Background
In Japan, as well as in several developed countries, an increasing prevalence of low body weight among the younger generation poses a critical health issue. The body mass index (BMI) of Japanese men and women is the lowest among the BMI values calculated for people of developed countries [
1]. Furthermore, according to a study of high school students in Japan, the United States, China, and Korea conducted by the National Institution for Youth Education in 2018, the lowest BMI was computed for Japanese high school students among the youth of all four countries [
2]. Approximately 20% of Japanese women in their 20 s are underweight (BMI < 18.5), a rate that has been largely static over the past decade [
3].
In women, menopause results in the rapid decline of bone mass (or density) owing to reduced estrogen production [
4,
5]. Furthermore, BMI demonstrates a strong positive correlation with bone mineral density (BMD) [
6‐
8]. It is known that excessive weight loss at a young age causes a deterioration in bone mass and accelerates postmenopausal osteoporosis. In a previous study, 17% of the 161 young Japanese women participants (age 19.8 ± 1.1 years) showed low BMD as compared to that of women aged 50–60 years [
9]. To impede the progression of osteoporosis, it is crucial to prevent postmenopausal bone loss and also to boost bone mass at a younger age [
10]. Attaining a higher bone mass by the end of the growth period can potentially prevent fractures and conserve bone mass [
10]. Orito et al. [
11] reported that the BMD of young Japanese women peaked at 18–29 years. Thus, augmenting BMD in women in this age range is important for maintaining bone health and preventing osteoporosis throughout their lifetime.
Bone mass is influenced by genetic factors, which determine approximately 80% of bone mass [
12]. Previous studies on the bone density of twins reported that monozygotic twins demonstrated a greater degree of similarity in bone density as compared to dizygotic twins [
13‐
15]. One such genetic factor is single-nucleotide polymorphism (SNP). Vitamin D and its receptors are involved in calcium metabolism, and bone density is reportedly influenced by the associated genotypes, e.g.,
BsmI (rs1544410), an SNP in the vitamin D receptor (VDR) genes [
14]. In their meta-analysis, Gong et al. [
16] reported that VDR genotypes and bone density were related; the obtained results differed depending on factors such as gender, age, postmenopausal age, and the presence/absence of osteoporosis. In addition, lifestyle-related factors, including dietary calcium intake, exercise, smoking, and alcohol consumption, can also affect bone mass during growth [
12,
17,
18]. Thus, it is important to understand the relationship between bone mass and the VDR gene polymorphisms in the participants, relative to other factors.
Several prior studies, also conducted in Japan, have investigated the effect of genetic and environmental factors on bone loss related to menopause. In contrast, there are relatively few studies that assessed the relationship among bone mass, VDR gene polymorphisms, and environmental factors in premenopausal Japanese women. Moreover, these studies typically contained a low number of participants with a relatively wide age range (18–44 years) [
19‐
21]. Estrogen levels and lifestyle factors among participants can vary if a wide age range is considered in a study. Therefore, the present study aimed to investigate how VDR gene polymorphisms and calcium intake affect bone mass in a narrow-age cohort of Japanese women in their early twenties.
Discussion
The present study evaluated the VDR genotypes, bone mass, and calcium intake in young Japanese women. As we have previously elucidated the relationship between bone mass and
Cdx2 (rs11568820), a representative SNP of VDR genes [
32], the present study focused on four representative VDR gene polymorphisms other than
Cdx2, including
BsmI (rs1544410),
TaqI (rs731236),
ApaI (rs7975232), and
FokI (rs2228570).
Several prior studies conducted worldwide have reported the relationship between the VDR genotypes and bone mass. Among these, a meta-analysis reported that the bone mass of the spine is significantly lower for the
BsmI AA genotype than the
BsmI GG and GA genotypes in postmenopausal women (51–75 years) [
33]. However, effects of the
BsmI AA and
TaqI CC genotypes on bone mass in Japanese women have rarely been examined because these genotypes are present at a relatively lower proportion than that seen in European countries; e.g., the respective allelic frequencies for the
BsmI genotype G and A and
TaqI genotype T and C in the European population are about 60% and 40%, respectively, compared to about 90% and 10% in the Japanese population [
29,
34], indicating a clear racial difference. Furthermore, previous studies involving less than 200 Japanese women showed that only a few of them expressed the
BsmI AA and
TaqI CC genotypes (n = 0–2); hence, the relevant data could not be included in the analyses [
20,
21,
35‐
37]. However, in the present study involving 499 participants, these genotypes were recognized (n = 8 for both), and thus, were included in the analysis. Consistent with the findings obtained in previous studies, the
BsmI genotype showed a significant difference in the BMD in young Japanese women; the OSI of the
BsmI AA genotype was lower than that for other genotypes.
In addition, the OSI values of the
TaqI CC genotype differed significantly from those of other genotypes only after adjusting for BMI (
p = 0.019). Furthermore, previous studies on the
TaqI genotype and bone mass in premenopausal Japanese women did not report consistent results, with some reporting no significant difference [
19,
38‐
41] while others reporting that participants with the
TaqI TT genotype display higher bone mass than those with the TC genotype [
21,
35]. These studies, however, did not include participants with the
TaqI CC genotype as their number was limited. In a previous large-scale cohort study (n = 778) on representative samples obtained from Japanese participants, the presence of the
TaqI genotype, including the CC genotype (n = 11, 1.4%), did not significantly influence BMD in premenopausal women; however, this study was not adjusted for BMI [
41]. Therefore, further studies with a sufficient number of participants would be needed to evaluate the effect of the
TaqI CC genotype on BMD in Japanese women.
The OSI values of the
ApaI and
FokI genotypes were not significantly different in Japanese women in the present study; this observation was consistent with the findings of previous studies on these specific genotypes in Japanese women, which did not report significant differences for genotype and bone mass [
19,
35,
39,
41].
We previously reported that the relationship between dietary calcium intake and bone mass differs depending on the VDR
Cdx2 genotype [
32]. Furthermore, certain studies have implied that VDR genotypes modulate the calcium absorption rate [
42‐
44]. Gennari et al. [
43] reported that postmenopausal participants with the
BsmI AA and
TaqI CC genotypes display reduced intestinal calcium absorption. Consequently, our study showed a significant difference in the OSI values between the calcium-intake groups of the
BsmI AA genotype, even after adjusting for BMI (
p = 0.020). Therefore, this genotype may interact with calcium intake and affect bone mass in young Japanese women. In contrast, no significant effect of the interaction between the
TaqI CC genotype and the calcium intake on bone mass was observed. Intriguingly, there was a significant difference between the calcium-intake groups of the
ApaI GT genotype; OSI was higher in the high-calcium intake group. Similarly, a previous study also showed that bone mass in individuals with the
ApaI GT genotype is elevated concomitantly with high calcium intake; this estimation is made based on the frequency of consumption of seven food groups considered to be rich in calcium: milk, milk products, bean and bean products, meat, fish, dried fish with bone, and green vegetables [
39].
The QUS used to measure bone mass in the present study is a non-invasive, painless method that does not involve exposure to radiation [
22], and thus it can be applied not only in osteoporosis screening but also in the screening of young Japanese women from the perspective of osteoporosis prevention. According to our results, young Japanese women with low bone mass screened by QUS may be instructed to consume more calcium depending on their VDR gene polymorphism to prevent osteoporosis. Or in near future, if it becomes possible to comprehensively investigate SNPs at a relatively early stage such as at birth and during growth, it will be important to detect the
BsmI AA and
TaqI CC genotypes and attempt to increase bone mass.
Nonetheless, the present study has a few limitations. The phenotypic ratio of VDR gene polymorphisms varies among genotypes; hence, the statistical significance of OSI can differ. Therefore, uniformity in the number of participants is essential. In particular, there were only a limited number of participants for the
BsmI AA and
TaqI CC genotypes and there may have been low variability in these homozygous minor genotypes. Additionally, sample size calculation was not performed in this study because of the limited number of students we were able to recruit. However, to our knowledge, there has been no study that reports the relation between BMD and calcium intake in these genotypes in Japanese women, which may be due to the low proportion of these genotypes in the Japanese population. Therefore, the data from the present study would prove to be valuable. Second, serum vitamin D levels related to bone formation were not considered. Nevertheless, there is reportedly no significant difference in serum vitamin D levels among genotypes for the four VDR gene polymorphisms (
BsmI,
TaqI,
ApaI, and
FokI) [
45,
46]. Third, there are several environmental factors that may affect bone mass such as smoking and alcohol consumption, and these factors were not considered herein. Furthermore, a previous study showed that smoking and alcohol consumption does not affect BMD at younger ages [
9].
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.