Genetics to Genomics: A Framework for Approaching Preterm Birth as a

Common Complex Disorder

Genetics, Genomics, Epidemiology, and MCH

December 6, 2008

Siobhan Dolan, MD, MPH

Assistant Professor of Obstetrics & Gynecology and Women’s Health Albert Einstein College of Medicine, Bronx, NY

9.611.0

12.3

7.6

12.5

0

5

10

15

1983 1993 2003 2004

Preterm is less than 37 completed weeks gestation.Source: National Center for Health Statistics, final natality dataPrepared by March of Dimes Perinatal Data Center, 2005

Pe

rce

nt

HP 2010 Objective

Preterm Birth RatesUnited States, 1983, 1993, 2003, 2004*

Percent

30 Percent Increase

Objectives

• Discuss risk factors and clinical approaches to preterm birth

• Outline genetics and genomics principles

• Introduce preterm birth as a common complex disorder

• Propose a framework for a genomic approach to research in preterm birth

Changing Epidemiology of Preterm Birth

Major categories of risk for preterm birth

Major Categories of Risk for Preterm Birth

Extremes of maternal age

Unintended pregnancy

34, 35, 36 weeks

Maternal race

Multiple gestation

Cesarean section

Clinical Approaches to the Management of Preterm Birth

Types of Preterm BirthTypes of Preterm Birth

SpontaneousPreterm Labor

SpontaneousPremature Ruptureof the Membranes

MedicalIntervention

PretermBirth

While this suggests distinct pathways, many of the risk factors for all 3 are similar.

Major Categories of Risk for Preterm Labor/Delivery

General maternal issues:• Medical and Obstetric History

• Behaviors

• Genetics

• Environmental

Risk Factors for Preterm Labor/Delivery

• The best predictor of having a preterm birth is multifetal gestation or history of preterm labor/delivery

• Other risk factors:

–multifetal pregnancy–maternal age (<17 and >35

years)–black race–low SES–unmarried–previous fetal or neonatal death–3+ spontaneous losses–uterine abnormalities–incompetent cervix–genetic predisposition

–low pre-pregnant weight–obesity–infections–bleeding –anemia –major stress –lack of social supports–tobacco use–illicit drug use–alcohol abuse–folic acid deficiency

American Journal of Public Health, March 2004

Risk Factors for Preterm Labor/Delivery

• The best predictor of having a preterm birth is multifetal gestation or history of preterm labor/delivery

• Other risk factors:

–multifetal pregnancy–maternal age (<17 and >35

years)–black race–low SES–unmarried–previous fetal or neonatal death–3+ spontaneous losses–uterine abnormalities–incompetent cervix–genetic predisposition

–low pre-pregnant weight–obesity–infections–bleeding –anemia –major stress –lack of social supports–tobacco use–illicit drug use–alcohol abuse–folic acid deficiency

Genetics:

The study of the patterns of inheritance of

specific traits.

Pedigree

Multifactorial - Neural Tube Defect

Preterm Birth is a Common Complex Disorder

Complex

• “Complex genetic traits refer to those phenotypes not fitting patterns of Mendelian segregation and/or assortment but exhibiting a preferential familial clustering that cannot be explained by cultural or environmental causes.”

Muenke et al. Genet Med 2004:6(1):1-15.

Complex Disorders

• 1. Genetic contribution

• 2. Environmental influences

• 3. Gene-environment interactions

Complex Disorders

• Genetic contribution– Familial aggregation– Recurrence of preterm birth– Racial disparity

The Risk of Preterm Birth Across Generations

Porter et al. Obstetrics & Gynecology. 1997;90:63-67.

Objective: To examine the risk of preterm birth for mothers who themselves were born before term.

1405 preterm mothers

2781 term mothers

Conclusions: An increased risk of preterm delivery exists for women who themselves were born before 37 weeks gestation. This risk is inversely correlated with the maternal gestational age at birth and is influenced by maternal age and parity.

Genetic influence on birthweight and gestational length determined by studies in

offspring of twins

Clausson et al. BJOG. 107:375-381. 2000.

Objective: To determine the relative importance of genetic effects on birthweight, gestational length and small for gestational age.

868 monozygotic female twin pairs

1141 dizygotic female twin pairs

Conclusions: Concordance rates and intra-class correlations for birthweight, gestational length and small for gestational age were consistently higher in monozygotic compared with dizygotic twins. Model fitting suggested heritability estimates in the range from 25% to 40%.

** PRETERM BIRTH = 36% (0.03 – 0.51) **

Maternal and Paternal Influences on Length of Pregnancy

Lie et al. Obstet Gynecol 2006;107:880-5.

Methods: 77,452 boys and girls in the Medical Birth Registry of Norway who later became parents themselves. Records were linked between parents and children.

Results: Gestational age of the child at birth increased on average 0.58 days for each additional week in the father’s gestational age (0.48-0.67) and 1.22 days for each additional week in the mother’s gestational age (1.21-1.32).

Complex Disorders

• Genetic contribution

• Environmental influences

• Gene-environment interactions

Complex Disorders

• Environmental influences

– Smoking

– Infection

– Stress

Complex Disorders

• Genetic contribution

• Environmental influences

• Gene-environment interactions

Maternal Cigarette Smoking, Metabolic Gene Polymorphism, and Infant Birth

Weight

Wang et al. JAMA. 2002;287:195-202.

Objective: To investigate whether the association between maternal cigarette smoking and infant birth weight differs by polymorphisms of 2 maternal metabolic genes: CYP1A1 and GSTT1.

741 mothers with singleton livebirths•174 ever smokers•567 never smokers

207 cases low-birth-weight or preterm

534 controls

Maternal Cigarette Smoking, Metabolic Gene Polymorphism, and Infant Birth Weight

Wang et al. JAMA. 2002;287:195-202.

Conclusions: Maternal CYP1A1 and GSTT1 genotypes modified the association between maternal cigarette smoking and infant birth weight,

suggesting an interaction between metabolic genes and cigarette smoking.

Smoking CYP1A1 GSTT1 # Gestation, Week (SE)

P value

Never AA Present 251 ReferentNever AA Absent 72 0.9 (0.4) .03Never Aa/aa Present 182 0.2 (0.3) .46Never Aa/aa Absent 62 0.2 (0.5) .64Continuous AA Present 58 -0.4 (0.5) .40Continuous AA Absent 177 0.3 (0.8) .75Continuous Aa/aa Present 38 -0.01 (0.6) .99Continuous Aa/aa Absent 11 -5.2 (1.0) <.001Test of interactionCrude

-5.5 (1.0) <.001

Test of interactionAdjusted

-5.4 (1.0) <.001

A polymorphism in the promoter region of TNF and bacterial vaginosis: Preliminary evidence of gene-environment interaction

in the etiology of spontaneous preterm birth

Macones et al. AJOG. 2004;190:1504-8.

Objective: To assess if the presence of symptomatic bacterial vaginosis amplifies the risk of spontaneous preterm birth in those with a “susceptible” TNF genotype (TNF-2).

125 cases: delivered before 37 weeks

as a result of ruptured membranes

or preterm labor

250 controls: delivered after 37 weeks

A polymorphism in the promoter region of TNF and bacterial vaginosis: Preliminary evidence of gene-environment interaction

in the etiology of spontaneous preterm birth

Macones et al. AJOG. 2004;190:1504-8.

Conclusion: This study provides preliminary evidence that an interaction between genetic susceptibilities (TNF-2 carriers) and environmental factors (BV) is associated with an increased risk of spontaneous preterm birth.

Group % TNF-2 carriers %TNF-2 carriers OR (95% CI)

in cases in controls

Overall 45% 23% 2.1 (1.7-4.5)

BV Positive 69% 27% 6.1 (1.9-21.0)

BV Negative 34% 22% 1.7 (1.0-3.1)

Genomics:

All of the structure and function of an entire genome (e.g., the human genome),

including its sequences, structures, regulation, interactions, and products.

Genome:

All of the genetic material (DNA) belonging

to a particular organism.

“HuGE”:

Human Genome Epidemiology

Framework for a Genomic Approach to Preterm Birth

Pathways to Preterm Birth• Inflammation / Infection (ascending), 40%

• Stress (maternal/fetal), 25%

• Bleeding / Clotting Abnormality (thrombophilia, decidual hemorrhage, abruption), 25%

• Abnormal Uterine Distension (stretching), 10%

proteases

Uterine Contraction

s

Cervical Change

• Infection: - Chorion-Decidual - Systemic

DecidualHemorrhag

eAbruption

CRHE1-E3

Prothrombin G20210AFactor V LeidenProtein C, S, ZType 1 PlasminogenMTHFR

PathologicalUterine

Distention

• Multifetal Preg• Polyhydramnios• Uterine

abnormalities

Inflammation

• Maternal-Fetal Stress

• Premature Onset of Physiologic Initiators

Activation of Maternal/Feta

l HPA Axis

CRH

+

+ChorionDeciduaChorionDecidua

uterotonins

Mechanical stretchGap jct

IL-8 PGE2

Oxytocin recep

pPROM

InterleukinsIL-1, IL-5, IL-8TNF- Fas L

Adapted from: Lockwood CJ, Paediatr Perinat Epidemiol 2001;15:78 and Wang X, et al. Paediatr Perinat Epidemiol 2001; 15: 63

Susceptibility to

Environmental toxins

CYP1A1GSTT1

MMPs

PTB

Common Complex Disorders

• “From a public health perspective, genes with mutations that are less highly penetrant but much more prevalent have a greater effect on the population than genes that are highly penetrant but uncommon.”

Guttmacher AE, Collins FS. Genomic Medicine – A Primer. N Engl J Med 2002:347(19):1512-1520.

Genomics ...

• Allows us to consider genetic variation as the background for environmental influences

• Encourages research to examine gene-environment interactions

Genomics ...

• May enhance our understanding of the mechanisms of disease and allow us to target or expand clinical interventions and public health strategies

Prevalence of spina bifida and anencephaly among all 24 surveillance programs

1995 1996 1997 198 1999 2000

Pre-fortification Optional Fortification Mandatory Fortification

2001

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Spina bifida

Anencephaly

Teratology 2002; 66:33-39. Updated 6/2004.

Source: Cummings AM, Kavlock RJ. Crit Rev Toxicol 2004;34:461-85.

Folate Metabolism

Botto, LD, Yang Q. 2000. Am J Epidemiol. 151:862.

MTHFR Gene - 1p36.3

• Polymorphism (variant) at position 677• Thymine is substituted for cytosine

Association with NTDs:

OR 95% CI• homozygotes 1.8 1.4-2.2• heterozygotes 1.2 0.99-1.3

Genomics ...

• Highlights the role of family history

Protocol for Folic AcidProtocol for Folic Acid

Average Risk

HighRisk

Routine components of preconception & prenatal care

Routine components of preconception & prenatal care

Targeted 4 mg folic acid supplement

+

Assess Personal

and Family History

Hypothetical Protocol for PretermHypothetical Protocol for Preterm

Average Risk

HighRisk

Extremely High Risk

Routine components of preconception & prenatal care

Routine components of preconception & prenatal care

Routine components of preconception & prenatal care

Targeted smoking cessation and weight reduction

Targeted smoking cessation and weight reduction

Consider progesterone+

+

+

Assess Family History

Genetic and Genomic approaches do not replace but

can add to:

• Community based interventions

• Patient / Consumer education

• Provider education

• Equity in health outcomes and health care

Common Complex Disorders

• “The study of genomics will most likely make its greatest contribution to health by revealing mechanisms of common, complex diseases, such as hypertension, diabetes, and asthma.”

Guttmacher AE, Collins FS. Genomic Medicine – A Primer. N Engl J Med 2002:347(19):1512-1520.

Common Complex Disorders

• “The study of genomics will most likely make its greatest contribution to health by revealing mechanisms of common, complex diseases, such as hypertension, diabetes, and asthma.” … birth defects and preterm birth.

Guttmacher AE, Collins FS. Genomic Medicine – A Primer. N Engl J Med 2002:347(19):1512-1520.

Thank you for your attention!