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01-10-2013 | Original Article

Association between a common CYP17A1 haplotype and anxiety in female anorexia nervosa

Authors: Efrat Czerniak, Michael Korostishevsky, Amos Frisch, Yoram Cohen, Ninette Amariglio, Gideon Rechavi, Elena Michaelovsky, Daniel Stein, Yardena Danziger, Silvana Fennig, Alan Apter, Abraham Weizman, Eva Gak

Published in: Archives of Women's Mental Health | Issue 5/2013

Abstract

Dehydroepiandrosterone (DHEA), the main brain neurosteroid, has been implicated in various psychiatric disorders especially those including gender differences. We studied genetic variability in the DHEA-producing enzyme CYP17A1 in relation to anorexia nervosa (AN) susceptibility and AN-related co-morbidities. We performed analysis of 100 Israeli AN family trios accounting for CYP17A1 haplotypes characteristic of populations of European origin and studied genotype–phenotype relationships using correlation analyses and transmission disequilibrium test. Although our analysis revealed no evidence of association between CYP17A1 and AN per se, it revealed an association between specific CYP17A1 haplotypes and AN co-morbidity, specifically anxiety. We found that a common CYP17A1 haplotype (H1) was associated with higher anxiety in AN patients (Clinical Global Impression; CGI-anxiety ≥4). Moreover, H1 homozygotes were at higher risk for expressing high CGI-anxiety levels (OR = 3.7), and H1 was preferentially transmitted to AN patients with high CGI-anxiety levels (P = 0. 037). We suggest that CYP17A1 H1 haplotype may contribute to genetic predisposition to higher CGI-anxiety levels in AN patients and that this predisposition may be mediated by reduced CYP17A1 enzymatic activity and corresponding lower DHEA production.

Baulieu EE, Robel P (1998) Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) as neuroactive neurosteroids. Proc Natl Acad Sci U S A 95(8):4089–4091PubMedCrossRef

Berkman ND, Lohr KN, Bulik CM (2007) Outcomes of eating disorders: a systematic review of the literature. Int J Eat Disord 40(4):293–309PubMedCrossRef

Birmingham CL, Su J, Hlynsky JA, Goldner EM, Gao M (2005) The mortality rate from anorexia nervosa. Int J Eat Disord 38(2):143–146PubMedCrossRef

Bulik CM, Sullivan PF, Tozzi F, Furberg H, Lichtenstein P, Pedersen NL (2006) Prevalence, heritability, and prospective risk factors for anorexia nervosa. Arch Gen Psychiatry 63(3):305–312PubMedCrossRef

Chakraborty A, Murthy NS, Chintamani C, Bhatnagar D, Mohil RS, Sharma PC, Saxena S (2007) CYP17 gene polymorphism and its association with high-risk north Indian breast cancer patients. J Hum Genet 52(2):159–165PubMedCrossRef

Eastwood H, Brown KM, Markovic D, Pieri LF (2002) Variation in the ESR1 and ESR2 genes and genetic susceptibility to anorexia nervosa. Mol Psychiatry 7(1):86–89PubMedCrossRef

Feigelson HS, Shames LS, Pike MC, Coetzee GA, Stanczyk FZ, Henderson BE (1998) Cytochrome P450c17alpha gene (CYP17) polymorphism is associated with serum estrogen and progesterone concentrations. Cancer Res 58(4):585–587PubMed

Frisch A, Laufer N, Danziger Y, Michaelovsky E, Leor S, Carel C, Stein D, Fenig S, Mimouni M, Apter A, Weizman A (2001) Association of anorexia nervosa with the high activity allele of the COMT gene: a family-based study in Israeli patients. Mol Psychiatry 6(2):243–245PubMedCrossRef

Gervasini G, Gordillo I, Garcia-Herraiz A, Flores I, Jimenez M, Monge M, Carrillo JA (2012) Polymorphisms in serotonergic genes and psychopathological traits in eating disorders. J Clin Psychopharmacol 32(3):426–428PubMedCrossRef

Godart NT, Flament MF, Perdereau F, Jeammet P (2002) Comorbidity between eating disorders and anxiety disorders: a review. Int J Eat Disord 32(3):253–270PubMedCrossRef

Godart NT, Perdereau F, Rein Z, Berthoz S, Wallier J, Jeammet P, Flament MF (2007) Comorbidity studies of eating disorders and mood disorders. Critical review of the literature. J Affect Disord 97(1–3):37–49PubMedCrossRef

Gordon CM, Grace E, Emans SJ, Feldman HA, Goodman E, Becker KA, Rosen CJ, Gundberg CM, LeBoff MS (2002) Effects of oral dehydroepiandrosterone on bone density in young women with anorexia nervosa: a randomized trial. J Clin Endocrinol Metabol 87(11):4935–4941CrossRef

Guy W (1976) Clinical global impression (CGI). US Department of Health, Education and Welfare, Rockville, MD

Haiman CA, Hankinson SE, Spiegelman D, Colditz GA, Willett WC, Speizer FE, Kelsey KT, Hunter DJ (1999) The relationship between a polymorphism in CYP17 with plasma hormone levels and breast cancer. Cancer Res 59(5):1015–1020PubMed

Henningson M, Johansson U, Borg A, Olsson H, Jernstrom H (2007) CYP17 genotype is associated with short menstrual cycles, early oral contraceptive use and BRCA mutation status in young healthy women. Mol Hum Reprod 13(4):231–236PubMedCrossRef

Holtkamp K, Muller B, Heussen N, Remschmidt H, Herpertz-Dahlmann B (2005) Depression, anxiety, and obsessionality in long-term recovered patients with adolescent-onset anorexia nervosa. Eur Child Adolesc Psychiatry 14(2):106–110PubMedCrossRef

Horvath S, Xu X, Laird NM (2001) The family based association test method: strategies for studying general genotype–phenotype associations. Eur J Hum Genet 9(4):301–306PubMedCrossRef

Juhasz-Vedres G, Rozsa E, Rakos G, Dobszay MB, Kis Z, Wolfling J, Toldi J, Parducz A, Farkas T (2006) Dehydroepiandrosterone sulfate is neuroprotective when administered either before or after injury in a focal cortical cold lesion model. Endocrinology 147(2):683–686PubMedCrossRef

Klump KL, Gobrogge KL (2005) A review and primer of molecular genetic studies of anorexia nervosa. Int J Eat Disord 37(Suppl):S43–S48, Discussion S87-49PubMedCrossRef

Koronyo-Hamaoui M, Danziger Y, Frisch A, Stein D, Leor S, Laufer N, Carel C, Fennig S, Minoumi M, Apter A, Goldman B, Barkai G, Weizman A, Gak E (2002) Association between anorexia nervosa and the hsKCa3 gene: a family-based and case control study. Mol Psychiatry 7(1):82–85PubMedCrossRef

Koronyo-Hamaoui M, Frisch A, Stein D, Denziger Y, Leor S, Michaelovsky E, Laufer N, Carel C, Fennig S, Mimouni M, Ram A, Zubery E, Jeczmien P, Apter A, Weizman A, Gak E (2007) Dual contribution of NR2B subunit of NMDA receptor and SK3 Ca(2+)-activated K⁺ channel to genetic predisposition to anorexia nervosa. J Psychiatr Res 41(1–2):160–167PubMedCrossRef

Lapchak PA, Araujo DM (2001) Preclinical development of neurosteroids as neuroprotective agents for the treatment of neurodegenerative diseases. Int Rev Neurobiol 46:379–397PubMedCrossRef

Le Melledo JM, Baker G (2004) Role of progesterone and other neuroactive steroids in anxiety disorders. Expert Rev Neurother 4(5):851–860PubMedCrossRef

Michaelovsky E, Frisch A, Leor S, Stein D, Danziger Y, Carel C, Fennig S, Mimouni M, Klauck SM, Benner A, Poustka A, Apter A, Weizman A (2005) Haplotype analysis of the COMT-ARVCF gene region in Israeli anorexia nervosa family trios. Am J Med Genet B Neuropsychiatr Genet 139B(1):45–50PubMedCrossRef

Milos G, Spindler A, Ruggiero G, Klaghofer R, Schnyder U (2002) Comorbidity of obsessive-compulsive disorders and duration of eating disorders. Int J Eat Disord 31(3):284–289PubMedCrossRef

Monteleone P, Luisi M, Colurcio B, Casarosa E, Monteleone P, Ioime R, Genazzani AR, Maj M (2001) Plasma levels of neuroactive steroids are increased in untreated women with anorexia nervosa or bulimia nervosa. Psychosom Med 63(1):62–68PubMed

Monteleone P, Luisi M, Martiadis V, Serritella C, Longobardi N, Casarosa E, Genazzani AR, Maj M (2006) Impaired reduction of enhanced levels of dehydroepiandrosterone by oral dexamethasone in anorexia nervosa. Psychoneuroendocrinology 31(4):537–542PubMedCrossRef

Mukai H, Tsurugizawa T, Ogiue-Ikeda M, Murakami G, Hojo Y, Ishii H, Kimoto T, Kawato S (2006) Local neurosteroid production in the hippocampus: influence on synaptic plasticity of memory. Neuroendocrinology 84(4):255–263PubMedCrossRef

Perdereau F, Faucher S, Wallier J, Vibert S, Godart N (2008) Family history of anxiety and mood disorders in anorexia nervosa: review of the literature. Eat Weight Disord 13(1):1–13PubMed

Ritsner M, Maayan R, Gibel A, Weizman A (2007) Differences in blood pregnenolone and dehydroepiandrosterone levels between schizophrenia patients and healthy subjects. Eur Neuropsychopharmacol 17(5):358–365PubMedCrossRef

Rosenkranz K, Hinney A, Ziegler A, Hermann H, Fichter M, Mayer H, Siegfried W, Young JK, Remschmidt H, Hebebrand J (1998) Systematic mutation screening of the estrogen receptor beta gene in probands of different weight extremes: identification of several genetic variants. J Clin Endocrinol Metabol 83(12):4524–4527CrossRef

Rupprecht R, di Michele F, Hermann B, Strohle A, Lancel M, Romeo E, Holsboer F (2001) Neuroactive steroids: molecular mechanisms of action and implications for neuropsychopharmacology. Brain Res Brain Res Rev 37(1–3):59–67PubMedCrossRef

Sarkar DK, Friedman SJ, Yen SS, Frautschy SA (1989) Chronic inhibition of hypothalamic-pituitary-ovarian axis and body weight gain by brain-directed delivery of estradiol-17 beta in female rats. Neuroendocrinology 50(2):204–210PubMedCrossRef

Small CM, Marcus M, Sherman SL, Sullivan AK, Manatunga AK, Feigelson HS (2005) CYP17 genotype predicts serum hormone levels among pre-menopausal women. Hum Reprod 20(8):2162–2167PubMedCrossRef

Sobti RC, Gupta L, Thakur H, Seth A, Singh SK, Kaur P (2009) CYP17 gene polymorphism and its association in north Indian prostate cancer patients. Anticancer Res 29(5):1659–1663PubMed

Stein D, Maayan R, Ram A, Loewenthal R, Achiron A, Modan-Moses D, Feigin M, Weizman A, Valevski A (2005) Circulatory neurosteroid levels in underweight female adolescent anorexia nervosa inpatients and following weight restoration. Eur Neuropsychopharmacol 15(6):647–653PubMedCrossRef

Strous RD, Maayan R, Weizman A (2006) The relevance of neurosteroids to clinical psychiatry: from the laboratory to the bedside. Eur Neuropsychopharmacol 16(3):155–169PubMedCrossRef

Wang K, Zhang H, Bloss CS, Duvvuri V, Kaye W, Schork NJ, Berrettini W, Hakonarson H (2011) A genome-wide association study on common SNPs and rare CNVs in anorexia nervosa. Mol Psychiatry 16(9):949–959PubMedCrossRef

Yazici H, Tigli H, Kadehci Z, Kucucuk S, Saip P, Issever H, Ozcelik H, Dalay N (2006) Are CYP17 genotypes a biomarker for ovarian cancer in patients with cancer history in their family? Oncol Res 16(1):43–47PubMed

Title: Association between a common CYP17A1 haplotype and anxiety in female anorexia nervosa
Authors: Efrat Czerniak
Michael Korostishevsky
Amos Frisch
Yoram Cohen
Ninette Amariglio
Gideon Rechavi
Elena Michaelovsky
Daniel Stein
Yardena Danziger
Silvana Fennig
Alan Apter
Abraham Weizman
Eva Gak
Publication date: 01-10-2013
Publisher: Springer Vienna
Published in: Archives of Women's Mental Health / Issue 5/2013
Print ISSN: 1434-1816
Electronic ISSN: 1435-1102
DOI: https://doi.org/10.1007/s00737-013-0363-x

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Association between a common CYP17A1 haplotype and anxiety in female anorexia nervosa

Abstract

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Abstract

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