ISSN 20790597, Russian Journal of Genetics: Applied Research, 2014, Vol. 4, No. 5, pp. 397–404. © Pleiades Publishing, Ltd., 2014. Original Russian Text © A.I. Kozlov, G.G. Vershubskaya, Yu.A. Ateeva, P. Orr, L. Larcombe, 2013, published in Ekologicheskaya Genetika, 2013, Vol. 11, No. 2, pp. 41–49.
Association of Vitamin D Receptor Gene With Anthropometric Measures in Komi Ethnic Group A. I. Kozlova, b, G. G. Vershubskayaa, b, Yu. A. Ateevab, P. Orrc, and L. Larcombec a
Institute and Museum of Anthropology, Moscow State University, 125009 Moscow, Mokhovaya St. 11, bld.1, Russia email:
[email protected] bPerm State HumanitarianPedagogical University, Sibirskaya St. 24, Perm, 614990 Russia c University of Manitoba, 745 Bannatyne Ave, Winnipeg Manitoba, R3E 0J9 Canada Received October 21, 2012; in final form, February 12, 2013
Abstract—The relationship between the vitamin D receptor gene (VDR) variants with serum 25OHD3 con centration, body height (BH), body weight (BW), and body composition were examined in the Komi ethnic group. The FFgenotype was associated with higher BW (p = 0.002) and lower bone mass (BM, p = 0.06) in comparison to the Ffgenotype carriers. The BBgenotype carriers were characterized by lower BL compared to those with Bbgenotype (p = 0.037); BM was lower among those having bb rather than Bb variants (p = 0.025). No differences in the 25OHD3 content were revealed. The results are consistent with the data obtained for populations from NorthWestern Europe and opposite to those reported for tropical and sub tropical Caucasians, as well as for nonCaucasians groups. Keywords: VDR, FokI, BsmI, ApaI, TaqαI, 25hydroxyvitamin D3, 25OHD3, body height, body mass, body composition, fat tissue, bone mass, muscle tissue DOI: 10.1134/S2079059714050074
INTRODUCTION A deficit of vitamin D is widely accepted to be characteristic for populations from the Northern regions (Gordon et al., 2004; Hodkinson et al., 1973; McKenna, 1992; Preece et al., 1975). However, the problem is caused by the fact that northern regions are rarely defined; however, it has become crucially important. It has been established that almost no vita min D was observed to be synthesized in November– March on the skin of individuals from regions to the north of 35° NL (Holick, 2004; Webb et al., 1988). Since the 35th parallel stands for the North American latitude, the northern regions have to include the whole territory of Europe, and especially Russia. Accordingly, the study of the status of vitamin D in the Russian population and the mechanisms of regulation of the mineral change in the bone (including that at the genetic level) is urgent due to the geographic loca tion of the Russian population. The development of methods allowing us to esti mate the serum concentration of the transport form of vitamin D—25hydroxyvitamin D3 (25OHD3) has recently become an important achievement. Studies of the 25OHD3 content in representatives from various populations remain scanty. It opens the possibilities for metaanalysis, the generalization of the data revealed by multiple studies, and the analysis of the influence of multiple factors, including geographical, ecological, socialeconomic, and medicalanthropo
logical, on the status of vitamin D of the group. Unfor tunately, information concerning the status of the vita min in various populations in Russia remains scarce. Studies with relatively large sample sizes were only conducted in populations from the temperate zone in Russia (Mikhailov et al., 2005; Smirnova et al., 2010; Shikh, Sychev, 2007) and Karelia (Viskari et al., 2006), as well as among Nenets from the Nentskiy Autono mous Region (Blazheevich et al., 1983), Komi and Russians from the Ural region (Kozlov et al., 2011, 2012; Potolycina et al., 2010; Bakhtyaroa et al., 2007). Even these data, together with information obtained from the vast studies in Europe and North America allow us to conclude that the status of vitamin D in populations is determined by a complex of factors rather than by geographic location (i.e., low or high latitude) (Holvik et al., 2008; Lips et al., 2001, 2006). The level of UVradiation ranging within 280–315 nm (erythemic radiation), seasonal modifications in inso lation, nutrition type, and the role of the local nutri tional resources determined by the climate and tradi tions in the clothes worn, the everyday level of physical activity, etc., should be taken into consideration. The question of the status of vitamin D and the necessity of calciferol in populations living at a high latitude is rather complex. On one hand, several find ings point to a reduced 25OHD3 content in serum according to European norms in Indians from the sub arctic regions in Canada and inuits (Eskimos) from
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Canada and Greenland (Hayek et al., 2010; Lebrun et al., 1993; Weiler et al., 2006), as well as individuals from the northern regions of the Komi Republic (Potolycina et al., 2010). On the other hand, there is increasing data showing high 25OHD3 content in northern individuals with a traditional style of life and nutrition compared to urbanized individuals (Blazeevich et al., 1983; Kozlov, Ateeva, 2011; Rejn mark et al., 2004). Undoubtedly, a significant role in this case is played by the traditional food content with its high vitamin D content in meat, fish, sea mammals, and reindeer fat (Kozlov, Ateeva, 2011; Björn, Wang, 2000). However, the possible role of anthropological (including that determined ethnically and ecologically) characteristics, possibly including the different tissue sensitivity to calciferol (Frost, 2012) and the population specifics of genetic determinants of the Dvitamin exchange should be taken into consideration. The intercellular receptor encoded by the vitamin D receptor gene (VDR) is involved in the binding of an active form of a vitamin. Its alleles are detected according to the corresponding sites of restriction endonucleases, among which FokI (rs10735810), BsmI (rs1544410), ApaI (rs7975232), and TaqαI are the most interesting with respect to their influence on cal cium assimilation and bone mass metabolism (Uitter linden et al., 2004). Their relation to the growth pecu liarities and bone mass development was detected in Caucasians, AfroAmericans and Mongoloids (Coo per, Umbach, 1996; d’Alesio et al., 2005; Fang, 2005; Ji et al., 2010; Minimitani et al., 1998; Morrison et al., 1994; Sainz et al., 1997; Tao et al., 1998; Vupputuri et al., 2006; Zmuda et al., 1997). The association revealed between the FokI, BsmI, ApaI, and TaqαI genotypes and bone mass develop ment resulted in the search of relations with other anthropometric characteristics. However, the obtained findings fail to be united. One of the first studies con ducted on a sample consisting of girls 7–12 years old from a Mexican population demonstrated no signifi cant differences in body length and weight, the body mass index (BMI), and body composition in individu als with various VDR genotypes (Sainz et al., 1997). However, the findings reported differences in the body height in BsmI (Arabi et al., 2009; Fang et al., 2007; Viitanen et al., 1996) and TaqαI (Ozaydin et al., 2010; Remes et al., 2005) allele carriers in various European (including Finnish), Arabian, and Turkish popula tions; it also showed the presence of a weak relation ship between BMI and FokI and TaqαI allele carriers in Asian Indians (Vupputuri et al., 2006). Suarez et al. (1997) provided the data that showed differences in the growth rate in French boys during the first two years of ontogenesis associated with the presence of the BsmI genotype (the differences were not signifi cant in girls). The inconsistencies in these (and many other) results might be caused by different reasons. The first one appears to include the effect of ethnical and envi
ronmental factors on the expression of the VDR gene. The differences in the bone mass between Caucasians and AfroAmericans from the United States with the same VDR genotype provides indirect evidence in sup port of this suggestion (Nelson et al., 2000). We decided to assume associations between VDR gene polymorphism and somathologic traits only in Caucasians to diminish the possible influence of the ethnic component. Unfortunately, despite the exist ence of extensive publications we succeeded in finding only a few studies concerning the correlations of inter est to us in populations in North Europe. In the present study, the data of the VDR gene allele frequencies in a sample of the Komi ethnic group are shown. The association of FokI, BsmI, ApaI, and TaqαI genotypes and the biochemical (25OHD3 content in serum) and somathologic characteristics in Komi (zyryan) as representatives of one population group from the Northern regions of the European part of the Russian Federation was analyzed. MATERIALS AND METHODS The material was collected in November, 2008. Students in senior classes in school aged 13–17 years (M = 15.0, SD = 1.2 years; n = 47) and university stu dents aged 18–23 years (M = 21, SD = 1.4 years, n = 48) from the Komi Republic located at 61–62 of NL were studied. The total sample comprised of 95 ethnic Komi. Below, we designate students at school as ado lescents, and university students, as adults. The study design included anthropometric analysis and blood intake (based on the 25hydroxyvitamin D3 content in serum) and polymorphisms of the VDR gene. The research was conducted in conjunction with the education departments of the corresponding regions within the annual medical examination of stu dents. The sample collection was performed after obtaining the informed consent from children, parents and/or the school administration for use of the revealed data for scientific purposes only. The design and organization of the study were approved by the Ethics Committee of Perm State HumanitarianPed agogical University and University of Manitoba. The blood intake was carried out in the morning on an empty stomach from the cubital vein into the Bek ton Dickinson BP (England) vacuum tubes. For the serum collection, the blood samples were centrifuged at 3000 RPM for 15 min. Serum samples were stored at –20°C prior to the analysis. The transport form of vitamin D (25hydroxyvita min D3, 25OHD3) was determined via the immune enzymatic analysis using the equipment of Immuno diagnostic Systems Ltd (United States). Genomic DNA was isolated from the whole blood samples collected on a filter paper using the QIAamp DNA Blood Mini Kit (QIAGEN). PCR for the VDR
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Table 1. Somathologic characteristics of the studied agegender Komi groups Gender Age; sample size Trait
Male 13–17 years; n = 22 M
Body weight (kg) 53.12 Body height (mm) 1657.6 BMI (BW/BH2) 19.3 Fat tissue (% BW) 12.38 muscle tissue (% BW) 42.73 Bone mass (% BW) 20.15
SD 8.105 63.72 2.14 2.534 2.807 1.538
Female
18–23 years; n = 14 M 68.69 1730.6 22.9 12.44 45.04 16.58
gene BsmI (T/C), ApaI (G/T), and FokI (T/C) alleles detection was performed according to the published protocols (Sainz et al., 1997; Selvaraj et al., 2004). For the BsmI restriction site, in the case of the absence of both alleles, the genotype was designated as BB; in the case of the restriction site being present in both alleles, the genotype was designated as bb; and for heterozy gotes, as Bb. For the other restriction sites, analogous designations were taken: ApaI G/T is further referred to as A/a; TaqαI C/T is referred to as T/t; and FokI T/C is referred to as F/f. The fragments were subjected to electrophoresis in 10% polyacrylamide gel; visualiza tion was conducted under UVlight using the KODAK Gel Logic 2000 Imaging System and KODAK 1D Image Analysis Software. Genotyping was performed in 95 samples. However, we failed to detect a genotype in all the studies sites. Anthropometric measurements were conducted in the morning according to the uniform technique (Bunak, 1941). The thickness of skinfolds was mea sured by a caliper with a constant pressure of 10 g/mm2 below the scapula, above the triceps and the biceps, on the stomach, breast (only in males), forearm, thigh, and leg. Based on the anthropometric data and the Matiegka (1921) methodic, the content of the fat, muscle, and the bone mass was determined. BMI was calculated according to the following for mula: BMI = BW/(BH)2, where BW is the body weight and BH is the body height in m. The highest border for the normal BMI in adoles cents is 25, and in adults it is 30 (Frisancho, 1990). Individuals exceeding these parameters were excluded from the analysis of associations between anthropo metric, biochemical, and genetic traits, in order to avoid the influence of the possible hormonal devia tions related to obesity. Correlation analysis between the traits was conducted in a sample of 91 individuals. Body length and weight values, BMI, values for the muscle, fat and bone body components, and 25OHD3 content in the serum were transformed to Zscores,
SD
13–17 years; n = 23 M
5.632 58.11 1.70 3.209 1.904 1.303
52.25 1599.2 20.5 21.95 39.47 16.48
SD 5.537 69.16 2.28 3.232 1.530 1.630
18–23 years; n = 33 M 54.67 1616. 0 20.9 22.75 40.69 15.53
SD 6.010 53.23 2.20 3.732 2.182 1.151
i.e., transferred to Z = (P – M)/S, where Z is the stan dardized value, P is the initial value, M is the arithmet ical mean in the group, and SD is the standard devia tion in the group where standardization is performed. Such a transformation reflects the number of standard deviations of an individual value distant from the aver age in a group. It makes it possible to exclude the influ ence of gender and age and to increase the size of the analyzed sample. After standardization procedures, all the values were combined. Subgroups with different genotypes with respect to the mentioned parameters were compared using the nonparametric KruskalWal lis test. Statistical analysis was performed via the Sta tistica software (StatSoft Inc., Tulsa, Oklahoma, United States). RESULTS The somathologic characteristics in the represen tatives of the studied agegender groups are shown in Table 1. The previously conducted analysis revealed that the total body sizes and BMI indices in contem porary Komi were closely related to the characteristics observed in Russians from this region, while the parameters of the physical development of students from the Komi population were congruent with the Russian and international norms (based on the criteria of the World Health Organization) (Kozlov et al., 2009; Frisancho, 1990). The preliminary research demonstrated no gender specific differences in the 25OHD3 content (Kozlov et al., 2011, 2012); thus, only subgroup characteristics divided by age (not by gender) are shown. The mean values of the 25OHD3 content in adolescents (M = 37.9, SD = 12.2 nmol/L, n = 44) were significantly lower than in adults (M = 47.7, SD = 12.0 nmol/L, n = 52; p < 0.001). The mean value of 25OHD3 in serum remains below 50 nmol/l in both age groups, usually depicted as the lower border of the recom mended level of the vitamin D content (Frost, 2012; Holick, 2007; Roth et al., 2005).
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Table 2. Allele and genotype frequencies of the VDR gene in the Komi sample FokI (rs10735810) allele F f FF Ff ff
N 101 89 24 53 18
BsmI (rs1544410)*
%
allele
53.2 46.8 25.3 55.8 18.9
B b BB Bb bb
N 68 118 19 30 44
ApaI (rs7975232)
%
allele
36.6 63.4 20.4 32.3 47.3
A a AA Aa aa
TaqαI (rs731236)
N
%
94 96 21 52 22
49.5 50.5 22.1 54.7 23.2
allele T t TT Tt tt
N
%
138 50 52 34 8
73.4 26.6 55.3 36.2 8.5
* Not congruent with the Hardy–Weinberg disequilibrium.
The frequencies of FokI, BsmI, and ApaI alleles, as well as TaqαI and VDR genotypes, in the studied sam ple are shown in Table 2.
No significant differences in the 25OHD3 content in the serum in representatives of the studied geno types and haplotypes were detected. The differences in the somathologic parameters in the carriers of differ ent ApaI and TaqαI genotypes were also not significant (p > 0.05). Hence, we focus on the specifics of the somathologic parameters for FokI and BsmI genotypes only.
Nine haplotypes differing in the alleles of the BsmI, ApaI, and TaqαI sites were detected. BATbat variants were the mostly frequent (25% of the sample) and the frequency of haplotypes bATbaT and baTbaT was almost the same (22.8% in both cases). The frequency of BatBat and BATbaT variants were rare (7.6 and 6.5%, respectively); while BATBAT, bATbAT, and batbat haplotypes were observed once.
The FFFokI genotype carriers differed from Ff in significantly higher body weight (p = 0.002); hence, despite some prevalence over Ffv in height, FFmonozy gotes possessed a higher parameter characterizing the massheight relation, such as BMI (p < 0.01). Differ ences of FFFokI genotype carriers from fallele carri ers in fat and muscle tissues were not significant, whereas the impact of bone mass on the total body
The somathologic and biochemical parameters of the subgroups differing in VDR genotype (as the Zscores obtained as a result of standardization) are demonstrated in Figs. 1, 2.
Body weight
Body height
BB *p = 0.0374
Bb
bb
*p = 0.0374
BMI
Fat tissue (% BW)
Muscle tissue (% BW)
Bone mass (% BW)
*p = 0.0252
*p = 0.0252
–0.8
–0.6
–0.4
–0.2
0 Zscores
0.2
0.4
0.6
0.8
Fig. 1. Standardized somathologic and biochemical parameters of subgroups differing in the FokI genotype (rs10735810). Aster isk stands for significantly differing values for each somathologic parameter. Level of significance is shown (pvalue). RUSSIAN JOURNAL OF GENETICS: APPLIED RESEARCH
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Body weight
401 *p = 0.021
*p = 0.021
Body height *p = 0.099 BMI
*p = 0.099
Fat tissue (% BW)
Muscle tissue (% BW)
Bone mass (% BW) –0.8
*p = 0.0622
–0.6
*p = 0.0622 –0.4
–0.2
0 Zscores
0.2
FF Ff
0.4
0.6
ff 0.8
Fig. 2. Standardized somathologic and biochemical parameters of subgroups differing in BsmI genotype (rs1544410). Asterisk stands for significantly differing values for each somathologic parameter. Level of significance is shown (pvalue).
weight was higher in Ffheterozygotes compared to FFmonozygotes (the differences were significant at the level of p = 0.06). Individuals with the homozygous BBBsmI geno type demonstrated significantly decreased body height compared to Bbgenotype carriers (p = 0.0037). How ever, the mean values of the Z scores of the body weight in carriers of all BsmIgenotypes appeared to be simi lar, and the differences in growth remained insignifi cant to the result on the occurrence of massheight indices between the subgroups. Carriers of the bb BsmI genotype were shown to possess relatively (com pared to body weight) lower bone mass content com pared to Bbheterozygotes (p = 0.025). The differ ences in the fat and muscle tissues in the carriers of various genotypes remained insignificant. The peculiarity of the somathologic characteristics in the representatives of various haplotypes con structed on the basis of BsmI, ApaI, and TaqαI sites was detected only in body height. BATbaT variant carriers significantly exceeded individuals with BAT Bat (Zscore values for the body height are Z1 = ⎯0.586, Z2 = + 0.862; p < 0.01); however, both sub groups were small (n1 = 6, n2 = 9). The mean body height in BatBat haplotype carriers was also relatively low (Z3 = –0.204, n3 = 7; p > 0.05) compared to BATbaT and BATBat subgroups). The body height in individuals with other haplotypes was close to the mean for the total sample.
DISCUSSION The vitamin D (25OHD3) content in the serum of Komi (zyryan) individuals from the southern regions of the Komi Republic should be assumed to be low (Kozlov et al., 2011, 2012). Although all the studied individuals inhabit the same geographic region and the samples collected for the analysis were from the same season, the 25OHD3 content significantly differed in the representatives from various age groups (p < 0.001). The lower 25OHD3 content in adolescents compared to the level detected in adults is congruent with other studies (Holick, 2007). The absence of an association between VDR gene polymorphisms and 25OHD3 content in serum is also at odds with our findings (Bezerra et al., 2008; Hibler et al., 2010). The studied sample differed insignificantly in FokI and BsmI allele frequencies from the Russians from Moscow (Myakotkin et al., 2011; Taghieva et al., 2005). It might be concluded that the distribution of the VDR gene alleles in the Komi (zyryan) sample is similar to the Caucasians’ variability spectrum. Accordingly, the obtained results were compared only with the material observed in Caucasians investigated in Europe in order to exclude the possible influence of eth nic specifics in Mongoloid and AfroAmericans, as well as of ethnically mixed (metis) groups of populations from the United States, Canada, Brazil, and India. The investigated FFFokI genotype carriers dif fered from individuals with fallele in their increased body weight with a lower bone mass and a relatively
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high (with respect to weight) body height. The differ ence in body weight and BMI (p < 0.01) and the rela tive bone mass (p = 0.06) are significant compared to Ffheterozygotes. It means that body weight increases relatively to the height due to the muscle and fat tissues but not to the bone tissues in FFgenotype carriers; while Ffgenotype carriers demonstrated the higher impact of skeleton weight compared to other compo nents of body composition. We do not assume the observed decrease in the bone mass content in FFcarriers contradictory to the reported increased resorption rates of bone mass in Russians and French women with the ffFokIgeno type compared to the FFgenotype (Myakotkin et al., 2011; Eccleshall et al., 1998). The mentioned studies were performed in older women, while young individuals in the period of rapid growth followed by stabilization of body size were studied in the present study. Hence, the observed differences should be analyzed in the context of age and possibly ecologic specifics of the VDR genotype’s influence on the bone mass metabolism. Individuals with the BbBsmI genotype in the present study differed in the increased body height and enhanced development of the bone mass compared to BB and bbvariant carriers, respectively (p < 0.05 in both cases). This shows the weaker impact of the bone mass in homozygotes in the total body weight and is con gruent with the observations that demonstrated that the summarized mass of the bone and muscle tissues (the fat less or lean body mass) in the population in Sweden in Bbgenotype carriers showed a trend for increased values in homozygotes, while the fat component in BBBsmI carriers is higher than in bb (Grundberg et al., 2004). Our findings, together with data obtained by E. Grundberg et al. (2004), indirectly confirm the conclusion of the diminished efficiency of calcium absorption by BBBsmI genotype carriers compared to bb (DawsonHughes et al., 1995; Ferrara et al., 2002). The body height differences (Bb > bb > BB) observed in the present study match the results obtained for the French population (Suarez et al., 1997); however, sub groups’ distribution in body height was different in the Dutch: BB > Bb > bb (Fang et al., 2007). In this context, the differences in the body height in the studied individuals with various haplotypes (BAT baT > BATBat; p < 0.01) should be mentioned. As we have underlined, the subgroups are small, hence, the manifestation of BsmI zygosity instead of haplotype specific cannot be excluded. The relative proximity of BatBat and BATBat haplotype carriers (both are characterized by a relatively small body height), in contrast to the highest BATbaT studied carriers, points to that. The combination of BatBat + BAT Bat in one subgroup (n = 13) and its comparison with BATbaT (n = 9) revealed significant differences in the body height (p < 0.05). Accordingly, the association of the high height with the BbBsmI genotype rather than with haplotype specifics cannot be excluded.
The body weight and BMI in bbBsmI genotype carriers was higher than in Ballele carriers in homo and heterozygous variants in the French population (Ye et al., 2011). In the present study, the ratio of the parameters is the same, although the differences remain statistically insignificant. The data regarding the association of the body size with TaqαI genotype are contradictory for Cauca sians. EuropeanAmerican and Turkish girls aged 7– 15 years and bearing the TTTaqαI genotype differed by the increased body weight and height from ttgeno type carriers (Ozaydin et al., 2010; Tao et al., 1998), while middleaged Finnish men with Tt and ttgeno types, in contrast, exceeded the Tvariant carriers in body height (Remes et al., 2005). Our sample, together with the English sample (Todhunter et al., 2005), was characterized by the absence of statistically significant somathologic differences in the carriers of various TaqαI variants. The absence of significant differences in the somathologic characteristics in various ApaI genotype carriers corresponds to the data obtained by Todhunter et al. (2005). Accordingly, the association of allelic variants of the VDR gene with body height was detected only for the BsmI polymorphism (p = 0.037) in the studied sample of the autochthonal population from the northern regions of European Russia. The differences in the weight and body mass index (BMI) between the subgroups formed with respect to FokI genotypes were statistically significant. The bone mass content (as a percentage of body weight) differed significantly in carriers of various FokI and BsmI allelic variants. The revealed findings are congruent or at least do not oppose the results obtained for northwestern European populations (France, Sweden, Holland), while the specifics of the somathologic characteristics of carriers of various VDR genotypes described in the samples of nonCaucasians or Caucasians inhabiting in subtropical and tropical regions were not observed in our sample. In particular, no increase in body height in FfFokI heterozygotes compared to the homozy gotes described in Japanese adolescent females and young women (Minamitani et al., 1998) was detected. In the present study, ffFokI genotype carriers were characterized by the average BMI values (Z = –0.03), while Asian Indians and individuals from Southern Italy differed by their small BMI values (Ferrara et al., 2002; Vupputuri et al., 2006). As a result of the conducted research, for the first time in the Russian sample, the data of the association of FokI and BsmI genotypes and somathologic param eters were obtained. The results confirm the hypothe sis that VDR genotype specifics might determine dif ferences in bone mass sensitivity to environmental conditions even in populations belonging to the same ethnic groups but inhabiting different ecologic regions. The accumulation of information of the peculiarities of tissue (especially, bone tissue) metabo
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lism and its genetic regulation in groups differing in their origin, nutrition, growth, and development spe cifics appears to be an urgent task for the northern and polyethnic Russia. ACKNOWLEDGMENTS The present study was supported by the Russian Foundation for Basic Research no. 100496005r Ural (A.K.), Perm State HumanitarianPedagogical University PSR 026F (A.K., G.V., Yu.A.), and National Sanitarium Association (P.O., L.L.). REFERENCES d’Alesio, A., Garabedian, M., Sabatier, J.P., et al., Two sin glenucleotide polymorphisms in the human vitamin D receptor promoter change protein–DNA complex for mation and are associated with height and vitamin D status in adolescent girls, Hum. Mol. Genet., 2005, vol. 14, no. 22, pp. 3539–3548. Arabi, A., Zahed, L., Mahfoud, Z., et al., Vitamin D recep tor gene polymorphisms modulate the skeletal response to vitamin D supplementation in healthy girls, Bone, 2009, vol. 45, no. 6, pp. 1091–1097. Bakhtiyarova, S., Lesnyak, O., Kyznesova, N., et al., Vita min D status among patients with hip fracture and eld erly control subjects in Yekaterinburg, Russia, Osteoporosis Intern., 2004, vol. 17, no. 3, pp. 441–446. Bezerra, F.F., Cabello, G.M.K., Mendoca, L.M.C., and Donangelo, C.M., Bone mass and milk calcium con centration are associated with vitamin D receptor gene polymorphisms in adolescent mothers, J. Nutr., 2008, no. 138, pp. 277–281. Bjorn, L.O. and Wang, T., Vitamin D in an ecological con text, Int. J. Circumpolar Health, 2000, vol. 59, no. 1, pp. 26–32. Blazheevich, N.V., Spirichev, V.B., Pereverzeva, O.G., et al., Characteristics of calcium–phosphorus metabo lism and vitamin D sufficiency in the Far North, Vopr. Pitaniya, 1983, no. 1, pp. 17–22. Bunak, V.V., Antropometriya (Anthropometry), Moscow: Uchpedgiz, 1941. Cooper, G.S. and Umbach, D.M., Are vitamin D receptor polymorphisms associated with bone mineral density? A metaanalysis, J. Bone Mineral Res., 1996, vol. 11, no. 12, pp. 1841–1849. DawsonHughes, B., Harris, S., and Finneran, S., Calcium absorption on high and low calcium intakes in relation to vitamin D receptor genotype, J. Clin. Endocrinol. Metab., 1995, vol. 80, pp. 3657–3661. Eccleshall, T.R., Garnero, P., Gross, C., et al., Lack of cor relation between start codon polymorphism of the vita min D receptor gene and bone mineral density in pre menopausal French women: the OFELY study, J. Bone Mineral Res., 1998, vol. 13, no. 1, pp. 31–35. Fang, Y., Vitamin D Receptor Gene Polymorphisms and Bone, Erasmus Medical Center, Rotterdam, The Nether lands, 2005. Fang, Y., van Meurs, J.B., Rivadeneira, F., et al., Vitamin D receptor gene haplotype is associated with body height and bone size, J. Clin. Endocrinol. Metab., 2007, vol. 92, no. 4, pp. 1491–1501.
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Translated by A. Kazantseva
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