Association of apolipoprotein E polymorphism with bone mineral density in postmenopausal women with rheumatoid arthritis

S. I. Lee, S. Y. Lee1 and W. H. Yoo

Department of Internal Medicine and 1 Diagnostic Radiology, Chonbuk National University Medical School and Research Institute of Clinical Medicine, Republic of Korea.

Correspondence to: W. H. Yoo, Division of Rheumatology, Department of Internal Medicine, Chonbuk National University Medical School and Research Institute of Clinical Medicine, #634-18, Keumamdong, Dukjingu, Jeonju, Jeonbuk, 561–712, Korea. E-mail: ywhim{at}moak.chonbuk.ac.kr

SIR, Pathological bone loss can occur by marginal erosions, juxta-articular osteoporosis and generalized osteoporosis in rheumatoid arthritis (RA) [1]. Several studies demonstrated that these different types of bone involvement are similarly mediated by receptor activator of nuclear factor {kappa}B ligand (RANKL), a factor stimulating osteoclast differentiation [2, 3]. Therefore, generalized osteoporosis has been suggested as a risk factor for severe joint destruction in RA. In fact, joint erosions related to generalized osteoporosis and high Larsen scores associated strongly with bone mineral density (BMD) reduction have been found in patients with RA [4]. Osteoporosis has a multifactorial aetiology, including several candidate genes, such as the genes for {alpha}2HS-glycoprotein, the oestrogen receptor, interleukin 6, type I collagen, the vitamin D receptor, transforming growth factor ß1 and apolipoprotein E (ApoE) [5]. ApoE may be linked to osteoporosis and fracture through action of vitamin K, which is an important cofactor for the carboxylation of osteocalcin. Individuals with the ApoE4 allele have an accelerated hepatic clearance of vitamin K in triglyceride-rich lipoprotein; thus, they may have a low serum vitamin K concentration available for uptake by bone cells [6]. Three codominant alleles (ApoE2, ApoE3 and ApoE4) are common in humans and several studies have focused on the deleterious influence of the ApoE4 allele on BMD and fracture risk; among postmenopausal or elderly women, those with the ApoE4 allele have lower lumbar spine or hip BMD than those without the ApoE4 allele [7, 8]. However, the relationship between ApoE genotypes and the severity of osteoporosis and joint destruction in patients with RA has not yet been clarified. Therefore, this study was designed to examine whether postmenopausal RA patients with ApoE4 allele have lower BMD than patients without the ApoE4 allele. This study also assessed the destruction of hand joints radiographically to determine the relationship between the ApoE4 allele and the severity of joint erosion in RA.

In this study, a total of 110 female patients with RA aged between 45 and 82 yr were recruited from our rheumatological clinic between 2000 and 2002. All patients were postmenopausal and were diagnosed with RA, for the first time, fulfilling the American Rheumatism Association 1987 revised criteria for RA [9]. Patients were chosen who had not received any antiresorptive therapy, DMARDs or glucocorticosteroids in the past 2 yr. All 110 patients had complete ApoE genotyping and bone density measurements before the treatment of RA and osteoporosis. ApoE genotypes were analysed by gel electrophoresis following the Amplified Refractory Mutation System (ARMS) polymerase chain reaction (PCR) method [10]. BMD was measured in the lumbar spine (L2–L4) and bilaterally in the femoral neck and greater trochanter using dual-energy X-ray absorptiometry (DEXA; Prodigy; GE Lunar Corporation, WI, USA). Plain radiographs of the hands and wrists were obtained and joint destruction was evaluated by the method described by Larsen [11]. Patient informed consent was obtained verbally; no written informed consent was required. The study was approved by the Medical Ethics Committee of the Chonbuk National University Hospital and conducted according to the principles of the Declaration of Helsinki.

The ApoE genotypes were analysed in all 110 postmenopausal women with RA. The genotypic distribution in our patients was 10% for ApoE2/3 (n = 11), 63.6% for ApoE3/3 (n = 70), 23.6% for ApoE3/4 (n = 26) and 2.7% for ApoE4/4 (n = 3). The genotypes ApoE2/2 and E2/4 were not found in the population of this study. The genotype frequencies in our study were in Hardy–Weinberg equilibrium ({chi}2 = 2.57, P = 0.765). The combined frequency for both ApoE3/4 and 4/4 genotypes was higher in the postmenopausal women with osteoporosis than in those without osteoporosis (31.4 vs 9.7%). In view of the deleterious influence of the ApoE4 allele on BMD, we classified these patients into the two groups ApoE4(+) and ApoE4(–) according to the presence or absence of the ApoE4 allele. There were no statistically significant differences in the clinical and laboratory characteristics between the ApoE4(+) and ApoE4(–) groups. The patients in the ApoE4(+) group had significantly lower BMD in the lumbar spine and the femoral greater trochanter than patients in the ApoE4(–) group. BMD in the lumbar spine of the ApoE4(+) group was 0.85±0.13 g/cm2 (n = 29), whereas that of the ApoE4(–) group was 0.96±0.14 g/cm2 (n = 81; P = 0.008). BMD in the femoral greater trochanter of the ApoE4(+) group was 0.69±0.12 g/cm2, while that of the ApoE4(–) group was 0.74±0.12 g/cm2 (P = 0.008) (Fig. 1). However, there were no significant differences in Larsen score (1.3±1.6 vs 1.4±2.0, P = 0.608) and the rate of erosive disease (72.5 vs 66.7, P = 0.608) between the ApoE4(+) and ApoE4(–) groups.



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FIG. 1. BMDs of lumbar (L2–4) and femoral greater trochanter in subjects with and without the ApoE4 allele. The difference in BMD according to the presence of ApoE4 allele in the two regions was statistically significant (P = 0.008; Mann–Whitney test).

 
In conclusion, data from the present study show that the ApoE4 allele is closely associated with a reduced bone mass, especially in the lumbar spine and femoral greater trochanter, and the ApoE4 allele is considered to be an independent risk factor for generalized osteoporosis in postmenopausal women with RA. Therefore, we recommend that postmenopausal RA patients with the ApoE4 allele should be treated aggressively for osteoporosis to minimize severe joint destruction. However, we have not found any significant differences in Larsen score and rate of erosive disease (%) between the ApoE4(+) and ApoE4(–) groups. Further prospective study is needed to compare the change in BMD and progression of joint destruction between ApoE4(+) and ApoE4(–) groups in patients with RA.

We kindly thank Mie-Jae Im for reviewing this manuscript.

The authors have declared no conflicts of interest.

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Accepted 1 April 2005





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