Menopause: The Journal of The North American Menopause Society Vol. 18, No. 5, pp. 575/581 DOI: 10.1097/gme.0b013e3181fcabaa * 2011 by The North American Menopause Society Involvement of G-463A MPO gene polymorphism in the response of postmenopausal women to hormone therapy Ainhoa Ruiz del Agua, PhD, 1 Igor Aurrekoetxea, PhD, 1 Miguel Angel Elorriaga, PhD, 2 Fernando Rodriguez, PhD, 2 Fran 0 oise Gue ´raud, PhD, 3 M. Begon ˜a Ruiz-Larrea, PhD, 1 and Jose ´ Ignacio Ruiz-Sanz, PhD 1 Abstract Objective: The aims of this work were to determine (1) the effects of estrogen plus progestogen therapy (EPT) and raloxifene on oxidative stress and cardiovascular risk biomarkers in postmenopausal women and (2) the involvement of the functional G-463A polymorphism of the myeloperoxidase (MPO) gene in the therapy responses. Methods: Postmenopausal women (45-55 y old) were assigned to three groups receiving (1) EPT (con- tinuous 50 Kg transdermal estradiol daily and 200 mg/d micronized progesterone orally the first 14 d of each month; n = 21), (2) raloxifene (60 mg daily; n = 17), and (3) no treatment (control; n = 21). Blood and urine samples were taken before and after 6 months of therapy. Measurements were serum lipid profile, C-reactive intercellular adhesion molecule 1 (ICAM-1), >-tocopherol, F-tocopherol, uric acid, total antioxidant activity (TAA), malondialdehyde, and urinary 1,4-dihydroxynonane-mercapturic acid (the major urinary 4-hydroxynonenal metabo- lite). The G-463A MPO polymorphism was analyzed by polymerase chain reaction and restriction fragment length polymorphism. Results: EPT significantly decreased TAA and the levels of ICAM-1, not modifying other cardiovascular risk or oxidative stress markers. The raloxifene and control groups experienced no modifications in oxidative stress or endothelial dysfunction markers. The MPO genotype specifically influenced the outcomes in the EPT group. Thus, TAA decreased significantly in GG (high-expression genotype) homozygotes, whereas ICAM-1 levels were reduced in A allele carriers. Conclusions: EPT exerted a negative action on the serum oxidant/antioxidant balance in the MPO GG homozygotes and a positive effect on the ICAM-1 endothelial dysfunction marker in carriers of the low-expression A allele. This observation provides evidence of the importance of this polymorphism in the response to EPT. Key Words: MPO gene Y Single-nucleotide polymorphism Y Menopause Y Hormone therapy Y Human. M enopause is a normal period during the female aging process, defined as the permanent cessation of menstruation resulting from the loss of ovarian follicular activity. In addition to the clinical symptoms that are characteristic of the transition to postmenopause, this condition is associated with the risk of osteoporosis and car- diovascular disease. Aging and degenerative diseases are associated with increased production of free radicals during the normal metabolism and the subsequent accumulation of oxidation products. Free radicals and oxidative stress also seem to play a major role in the development and progression of atherosclerosis. 1,2 Myeloperoxidase (MPO), a free radical generating hemoprotein expressed in neutrophils and mono- cytes, is present in atherosclerotic lesions. 3 The enzyme is considered to be proatherogenic. 4,5 It has also been reported that individuals with partial or total hereditary MPO defi- ciency show a decreased incidence of cardiovascular events. 6 MPO gene expression is significantly altered by a single- nucleotide polymorphism in the promoter region at position j463. The G-to-A base substitution creates high-expression (G) and low-expression (A) alleles. 7,8 This polymorphism is associated with the prevalence of coronary artery disease, 9,10 suggesting that specific MPO genotypes may be associated with different outcomes of atherosclerosis, depending on the prevailing risk factors. To prevent the adverse effects of the lack of estrogens, replacement therapies are often used. Among them, hormone therapies (HTs) consisting of estrogens either alone or in Received July 8, 2010; revised and accepted September 14, 2010. From the 1 Department of Physiology, Medicine and Dentistry School, University of the Basque Country, Leioa, Spain; 2 Department of Obstetrics and Gynaecology, Cruces Hospital, Barakaldo, Spain; and 3 INRA, Institut National de la Recherche Agronomique, Toulouse, France. Funding/support: This work was supported by the Basque Government (ref. IT514-10), the Basque Country University (predoctoral and post- doctoral grants to A.R.D.A), the Ministry of Education and Science (predoctoral grant to I.A.), and Instituto de Investigacio ´n en Radicales Libres y Metabolismo/Erradikal Aske-eta Metabolismo-Ikerketarako Institutoa (postdoctoral grant to A.R.D.A). Financial disclosure/conflicts of interest: None reported. Address correspondence to: M. Begon ˜ a Ruiz-Larrea, PhD, Department of Physiology, Medicine and Dentistry School, University of the Basque Country, 48080 Bilbao, Spain. E-mail: mbego.ruizlarrea@ehu.es Menopause, Vol. 18, No. 5, 2011 575 Copyright © 2011 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.