there are feweffective strategies to predict preterm birth and fewclinical interventions to prevent it. Genomic researchapproaches that identify risk factors at the intersectionof genetics and the environment will likely provideinsights. Both genetic and environmental factors areknown to contribute to the racial disparity seen inpreterm birth. Through the identification of relevant

Address Correspondence to:

Siobhan M. DolanDepartment of Obstetrics and

Gynecology and Women’sHealth

Albert Einstein College ofMedicine

Bronx, NYEmail: siobhanmdolan@yahoo.com

gene-environment interactions that contribute topreterm birth and may underlie the racial disparity inpreterm birth, research that will translate to clinicalpractice and ultimately prevent a number of pretermbirths is possible. Mt Sinai J Med 77:160–165,2010. 2010 Mount Sinai School of Medicine

Key Words: common complex disorder, genetics,genomics, preterm birth.

The preterm birth rate exceeds 12% in the UnitedStates, and preterm birth continues to be a clinicaland public health challenge globally.1 Persistentracial disparities have been observed. In 2007, therate of preterm birth in the United States washighest for black infants (18.3%), who were followedby Native Americans (13.9%), Hispanics (12.3%),whites (11.5%), and Asians (10.9%; Figure 1).2

In 2007, the rate of preterm birthin the United States was highest forblack infants (18.3%), who werefollowed by Native Americans(13.9%), Hispanics (12.3%),whites (11.5%), and Asians(10.9%).

Defined as birth before the completion of 37 weeksof gestation, preterm birth is the leading causeof infant mortality (from birth to 1 year of life)among black infants and the second leading causeamong all infants.3 In analyses that used a moreinclusive classification of preterm-related causes ofdeath, an even higher proportion of infant deaths(36.5% in 2006) were attributed to preterm birth,4

and the preterm-related infant mortality rate for blackinfants was 3.5 times higher than that for whites.5

However, despite the impact of preterm birth on birthoutcomes and lifelong health, there are few effective

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2010 Mount Sinai School of Medicine

MOUNT SINAI JOURNAL OF MEDICINE 161

Fig 1. Preterm births by race/ethnicity: United States, 2004–2006 average.Reprinted with permission from the March of Dimes Foundation.47

strategies to predict or prevent it. Furthermore, theexplanation for the persistent racial disparity is poorlyunderstood. There is tremendous interest in using thenew research directions that genetics and genomicscan provide to better understand the etiology andracial disparities in preterm birth.

PRETERM BIRTH

Many sociodemographic risk factors for preterm birthhave been identified. In the United States, racialvariation in preterm birth has been consistentlyidentified and likely reflects genetic predisposition,environmental factors including differential access tocare and varying socioeconomic status, and a com-plex interplay of gene-environment interactions.6,7

In the United States, racialvariation in preterm birth likelyreflects genetic predisposition,environmental factors includingdifferential access to care andvarying socioeconomic status, anda complex interplay ofgene-environment interactions.

Other factors known to increase the risk ofpreterm birth include cigarette smoking,8 extremesof maternal age (younger women and older women),multiple gestation,9 and use of assisted reproductivetechnology in singletons as well as multiple births.10

Much of the increase in the preterm birth rate overrecent years can be attributed to increases in late

preterm births between 34 0/7 and 36 6/7 weeks ofgestation.11

A major challenge in studying preterm birth isconsistency in the definition of preterm birth. Pretermbirth following spontaneous labor may be distinctfrom that following preterm premature rupture ofthe membranes (PPROM), and thus a clearly definedphenotype is of utmost importance in performingresearch.12 Among epidemiological correlates ofpreterm birth, one of the most consistent is thatthe risk of preterm birth is increased in womenwith a previous preterm birth.13 Traditionally, thisobservation has been explained by the persistence ofenvironmental risk factors such as poverty, stress, andlimited access to prenatal care as well as social andnutritional deficits that secondarily increase the risk ofinfections and other medical disorders.7,14 However,the increased recurrence risk may also be explainedby genetic susceptibility that persistently regulates awoman’s response to environmental stressors.

GENETIC CONTRIBUTION TOPRETERM BIRTH

In a familial aggregation study in Utah, Porteret al.15 demonstrated that a component of pretermbirth risk is heritable. Using linked birth cohortscomposed of 1405 preterm mothers and 2781 termmothers, they showed an increased risk of pretermdelivery for women who themselves were bornbefore 37 weeks of gestation (odds ratio = 1.18,95% confidence interval = 1.02, 1.37). Furthermore,a dose-response relationship was demonstratedbetween a mother’s own gestational age at birthand her risk of delivering her child preterm,with mothers born earlier at increased risk of

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162 S. M. DOLAN: RACIAL DISPARITIES IN PRETERM BIRTH

Porter et al. demonstrated that acomponent of preterm birth risk isheritable. Using linked birthcohorts composed of 1405 pretermmothers and 2781 term mothers,they showed an increased risk ofpreterm delivery for women whothemselves were born before37 weeks of gestation.

delivering their children preterm. More recent workhas affirmed the maternal contribution to pretermbirth and demonstrated a paternal contribution, albeitsmaller, as well.16,17

Subsequent twin studies were conducted todetermine the relative importance of genetic effectson gestational length. In a Swedish study,18 twinconcordance rates and intraclass correlation forgestational length were consistently higher inmonozygotic twins than dizygotic twins, and thissuggested a genetic contribution to gestational lengthwith a heritability index for preterm birth in therange of 36% (95% confidence interval = 0.03–0.51).Similarly, a twin study from Australia revealed aheritability index ranging from 17% to 27%.19 Thesestudies suggest that somewhere between a quarterand a third of the variation in the risk of pretermbirth is attributable to genetic influences.

In considering genetics, race is important as itnot only reflects social and cultural affiliation butoften can serve as a proxy for geographic ances-try. The fact that race can provide some cluesabout shared ancestry and therefore shared genet-ics is important but complicated as the relationshipbetween race and genetics is not precise.20–22 Fur-thermore, race can also be a proxy for other factorssuch as discrimination and inequities that have littleto do with genetics but underpin racial dispari-ties in health outcomes, including preterm birth.

Although race can serve as aproxy for geographic ancestry racecan also be a proxy for otherfactors such as discriminationand inequities that have little to dowith genetics but underpin racialdisparities in health outcomes,including preterm birth.

GENE-ENVIRONMENT INTERACTIONS

A gene-environment interaction is defined as ‘‘adifferent effect of an environmental exposure ondisease risk in persons with different genotypes.’’23

Evidence for the contribution of gene-environmentinteractions to the occurrence of low birthweightand preterm birth was put forth by Wang et al.24 in2002. Their study examined whether the associationbetween maternal cigarette smoking and pretermbirth differed with polymorphisms of 2 maternalcytochrome p450 genes, cytochrome P450 1A1(CYP1A1) and glutathione S-transferase theta 1(GSTT1). Women who smoked and had the particularpolymorphisms under study delivered more than5 weeks earlier than nonsmokers without the geneticvariants. This effect was greater than the sum ofthe individual effects of the polymorphisms andmaternal smoking. The identification of a subgroupof women who would benefit tremendously fromtargeted smoking cessation efforts illustrates thepotential offered by the genomic approach.

PATHOPHYSIOLOGICAL PATHWAYSTO PRETERM BIRTH

The genomic approach to preterm birth sug-gests that a combination of common genetic vari-ants (polymorphisms), while not explicitly caus-ing disease, will render some women moresusceptible to the environmental influences thatare well known to contribute to preterm birth.

The genomic approach to pretermbirth suggests that a combinationof common genetic variants(polymorphisms), while notexplicitly causing disease, willrender some women moresusceptible to the environmentalinfluences that are well known tocontribute to preterm birth.

To understand where candidate polymorphismsmight lie, pathophysiological pathways leading topreterm birth can be analyzed for specific geneticvariants that are consistently associated with a higherrisk of preterm birth. Although these pathwaysmight overlap and intersect, they have traditionallyincluded (1) inflammation, (2) maternal/fetal stress,

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(3) uterine distension, (4) decidual hemorrhage, and(5) metabolic enzymes.25,26

Inflammation

Inflammatory responses are often initiated by expo-sure to foreign pathogens. Several studies havelooked at the association between single nucleotidepolymorphisms (SNPs) in the gene for the inflam-matory mediator tumor necrosis factor α (TNF-α)27,28

and preterm birth and the role that race might play.TNF-α is part of the major histocompatibility complexon chromosome 6p, and it has a promoter region at−308 bp that has been shown to be highly poly-morphic in the population. Dizon-Townson et al.27

used a case control study design to show that a vari-ant in the promoter region, TNF T2, which increasestranscription of the gene, was not more frequent inwomen who delivered preterm versus women whodelivered at term. In a case control study restrictedto African American women who experienced aprevious spontaneous preterm birth (one that fol-lowed preterm labor or PPROM), Roberts et al.28

found that carriage of 1 TNF T2 polymorphismwas a risk factor for PPROM (odds ratio = 3.18,95% confidence interval = 1.33–7.83, P = 0.008).Another study provided preliminary data suggestingthat TNF-α modifies susceptibility to bacterial vagi-nosis and that race/ethnicity modifies the relationshipbetween TNF-α and preterm birth.29 Finally, a meta-analysis of the association between the SNP in theTNF-α gene (G-308>A) and preterm birth failed toshow a statistically significant association.30 This illus-trates the challenge of identifying robust gene-diseaseassociations.31 However, this line of research contin-ues to be productive as Menon et al.32 demonstratedhigher TNF-α concentrations in the amniotic fluid ofblack women delivering preterm in comparison withwhites, and they have performed genetic studies sug-gesting that race may play a key role in a differentialinflammatory response that contributes to pretermbirth, especially among blacks.33–35

Maternal/Fetal Stress

The maternal/fetal stress pathway to pretermbirth has identified a key role for stress hor-mones, including corticotropin-releasing hormone.36

Corticotropin-releasing hormone, which is highlypolymorphic in various populations and whose levelshave been correlated with pregnancy outcome,37,38

is a candidate for further study of polymorphisms.Recent research has found that high maternal urinarycatecholamine levels in women who go on to have a

preterm birth may suggest excess stress and/or a pre-disposition to elevated sympathetic activation.39 Thecomplex interplay between race and stress that con-tributes to preterm birth continues to be the subjectof promising research.

Uterine Distension

Uterine factors in abnormal uterine distension andcervical function may also be influenced by geneticvariation. Matrix metalloproteinases, which affecttissue remodeling, are candidates for polymorphicvariation in women who deliver preterm versus thosewho deliver at term.40

Matrix metalloproteinases play a role in PPROM,which often precedes preterm birth.41 AfricanAmerican women have been found to be at increasedrisk for PPROM, and thus PPROM may factor intothe higher rate of preterm birth for black women.In an interesting line of research, Wang et al.42

identified a functional SNP in the promoter ofthe serpin peptidase inhibitor clade H member 1(SERPINH1) gene that had a greater frequency inAfrican Americans versus European Americans. Thevariant in SERPINH1, which plays a role in collagensynthesis, was associated with PPROM in a casecontrol study of preterm birth, and this supports thehypothesis that genetic variation explains some ofthe racial disparity seen in preterm birth.

Decidual Hemorrhage

The contribution of genetic variation to inheritedthrombophilias that predispose to poor perinataloutcomes, including preterm birth and multiplemiscarriages,43 is well established. The descriptionof variants in factor V Leiden, prothrombin G20210A,methylenetetrahydrofolate reductase, and the type 1plasminogen activator inhibitor gene44 has alreadyestablished the scientific basis for some clinicalinterventions in the form of anticoagulation45 andhas allowed the initiation of studies designed toevaluate women with preterm birth with respectto these variants. Such studies will also needto consider the interaction between these geneticvariants and race/ethnicity as they contribute topreterm birth.

Metabolic Enzymes

As cited previously, Wang et al.24 reported 2polymorphic maternal metabolic genes, CYP1A1 andGSTT1, that are part of the cytochrome p450 system

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164 S. M. DOLAN: RACIAL DISPARITIES IN PRETERM BIRTH

and contribute to the detoxification of smokingbyproducts. Certainly, there are many metabolicenzymes that are essential to achieving homeostasis.There is still the challenge of identifying additionalrelevant enzymes that are polymorphic in thepopulation and that increase susceptibility to pretermbirth by participating in key gene-environmentinteractions, which may contribute to the racialdisparity seen in preterm birth.

CONCLUSION

The prevention of preterm birth will require a reeval-uation of clinical practice, a focus on disparities, anda comprehensive research strategy using genomicapproaches. Screening tools, including questionsabout the personal and family history of pretermbirth, will allow targeted risk factor reduction strate-gies for high-risk women, including African Americanwomen who are at increased risk. In practical terms,a woman with a positive personal or family historyof preterm birth should be offered preconceptioncare that includes targeted smoking cessation inter-vention, screening for infection, and consideration ofprogesterone supplementation. An increased under-standing of the racial disparity seen in preterm birthand the identification of genetic contributions topreterm birth as well as environmental influences andgene-environment interactions will allow the toolsand promise of the genomic era to open researchand therapeutic opportunities to improve pregnancyoutcomes.46

ACKNOWLEDGMENT

This article was presented on November 17, 2008, atthe Mt. Sinai School of Medicine in New York Cityas part of the conference Achieving Health Equity:Genes, Race, Ethnicity and the Environment.

DISCLOSURES

Potential conflict of interest: Nothing to report.

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