genetics to genomics: a framework for approaching preterm birth as a common complex disorder...
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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
0.0
1.0
2.0
3.0
4.0
5.0
6.0
Pre
vale
nce
(p
er
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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!