Parental exposure to environmental toxicants, GSTM1 and GSTT1 polymorphisms and the risk of congenital heart disease
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1 Parental exposure to environmental toxicants, GSTM1 and GSTT1 polymorphisms and the risk of congenital heart disease Monica Cresci, Ilenia Foffa, Maria Giovanna Neri, Lamia Ait-Ali, Nicoletta Botto and Maria Grazia Andreassi Genetics Research Unit, Institute of Clinical Physiology, IFC-CNR, Genetics Research Unit, Fondazione G. Monasterio CNR-Regione Toscana, Institute of Clinical Physiology,CNR, Massa Italy Massa Italy
2 Incidence of Congenital Heart Disease CHD is the most prevalent all birth defects Leading cause of death in first year of life in the Western Countries Moderate and severe CHD: 1 per 100 without BAV and 2 per 100 with BAV 7.5 per 100 live births (small VSDs included in Boneva et al. Circulation 2001 series) Hoffman and Kaplan JACC 2002
3 Estimated cases of Grown-up CHD Adult with congenital heart disease in USA Knowledge of etiology causing CHD is of great clinical importance in order to better understand: risk factors molecular and pathogenic mechanisms genetic counselling Deanfield J, et al. Eur Heart J. 2003
4 Baltimore-Washington Infant Study ENVIRONMENTAL EXPOSURES DURING THE FETAL PERIOD Father radiation exposure in the 30 weeks before conception Correa-Villasenor A et al. J Expo Annal Environment Epidemiol 1993
5 Paternal Exposure and health in offspring Chapin et al. et Environ al Health Perspect 2004
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8 Aim To evaluate the association between environmental exposures of both parents and CHD. To explore the modification effect of genetic susceptibility in patients who lack capacity to produce glutathione S-transferase enzymes (GSTM1 and GSTT1).
9 Study Population Epidemiological study Paired case-control study (1:1) of 330 parents of a child with isolated CHD and 330 parents of child without any congenital malformations. Genetic study In a case-only design, DNA was obtained from 165 CHD patients (95 male, 6.3±7.2 years).
10 Methods Epidemiological study Both case and control parents completed a structured questionnaire on demographics, preconceptional and lifestyle exposures. Potential teratogens/mutagens linked to human reproductive impairment: ionizing radiation, solvents, pesticides, and heavy metals. Paternal questionnaire: carefully evaluation the period of 3 months before conception, based on the duration of spermatogenesis (about 70 days). Maternal questionnaire: period before conception to the end of the first trimester of pregnancy.. Genomic DNA PCR-analysis Genetic study GSTM1 and GSTT1 genotypes were determined using a coamplification polymerase chain reaction (PCR) approach with GSTM4 gene, which is never deleted, as control.
11 Baseline characteristics of the study population
12 Pre- and peri-conceptional characteristics of the parents and the risk of CHD Fathers who were smokers showed an increased risk of CHD Both maternal and paternal exposure to toxicants increased the risk of CHD
13 OR Risk factor: smoking p=0.01 p= Both parents who were heavy smokers ( 20cigarettes/day ) had a significant high risk to have offspring with CHD
14 OR Risk factor: toxicants p < p < Occupational Exposure: Ex. Ionizing radiation, chemical substances, pesticides, hydrocarbons, heavy metals Environmental exposure: Ex. Electrical industries, industries, electromagnetic radiation, landfill, mother s diseases (gestational ( infection diabetes and viral
15 OR OR ADDITIVE EFFECT Smoking Smoking by both as well as the exposure to p=0.04 p=0.03 toxicants of both parents showed a significant additive risk Toxicant exposure p<0.001
16 OR OR OR PARENTAL EXPOSURE, GLUTATHIONE S-TRANSFERASE GENETIC POLYMORPHISMS AND RISK FOR CONGENITAL HEART DEFECTS Genotype combinations GSTM1 wild GSTT1 wild Either GSTM1 null or GSTT1 null genotype GSTM1 null GSTT1 null Maternal exposure (%) n No, n(%) Yes, 47 (43.5) 14 (24.6) 53 (49.1) 36 (63.1) 8 (7.4) 7 (12.3) Paternal exposure (%) n No, n(%) Yes, 43 (44.4) 21 (28.0) 43 (47.4) 46 (61.3) 7 (7.8) 8 (10.7) Maternal exposure to toxicants Paternal exposure to toxicants Exposure to toxicants and GST in children with CHD * * * * * * GSTM1 /GSTT1
17 Conclusions Environmental toxicant exposure of both parents affects the risk of children with CHD. Polymorphisms in GSTs genes can modify a person s risk for toxicant exposuredisease.
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