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Cardiovascular Toxicology

Erschienen in:

28.11.2017

A Functional Aryl Hydrocarbon Receptor Genetic Variant, Alone and in Combination with Parental Exposure, is a Risk Factor for Congenital Heart Disease

verfasst von: Silvia Pulignani, Andrea Borghini, Cecilia Vecoli, Ilenia Foffa, Lamia Ait-Ali, Maria Grazia Andreassi

Erschienen in: Cardiovascular Toxicology | Ausgabe 3/2018

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Abstract

Recent experimental studies showed that ablation of the aryl hydrocarbon receptor (AhR) as well as its activation by exogenous ligands disrupt the molecular networks involved in heart formation and function, leading to congenital heart disease (CHD). However, no evidence is available about the role of AhR in humans. We assessed the prevalence of a functional AhR genetic variant (p.Arg554Lys) in CHD patients as well as its joint effects with parental exposure. A total of 128 CHD patients (76 males; age 6.2 ± 6.7 years) and 274 controls (160 males; age at birth) were genotyped for the AhR polymorphism by using the TaqMan^® Drug Metabolism Genotyping assay. Both case and control parents completed a structured questionnaire on demographic, lifestyle and preconception exposures. Genotype (p = 0.001) and allele (p < 0.0001) distributions of AhR p.Arg554Lys differed significantly between patients and controls. A significant elevated CHD risk was found under dominant (OR = 2.9, 95% CI 1.9–4.6, p < 0.0001) and additive genetic models (OR = 6.2, 95% CI 2–19, p = 0.001). There was a significant interaction between 554-Lys allele and paternal smoking exposure (OR_smoking = 1.6, 95% CI = 0.9–2.9; OR_allele = 2.6, 95% CI = 1.3–5; OR_interaction = 4.9, 95% CI = 2.4–9.9, p _interaction < 0.0001). Additionally, 554-Lys allele exacerbated the effect of maternal periconceptional exposure (OR_exposure = 1.6, 95% CI = 0.8–3; OR_allele = 2.6, 95% CI = 1.5–4.5; OR_interaction = 5.7; 95% CI = 2.6–12, p _interaction < 0.0001). Our findings showed that the AhR p.Arg554Lys polymorphism, alone and in combination with parental exposures, is associated with the CHD risk, highlighting the significant role of AhR in the cardiovascular development.

Van der Linde, D., Konings, E. E., Slager, M. A., Witsenburg, M., Helbing, W. A., Takkenberg, J. J., et al. (2011). Birth prevalence of congenital heart disease worldwide: A systematic review and meta-analysis. JACC, 58, 2241–2247.CrossRefPubMed

Bouma, B. J., & Mulder, B. J. M. (2017). Changing landscape of congenital heart disease. Circulation Research, 120, 908–922.CrossRefPubMed

Van der Bom, T., Zomer, C. A., Zwinderman, A. H., Meijboom, F. J., Bouma, B. J., & Mulder, B. J. (2011). The changing epidemiology of congenital heart disease. Nature Reviews Cardiology, 8, 50–60.CrossRefPubMed

Sabina, S., Pulignani, S., Rizzo, M., Cresci, M., Vecoli, C., Foffa, I., et al. (2013). Germline hereditary, somatic mutations and microRNAs targeting-SNPs in congenital heart defects. Journal of Molecular and Cellular Cardiology, 60, 84–89.CrossRefPubMed

Vecoli, C., Pulignani, S., Foffa, I., & Andreassi, M. G. (2014). Congenital heart disease: The crossroads of genetics, epigenetics and environment. Current Genomics, 15, 390–399.CrossRefPubMedPubMedCentral

Donofrio, M. T., Moon-Grady, A. J., Hornberger, L. K., Copel, J. A., Sklansky, M. S., Abuhamad, A., et al. (2014). Diagnosis and treatment of fetal cardiac disease: A scientific statement from the American Heart Association. Circulation, 129, 2183–2242.CrossRefPubMed

Cresci, M., Foffa, I., Ait-Ali, L., Pulignani, S., Gianicolo, E. A., Botto, N., et al. (2011). Maternal and paternal environmental risk factors, metabolizing GSTM1 and GSTT1 polymorphisms, and congenital heart disease. American Journal of Cardiology, 108, 1625–1631.CrossRefPubMed

Cresci, M., Vecoli, C., Foffa, I., Pulignani, S., Ait-Ali, L., & Andreassi, M. G. (2013). Lack of association of the 3′-UTR polymorphism (rs1017) in the ISL1 gene and risk of congenital heart disease in the white population. Pediatric Cardiology, 34, 938–941.CrossRefPubMed

Deng, K., Liu, Z., Lin, Y., Mu, D., Chen, X., Li, J., et al. (2013). Periconceptional paternal smoking and the risk of congenital heart defects: A case-control study. Birth Defects Research Part A: Clinical and Molecular Teratology, 97, 210–216.CrossRefPubMed

10.

Wang, C., Xie, L., Zhou, K., Zhan, Y., Li, Y., Li, H., et al. (2013). Increased risk for congenital heart defects in children carrying the ABCB1 Gene C3435T polymorphism and maternal periconceptional toxicants exposure. PLoS One, 8, e68807.CrossRefPubMedPubMedCentral

11.

Tang, X., Hobbs, C. A., Cleves, M. A., Erickson, S. W., MacLeod, S. L., Malik, S., et al. (2015). Genetic variation affects congenital heart defect susceptibility in offspring exposed to maternal tobacco use. Birth Defects Research Part A: Clinical and Molecular Teratology, 103(10), 834–842.CrossRefPubMedPubMedCentral

12.

Li, X., Liu, Z., Deng, Y., Li, S., Mu, D., Tian, X., et al. (2015). Modification of the association between maternal smoke exposure and congenital heart defects by polymorphisms in glutathione S-transferase genes. Scientific Reports, 5, 14915.CrossRefPubMedPubMedCentral

13.

Wang, Y., Fan, Y., & Puga, A. (2010). Dioxin exposure disrupts the differentiation of mouse embryonic stem cells into cardiomyocytes. Toxicological Sciences, 115, 225–237.CrossRefPubMed

14.

Wang, Q., Chen, J., Ko, C. I. I., Fan, Y., Carreira, V., Chen, Y., et al. (2013). Disruption of aryl hydrocarbon receptor homeostatic levels during embryonic stem cell differentiation alters expression of homeobox transcription factors that control cardiomyogenesis. Environmental Health Perspectives, 121, 1334–1343.PubMedPubMedCentralCrossRef

15.

Wang, Q., Kurita, H., Carreira, V., Ko, C. I., Fan, Y., Zhang, X., et al. (2016). Ah receptor activation by dioxin disrupts activin, BMP, and WNT signals during the early differentiation of mouse embryonic stem cells and inhibits cardiomyocyte functions. Toxicological Sciences, 149(2), 346–357.CrossRefPubMed

16.

Carreira, V. S., Fan, Y., Wang, Q., Zhang, X., Kurita, H., Ko, C. I., et al. (2015). Ah receptor signaling controls the expression of cardiac development and homeostasis genes. Toxicological Sciences, 147(2), 425–435.CrossRefPubMedPubMedCentral

17.

Carreira, V. S., Fan, Y., Kurita, H., Wang, Q., Ko, C. I., Naticchioni, M., et al. (2015). Disruption of Ah receptor signaling during mouse development leads to abnormal cardiac structure and function in the adult. PLoS One, 10(11), e0142440.CrossRefPubMedPubMedCentral

18.

Dietrich, C. (2016). Antioxidant functions of the aryl hydrocarbon receptor. (2016). Stem Cells International, 7943495.

19.

Harper, P. A., Wong, J. M., Lam, M. S., & Okey, A. B. (2002). Polymorphisms in the human AH receptor. Chemico-Biological Interactions, 141(1–2), 161–187.CrossRefPubMed

20.

Puga, A. (2011). Perspectives on the potential involvement of the Ah receptor-dioxin axis in cardiovascular disease. Toxicological Sciences, 120(2), 256–261.CrossRefPubMed

21.

Caccamo, D., Cesareo, E., Mariani, S., Raskovic, D., Ientile, R., Currò, M., et al. (2013). Xenobiotic sensor- and metabolism-related gene variants in environmental sensitivity-related illnesses: A survey on the Italian population. Oxidative Medicine and Cellular Longevity, 2013, 831969.CrossRefPubMedPubMedCentral

22.

Rowlands, J. C., Staskal, D. F., Gollapudi, B., & Budinsky, R. (2010). The human AHR: Identification of single nucleotide polymorphisms from six ethnic populations. Pharmacogenetics and Genomics, 20(5), 283–290.CrossRefPubMed

23.

Smart, J., & Daly, A. K. (2000). Variation in induced CYP1A1 levels: Relationship to CYP1A1, Ahr receptor and GSTM1 polymorphisms. Pharmacogenetics, 10, 11–24.CrossRefPubMed

24.

Wong, J. M., Okey, A. B., & Harper, P. A. (2001). Human aryl hydrocarbon receptor polymorphisms that result in loss of CYP1A1 induction. Biochemical and Biophysical Research Communications, 288, 990–996.CrossRefPubMed

25.

Helmig, S., Seelinger, J. U., Döhrel, J., & Schneider, J. (2011). RNA expressions of AHR, ARNT and CYP1B1 are influenced by AHR Arg554Lys polymorphism. Molecular Genetics and Metabolism, 104, 180–184.CrossRefPubMed

26.

Aftabi, Y., Colagar, A. H., & Mehrnejad, F. (2016). An in silico approach to investigate the source of the controversial interpretations about the phenotypic results of the human AhR-gene G1661A polymorphism. Journal of Theoretical Biology, 393, 1–15.CrossRefPubMed

27.

Kobayashi, S., Sata, F., Sasaki, S., Ban, S., Miyashita, C., Okada, E., et al. (2013). Genetic association of aromatic hydrocarbon receptor (AHR) and cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) polymorphisms with dioxin blood concentrations among pregnant Japanese women. Toxicology Letters, 219(3), 269–278.CrossRefPubMed

28.

Kayano, S., Suzuki, Y., Kanno, K., Aoki, Y., Kure, S., Yamada, A., et al. (2004). Significant association between nonsyndromic oral clefts and arylhydrocarbon receptor nuclear translocator (ARNT). American Journal of Medical Genetics Part A, 130A(1), 40–44.CrossRefPubMed

29.

Bock, K. W., & Köhle, C. (2006). Ah receptor: Dioxin-mediated toxic responses as hints to deregulated physiologic functions. Biochemical Pharmacology, 72(4), 393–404.CrossRefPubMed

30.

Gonzalez, F. J., & Fernandez-Salguero, P. (1998). The aryl hydrocarbon receptor: Studies using the AHR-null mice. Drug Metabolism and Disposition, 26(12), 1194–1198.PubMed

31.

Mackenzie, S. G., & Lippman, A. (1989). An investigation of report bias in a case-control study of pregnancy outcome. American Journal of Epidemiology, 129(1), 65–75.CrossRefPubMed

32.

Van Driel, L. M., Smedts, H. P., Helbing, W. A., Isaacs, A., Lindemans, J., Uitterlinden, A. G., et al. (2008). Eight-fold increased risk for congenital heart defects in children carrying the nicotinamide N-methyltransferase polymorphism and exposed to medicines and low nicotinamide. European Heart Journal, 29(11), 1424–1431.CrossRefPubMed

Titel: A Functional Aryl Hydrocarbon Receptor Genetic Variant, Alone and in Combination with Parental Exposure, is a Risk Factor for Congenital Heart Disease
verfasst von: Silvia Pulignani
Andrea Borghini
Cecilia Vecoli
Ilenia Foffa
Lamia Ait-Ali
Maria Grazia Andreassi
Publikationsdatum: 28.11.2017
Verlag: Springer US
Erschienen in: Cardiovascular Toxicology / Ausgabe 3/2018
Print ISSN: 1530-7905
Elektronische ISSN: 1559-0259
DOI: https://doi.org/10.1007/s12012-017-9436-9

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

A Functional Aryl Hydrocarbon Receptor Genetic Variant, Alone and in Combination with Parental Exposure, is a Risk Factor for Congenital Heart Disease

Abstract

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

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