Estrogen receptor a and vitamin D receptor gene polymorphisms and bone mineral density: association study of healthy pre- and postmenopausal Chinese women Yuan-Yuan Zhang, a,b Ji-Rong Long, b Peng-Yuan Liu, b Yong-Jun Liu, b Hui Shen, b Lan-Juan Zhao, b and Hong-Wen Deng a,b, * a Laboratory of Molecular and Statistical Genetics, College of life Sciences, Hunan Normal University, Changsha, Hunan 410081, PR China b Osteoporosis Research Center, Creighton University Medical Center, Omaha, NE 68131-2137, USA Received 10 July 2003 Abstract In the present study, we tested the association between the estrogen receptor a (ER-a) and vitamin D receptor (VDR) genes with bone mineral density (BMD). A total of 649 healthy Chinese women, classified as pre-menopausal (N ¼ 388) and post-menopausal (N ¼ 261) groups, were genotyped at the ER-a PvuII, XbaI, and VDR ApaI sites. BMDs at the lumbar spine (L 1 –L 4 ) and total hip were measured by dual-energy X-ray absorptiometry. For the VDR ApaI locus, AA carriers had lower spine BMD than Aa (p ¼ 0:02) and aa carriers (p < 0:01) in the pre-menopausal group. For the ER-a gene, carriers of haplotype px had lower spine BMD than the non-carriers (p ¼ 0:03) in the pre-menopausal group. Furthermore, we observed significant interaction between the ER-a and VDR genes in the post-menopausal group: with AA genotype (or A allele) at the VDR ApaI locus, pX carriers had higher spine BMD than the non-carriers (p ¼ 0:02), and PX carriers had lower hip BMD than the non-carriers (p ¼ 0:04). Our data suggest that the ER-a and VDR genes may be associated with the BMD variation in Chinese women. Ó 2003 Elsevier Inc. All rights reserved. Keywords: Bone mineral density (BMD); Haplotype; Estrogen receptor a gene; Vitamin D receptor gene Osteoporosis is a serious health problem worldwide, especially in elderly women. Low bone mineral density (BMD), which could occur due to a low peak bone mass (PBM) achieved in early adulthood or a high rate of bone loss later in life [1], is a major measurable predictor for osteoporosis [2]. The heritability of BMD ranges from 0.5 to 0.9 [3]. Extensive molecular genetic studies have been performed in Caucasians and suggested a long list of candidate genes [4]. Of these candidates, those encoding estrogen receptor a (ER-a) [5–7] and vitamin D receptor (VDR) [8–11] are the most promi- nent, though inconsistency remains in their effects on BMD [3,12]. The ER-a is a strong candidate gene be- cause of the well-known relationship between estrogen status and bone mass in women [13], its presence in osteoblasts, chondrocytes, and osteoclasts [14], and the well-described effect of estrogen replacement on bone mass in postmenopausal women [12]. The VDR gene is interesting because of the long-time association of vita- min D with the skeleton [15]. Vitamin D is a major regulator of calcium and bone metabolism, as its action modulates intestinal calcium absorption, osteoclastic, and osteoblastic activities, PTH production, and renal hydroxylation of 25-OH-vitamin D [16]. Subtle varia- tions in expression and/or function of VDR may contribute to major differences in the regulation of other target genes. The VDR gene, acting through target gene response elements, may modulate calcium and bone metabolism and thus skeletal mineralization [15,16]. The prevalence of osteoporosis varies across race and ethnicity. Chinese have lower BMD but a lower risk of osteoporotic fractures than Caucasians [17]. For the ER-a and VDR genes, most of the association studies have been performed in Caucasians [18,19], with relatively few studies done in Chinese. Gene-by-gene Biochemical and Biophysical Research Communications 308 (2003) 777–783 www.elsevier.com/locate/ybbrc BBRC * Corresponding author. Fax: 1-402-280-5034. E-mail address: deng@creighton.edu (H.-W. Deng). 0006-291X/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0006-291X(03)01479-7