Multilocus analysis of estrogen-related genes in Spanish postmenopausal women suggests an interactive role of ESR1, ESR2 and NRIP1 genes in the pathogenesis of osteoporosis
Introduction
Osteoporosis fractures and bone mass loss are important health care problems affecting the majority of elderly individuals in developed countries [1]. This pathology is defined as the gradual reduction in bone strength with advancing age. It is also well established that age and sex are very important factors that influence this condition [2]. Moreover, a range of environmental, hormonal, and genetic factors is modifying the risk of osteoporosis and the variation of body mass index between individuals ([2], [3] and references therein).
The prevalence of osteoporosis and the presence of well-established risk factors for osteoporosis are being studied in Spain [4], [5], [6]. A recent population-based series of 5195 postmenopausal women has been analyzed looking for demographic, anthropometric, and clinical variables involved in osteoporosis aetiology. The most important risk factors detected in these epidemiological works included age, body mass index, early menopause (<45 years), benzodiazepine use, and previous falls [6].
In addition to previously mentioned environmental or clinical factors, there is enough previously reported evidence to support the existence of genetic factors influencing both body mass index and osteoporosis disease in humans ([2], [3], [7] and references therein). In fact, the current risk model of the pathology comprises the combination of both, genetic and environmental factors following a complex and interactive network of risk components that define – and is expected to predict – the exact risk of any individual [7]. For all these reasons, osteoporosis is now considered a complex and multifactorial disease. Unfortunately, the number of factors involved in each interaction, the link between them or a specific joint model integrating the available information has not been achieved to date.
Due to the vast amount of experimental, epidemiological, and genetic data available, it is well established that estrogenic steroids exert a broad range of effects on skeletal tissues and are considered calcicotropic hormones [3]. In fact, using a marker-by-marker approach, the role of different estrogen-related genes, including the Estrogen Receptor Alpha (ESR1) gene, the Estrogen Receptor Beta (ESR2) gene, and the CYP19 aromatase (CYP19A1) gene, has been analyzed in different populations [8], [9], [10]. For these reasons, we postulated that osteoporosis could be an estrogen-related disease in which genes involved in the production of estradiol (E2), genes involved in the mechanism of action via estrogen receptors, and other genes involved in E2 bio-availability or degradation could be related with osteoporosis following a complex multigenic and interactive model [11].
The existence of genetic interaction between unlinked loci (joint effects) in relation with osteoporosis or bone mineral density has been observed by several independent research groups. Most of these genetic studies combined Vitamin D Receptor (VDR) genotypes with two or more additional loci [12], [13], [14], [15], [16], [17], [18], [19]. Specifically, a two-locus genotype, including VDR Bsm I and ESR1 PvuII polymorphisms, was related to hormone replacement therapy (HRT) outcome in postmenopausal women [12]. This digenic VDR/ESR1 genetic interaction was also related to bone mineral density (BMD) variation in the Chinese postmenopausal women population [13] and BMD values in young children from the Iowa Bone Development Study [14].
Moreover, Interactive VDR and Collagen Type IaI genotypes have also been associated to susceptibility to fracture [15] and bone change and density [16]. More recently, a novel interaction between VDR and CYP19 genotypes in relation to bone mineral density in older African–American women has been detected [17]. Finally, an interesting interaction between ESR1 gene and AIB1 co-transcriptional activator has been associated with quantitative calcaneal ultrasound densitometry values [18], these data suggest the existence of modifier loci related to risk of osteoporosis via estrogen receptor signaling pathway.
Here, we present a multilocus analysis of the BMD trait in 437 unrelated postmenopausal women who underwent densitometric screening for osteoporosis or were diagnosed with osteoporotic fracture. We have analyzed five single nucleotide polymorphisms located at different candidate genes of the estrogen pathway. Association studies provided evidences of a digenic interaction between ESR2 and NRIP1 (Nuclear Receptor Interacting Protein 1) genes in relation to osteoporosis status. A trigenic model including ESR1, ESR2, and NRIP1 genes involved in postmenopausal osteoporosis and fracture risk is also proposed.
Section snippets
Patients
We are conducting a multicenter population-based study of osteoporosis in Spain. The referral centers involved in our research are Hospital Universitario Virgen de las Nieves (Granada), CEOGA (Lugo), Hospital San Juan de Alicante (Alicante), Sanatorio Bilbaíno (Bilbao) and Clínica Diatros (Barcelona).
A two-step analytical research design was applied during our study (discovery and reanalysis steps). In the first step (discovery), 281 Caucasoid postmenopausal women are recruited. Women were
Two-point analyses
We investigated the allelic frequencies and genotype distributions of five Single Nucleotide Polymorphisms (SNPs) in 281 postmenopausal women and 95 controls. Genotype frequencies observed during this study are in accordance with the Hardy–Weinberg Equilibrium (HWE) law, both in postmenopausal women and in control population P > 0.34 (Table 2). Moreover, genotypic distribution and allele frequencies in postmenopausal women do not differ from those obtained in the unrelated control population (P
Discussion
Estrogens play a crucial role in multiple tissues. An intense molecular genetics analysis [more than 880 references in Medline] have illustrated that several conditions could be related to variation in genes involved in aberrant estrogen synthesis induction, production, mechanism of action, degradation, or environmental exposure to xenoestrogens. Most estrogen-related diseases are complex traits, and it seems evident that estrogens affect a range of organs and physiological systems [29]. These
Acknowledgments
We are deeply grateful to osteoporosis patients and controls for having participated in this study. We are very grateful to Mercedes Reina and Ana Gallego for their collaboration during this work. Neocodex has been partially funded by the Ministerio de Ciencia y Tecnología of Spain (FIT-010000-2004-68 FIT-010000-2004-69, PTQ2003-0546, PTQ2003-0782 and PTQ2004-0838).
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These authors contribute equally to this work.