HLA-A∗24-B∗07-DRB1∗01 Haplotype Implicated with Genetic Disposition of Peak Bone Mass in Healthy Young Japanese Women

Abstract

HLA exhibits the most extensive polymorphism of any of the known human genes and is known as a genetic marker which allows genetic background of many diseases and physical phenomena. In this study, we, therefore, tried to investigate the regulation of HLA polymorphism and peak bone mass (PBM) in order to elucidate the genetic backgrounds of bone metabolism in young women. Subjects were 67 healthy young Japanese women (average age: 23.6 ± 2.6 years, Body Mass Index (BMI): 19.9 ± 2.0 who were randomly chosen. Allelic polymorphisms in HLA class I (HLA-A and -B) and HLA-class II (DRB1) were investigated by PCR-SSOP and PCR-SSP. Vitamin D Receptor (VDR) and Estrogen Receptor (ER) gene polymorphisms were also analyzed. Lifestyle factors, such as exercise and nutrition, were examined by questionnaire. Bone mineral density was examined using with Lunar DPX-L. Subjects who possessed HLA-B∗07 had a significantly lower PBM than those without B∗07 (p < 0.05). All subjects were divided into 3 groups according to HLA haplotypes linked with HLA-B∗07, as follows: A∗24(+/−)B∗07(−)DRB1∗01(+/−), A∗24(+)B∗07(+)DRB1∗01(−), and A∗24(+)B∗07(+)DRB1∗01(+). There were no significant differences between these three groups in factors that affect bone metabolism, such as age, age at menarche, BMI, calcium intake, exercise habits, VDR or ER allele frequency. The HLA-A∗24-B∗07-DRB1∗01 haplotype had a significantly lower Z score in the lumbar spine compared with subjects without this haplotype (p < 0.05). When the Z score was divided by values higher or lower than +1 or −1, all 3 subjects whose Z score was lower than −1.0 were found to have the HLA-A∗24-B∗07-DRB1∗01 haplotype. A significant association between HLA-A ∗24-B∗07-DRB1∗01 and Z score < −1 was found (Yate’s correction χ² = 10.82, p = 0.001, RR = 204). In conclusion, the HLA-A∗24-B∗07-DRB1∗01 haplotype can be considered a new genetic marker implicated with low PBM in healthy young Japanese women.

Introduction

Genetic factors, either alone or through interactions with environmental factors known to affect peak bone mass (PBM), may contribute to the development of osteoporosis later in life [1]. PBM is known to have a strong genetic component, as well-documented in twin 2, 3and family studies 4, 5. Those studies have suggested that heritability contributes to about 60% of the variance in PBM in Caucasian [6]. The mechanisms of this genetic effect has been partially attributed to polymorphism in the vitamin D receptor (VDR) [7]or estrogen receptor (ER) [8]gene. However, this has not been confirmed in the general population. One reason is that the distribution frequencies of VDR and ER gene polymorphism were found to differ according to race 9, 10, 11, 12, 13. In particular, the distribution of VDR alleles observed in other ethnic populations has not been found in the Japanese population [9]. Thus, there may be racial differences in genetic background associated with bone metabolism, and racial differences in PBM values have been reported. In fact, PBM in young Japanese women has been reported to be lower even in the same environment after adjusting for height and weight [14].

HLA possesses the most extensive polymorphism of any of the known human genes and also is strongly associated with racial differences and numerous diseases [15]. Additionally, it has played an important role in elucidating the genetic background of many diseases and physical phenomena 16, 17. We decided to examine HLA polymorphism as a possible genetic marker implicated with PBM in Japanese. This is the first report of an association between HLA polymorphism examined at the DNA level and PBM in young Japanese women.