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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 10 3563-3568
Copyright © 1998 by The Endocrine Society

Original Studies

Interactive Effect of Estradiol and Vitamin D Receptor Gene Polymorphisms as a Possible Determinant of Growth in Male and Female Infants

Françoise Suarez, Claude Rossignol and Michèle Garabédian

Centre National de la Recherche Scientifique, URA 583-UPR 1524, Hôpital Saint Vincent de Paul (F.S., M.G.), 75014 Paris; and Centre des Bilans de Santé de l’Enfant, CPAM de Paris (C.R.), 75011 Paris, France

Address all correspondence and requests for reprints to: Dr. M. Garabédian, CNRS URA 583, Hôpital Saint Vincent de Paul, 82 avenue Denfert Rochereau, 75014 Paris, France.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
An association between vitamin D receptor (VDR) gene polymorphism and body size has been observed in infants. We hypothesized that the estradiol receptor (ER) gene is another determinant of infant growth and that the effects of the VDR and ER genotypes may interact with each other. The ER genotype (PvuII and XbaI sites), VDR genotype (BsmI site), and body size during the first 2 yr of life were analyzed in 161 healthy Caucasian full-term babies homozygous for the BsmI polymorphism of the VDR gene (BB or bb). There was no significant association between ER polymorphism and 1) body weight in boys and girls, 2) body length in girls, or 3) body length in boys with a bb genotype. In contrast, ER polymorphism and body length were significantly associated in BB boys. Boys with the BBpp genotype were shorter at birth (P < 0.005) and at 10 months of age (P < 0.001) than boys with other genotypes. They were even shorter than girls with the same genotype. These results indicate some degree of interaction between the effects of the VDR and ER genes, leading to significant variations in body growth during infancy, especially in boys.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GROWTH is a complex process that is regulated by multiple genetic and environmental factors interacting via pathways that have not yet been fully elucidated. Infancy is a particularly important period during which to analyze this regulation, as it is the time when growth is fastest. It is also easier to study growth regulation at this age because interfering events, such as epiphyseal closure during adolescence, do not have to be taken into account. Finally, in view of a recent report showing an association between weight at 1 yr of age and the bone mineral content during the seventh decade of life (1), studies on growth in infancy may help to identify some of the regulatory pathways leading to final body size and also to bone mass in adults.

After the demonstration by Morrison et al. (2, 3) of a vitamin D receptor (VDR) gene polymorphism and its likely consequences for bone metabolism, several studies have analyzed the restriction fragment length polymorphism (RFLP) of the VDR gene. Most of them have focused on a possible association between allelic variations in the VDR locus and bone mass in adults. The results have been negative or have shown a weak association, suggesting that the VDR gene is one of the many genetic determinants of bone mass (4, 5). More recent studies suggest that the VDR gene influences bone density even before puberty (6), but this influence may be undetectable, as reported in a Norwegian study on prepubertal and pubertal girls and boys (7).

Given the possible relationship between bone mass and early body growth (1), part of the effect of the VDR gene on bone mass could be linked to its influence on prenatal and early infant growth. We (8) and others (9) have recently proposed that the VDR gene is a genetic contributor to intrauterine and early postnatal growth, at least up to the second year of life. Of interest, we showed that the association between the VDR genotype and body size differed in girls and boys (8). In other studies, this association occurred only in girls (10) or was not found when infants had not been separated according to gender (11). This suggests that the VDR genotype influences early growth via interactions with gender-related growth regulators.

Estradiol is a well known regulator of growth and skeletal maturation in girls, and clinical reports have disclosed its role in male subjects as well (12, 13, 14). The estradiol receptor (ER) gene is itself a likely determinant of growth during puberty, as suggested by the associations found between allelic variations of the ER gene and the height of adult women (15, 16, 17, 18) or the gain in weight during puberty of adolescent girls (19).

For these reasons, we hypothesized that the ER gene is, like the VDR gene, a determinant of infant growth and that the effects of the VDR and ER genotypes may interact with each other. To test this hypothesis, we investigated possible associations among the ER genotype (PvuII and XbaI sites), the VDR genotype (BsmI site), and body growth during the first 2 yr of life, in a cohort of 161 healthy Caucasian full-term babies who were homogeneous for age, diet, and vitamin D status and who were homozygous for the BsmI polymorphism of the VDR gene.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The estradiol and VDR gene polymorphisms were analyzed in the blood samples of 161 healthy infants seen at the Centre des Bilans de Santé de l’Enfant, CPAM (Paris, France), for a systematic physical and biological examination at 10 months and 2 yr of age. These infants had been selected from a total cohort of 589 babies, previously analyzed for their VDR genotype (8). In this population, BB alleles were found in 14% of the infants, bb alleles were found in 39%, and Bb alleles were found in 47%. This distribution of the VDR genotype was similar to that reported for other Caucasian populations (4). The 161 infants had been selected from the total population on the basis of the following criteria: 1) available data on body size at birth, 2) available data on crown-heel length and weight measured in the CPAM check-up center at 10 months and/or 2 yr of age, 3) full-term birth (only babies born after 37.5 weeks of pregnancy were considered to eliminate possible interferences due to the catch-up growth of premature babies), and 4) homozygosity for the BsmI polymorphism of the VDR gene.

The selected infants included 73 girls and 88 boys. As a consequence of the selection criteria, data on body size at birth, 10 months, and 2 yr were available for 125 infants. These data were available at birth and either at 10 months or 2 yr of age for the remaining 36 infants. Almost half (42%) of the infants had all 4 grandparents originating in France. The others were of mixed European or North African origin. No information on geographical origin and past history and no blood samples others than those specifically collected for the check-up were used in this study.

Blood samples were obtained from capillary blood collected in the morning during the routine check-up. Genomic DNA was extracted from whole blood using a commercial kit and was analyzed for polymorphism of the VDR and ER genes after amplification by PCR.

Primers designed to amplify the intragenic polymorphic BsmI site of the VDR gene were the following: forward, 5'-CAACCAAGACTACAAGTACCGCGTCAGTGA-3'; and reverse, 5'-AACCAGCGGGAAGAGGTCAAGGG-3' (3). Amplification conditions, using a Perkin-Elmer (Norwalk, CT) DNA thermal cycler 480, were as follows: 94 C for 5 min followed by 35 cycles at 94 C for 60 s, 56 C for 60 s, and 72 C for 90 s and a terminal extension at 72 C for 10 min. After amplification, the PCR product (0.825 kb) was digested with restriction endonuclease BsmI and electrophoresed in a 1.2% agarose gel.

Primers designed to amplify intragenic polymorphic PvuII and XbaI sites of the ER gene were the following: forward, 5'-CTGCCACCCTATCTGTATCTTTTCCTATTCTCC-3'; and reverse, 5'-TCTTTCT-CTGCCACCCTGGCGTCGATTATCTGA-3' (20). Amplification conditions were as follows: 94 C for 5 min followed by 35 cycles at 94 C for 60 s, 61 C for 60 s, and 72 C for 90 s and a terminal extension at 72 C for 10 min. After amplification, the PCR product (1.3 kb) was digested with restriction endonucleases PvuII and XbaI and electrophoresed in a 1.2% agarose gel.

The RFLPs were coded as Bb (BsmI), Pp (PvuII), and Xx (XbaI), where the uppercase letter signifies the absence of the site, and the lowercase letter signifies its presence.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The selected infants were homozygous for the VDR genotype; 124 had a bb genotype (BsmI site present), and 37 had a BB genotype (BsmI site absent). Two areas of the ER gene were analyzed, the PvuII and XbaI sites. The allele frequencies at the PvuII and XbaI polymorphism sites were similar to those reported for other Caucasian populations (20, 21) in both the bb and BB subpopulations (Table 1Go). PvuII and XbaI alleles were closely linked (81%), and there were 6 RFLP genotypes with a frequency greater than 1%: PpXx (42%), ppxx (29%), Ppxx (10%), PPXX (9%), PPXx (7%), and PPxx (3%).


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  		Table 1. ER genotype in 161 infants: PvuII and XbaI allele frequencies (percentages)

 
Interactions between the effects of ER and VDR polymorphisms on body size were analyzed using the PvuII RFLP to allow comparison with the published studies on ER in older subjects (15, 16, 17, 18, 19). Six subgroups were identified. Homozygous groups were mainly bbpp (22% of the total cohort), bbPP (15%), and BBpp (7%). Only five girls and one boy had a BBPP genotype (4% of the total cohort).

Associations between anthropometric data and genotypes were analyzed at birth, 10.1 ± 0.6 months of age, and/or 22.9 ± 1.0 months of age (mean ± 1 SD). As reported previously (8), BB boys were significantly smaller (P = 0.03) and lighter (P = 0.03) than bb boys at 10 months of age (Tables 2Go and 3Go).


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  		Table 2. Sex differences in body length according to VDR and ER genotype (mean ± 1 SD)

 

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  		Table 3. Sex differences in body weight according to VDR and ER genotype (mean ± 1 SD)

 
There was no association between ER polymorphism and weight in any of the male groups at any age tested (Table 3Go) or between ER polymorphism and length in the bb group of boys (Fig. 1Go). In contrast, there was a significant association between ER polymorphism and body length in the BB boys (Fig. 1Go). Boys with the BBpp genotype were shorter at birth (P < 0.005) and at 10 months of age (P < 0.001) than boys with other genotypes (BBPp or any of the bb genotypes). The mean crown to heel length of these BBpp boys was 1 SD less the mean length of French reference male populations at birth (50 ± 1.5 cm) (22) and at 10 months of age (72 ± 2 cm) (22, 23). The mean lengths of the BBpp boys was also below the 25th percentile value at birth (49 cm) and was close to the 10th percentile value at 10 months of age (70.6 cm) with respect to the reference curves for Caucasian children living in the United States (24). The mean body lengths of the other genotypic groups were slightly above the French reference values and were between the 50th and 75th percentile values of the American reference curves. The smaller size of the BBpp boys was not related to a slower growth rate between birth and 10 months of age (Table 4Go) and was no longer observed at 2 yr of age (Fig. 1Go).



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  		Figure 1. Crown to heel length in relation to VDR and ER genotypes. Length was measured at birth, 10 months of age, and/or 2 yr of age in 87 male (upper part) and 73 female (lower part) full-term babies homozygous for the VDR genotype at the BsmI site (BB and bb). Values are the mean ± 1 SE of body length in the five subgroups of infants identified on the basis of their VDR (BsmI site) and ER (PvuII site) genotypes. The number of infants in each subgroup is shown in the bars. *, P = 0.0049 (by Mann-Whitney U test); P = 0.031 (by Kruskal-Wallis test) compared with the other subgroups of infants of the same age and sex. **, P = 0.0006 (by Mann-Whitney U test); P = 0.025 (by Kruskal-Wallis test) compared with the other subgroups of infants of the same age and sex.

 

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  		Table 4. Sex differences in body length gain according to VDR and ER genotype (mean ± 1 SD)

 
Body size parameters were not significantly associated with genotype in girls, but, unlike boys, girls with the BBpp genotype tended to be longer and heavier than girls with the other genotypes at birth and 10 months of age, rather than shorter and lighter (Tables 2Go and 3Go and Fig. 1Go). Because of the different associations between body size and genotype in boys and girls, gender-related differences in length and weight were observed in only some of the genotypic subgroups. As expected, boys at birth, 10 months, and 2 yr were significantly taller (Table 2Go) and heavier (Table 3Go) than girls in the three groups with a bb genotype, but the boys and girls in the overall BB group had similar body lengths and weights at all ages tested, whereas the boys in the BBpp group were even shorter than the girls at birth (P = 0.007) and 10 months of age (P = 0.04).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
A number of clinical and experimental studies have pointed out the crucial influence of estradiol on skeletal growth and maturation in both women and men. The present finding of a relationship between body size in infancy and polymorphism of both the ER (PvuII) and VDR (BsmI) genes suggests that these genes interact to influence the regulation of prenatal and infantile growth, especially in boys.

This study first confirms the previously reported association between the BsmI polymorphism of the VDR gene and body size during infancy (8, 9). A cluster of linked polymorphisms has been reported in the 3'-end of the VDR gene, including the BsmI polymorphism in the intron separating exons VIII and IX (3). This latter polymorphism does not influence the amino acid sequence of the VDR protein, but it may be linked to other genetic variations affecting crucial steps of the synthesis or regulation of this protein. For example, BsmI has been linked in some populations to poly(A) microsatellite repeats in the 3'-untranslated region, a genetic variation that may influence trans-activation activity and messenger ribonucleic acid stability (25).

The results of this study also provides support for the hypothesis that ER genotype is another determinant of intrauterine and early postnatal growth, as suggested by the association between the PvuII polymorphism of the ER gene and the crown to heel length of BB boys at birth and 10 months of age. The size of the variations linked to ER/VDR polymorphism was about 1 SD on the reference growth curve for French children (22). Two ER types have been reported, ER-{alpha} and ER-ß. The analyzed PvuII polymorphism appears to be specific for ER-{alpha}, as at least one of the primer sequences chosen for PCR amplification is not present in the ER-ß gene. Similar to those of the VDR gene polymorphism, the functional consequences of the studied ER gene polymorphism are not clear. Although this PvuII RFLP has been associated with breast cancer (21) and variations in the final body size of healthy individuals (15, 16, 17, 18, 19), it reflects a T/C point variation in the intron I of the ER gene and therefore has no influence on the amino acid sequence of the ER protein (26).

Estrogens appear to influence not only pubertal but also prepubertal growth, even when circulating levels of estrogen are low (27, 28). Low doses of ethinyl estradiol increase growth velocity in prepubertal girls (29) as well as boys (30), and there appears to be a significant positive association between the neonatal serum concentration of estradiol and the height of boys and girls aged approximately 4 yr (31). In view of the present results, estradiol may also influence statural growth during prenatal and early postnatal life, when growth is fastest. An association between the ER/VDR polymorphism and the crown to heel length was found in boys at birth and at 10 months of age, but it was no longer found at 2 yr and did not result from variations in growth velocity during the first year of life. The hypothesis of an early effect of estradiol on statural growth fits well with the very high blood levels of estradiol found at birth, because of placental production throughout pregnancy (32), and with the postnatal estradiol levels that remain slightly above prepubertal levels during the first 2 months of life in both girls and boys (33). There is also a marked surge in testosterone production in boys between birth and the first 2–3 months of life (33). This testosterone may be a local source of estradiol due to aromatization in its target tissues. Also consistent with estradiol being an early regulator of skeletal growth, estradiol receptors have been found in both female and male human fetal cartilage (34). However, it is not yet possible to say whether the association between the ER gene polymorphism and body size in male infants results from an action of estrogen on growth plate cartilage and/or on the pituitary or even hypothalamic cells, as endogenous estrogen appears to facilitate the neuroendocrine control of the somatotropic axis in adolescent males (35).

Of interest, unlike in boys, associations between body size and ER/VDR polymorphism were not significant in girls. This sex difference may be artifactual and related to the small size of the studied populations, but it could also reflect the marked differences in the circulating levels of sex steroids, especially of testosterone, at this age (33); gender-related differences in the sensitivity of cartilage cells to estradiol despite similar receptor levels in males and females (34, 36); or gender-related differences in other regulatory or structural genes that influence growth (37).

Finally, the effect of ER gene polymorphism was seen in the infants with a BB genotype at the VDR gene locus, but not in those with a bb genotype. Thus, there appears to be a gene-gene interaction on infant growth for polymorphism of both the ER and VDR genes. Similarly, other interactions between the VDR and ER genes have been reported to influence bone mineral density in pre- and postmenopausal women (38, 39) and weight gain in adolescent girls (19). The mechanism and site(s) of these interactions remain unknown, but different hypotheses can be proposed. In the numerous cell types that express both ER and VDR, these receptors may interact on gene transcription via a heterodimerization similar to that described between VDR and other receptors of the same family, mainly retinoid X receptor (40). VDR and ER may also interact via effects of each on the expression of the other. Estrogens modulate the expression of the VDR gene, as reported in bone cells (41) and breast cancer cells (42). Inversely, 1,25-dihydroxyvitamin D3 modulates ER expression, as reported in bone marrow-derived cells (43). Thus, VDR and ER polymorphisms may interact to modulate the activities of osteoblasts, chondrocytes, and possibly other cells producing hormones and factors involved in the regulation of statural growth. Another and potentially crucial possibility of interaction between estrogens and vitamin D during growth derives from the direct effect of the vitamin D-VDR complex on messenger ARN expression and enzymatic activity of the aromatase cyctochrome P450 in bone cells (44). As this enzyme converts androgens to estrogens in placenta, gonads, brain, adipose tissue, and bone cells, VDR polymorphism may influence the effect of ER polymorphism on growth via direct modulation of the cell responses to estrogens and by stimulating the local production of estrogens during fetal and early postnatal life.

Our results, therefore, indicate some degree of interaction between the effects of the vitamin D and estradiol receptor genes leading to significant variations in body growth during infancy, especially in boys. Most association studies to date on the genetic effects of the ER and VDR genes have focused on the body size and bone mineral content of women. Further studies will show whether the early genetic effect found in boys influences final body size and/or bone mineral content.


   Acknowledgments
 
The authors thank all of the biologists at the Centre des Bilans de Santé de l’Enfant for their help and friendly interest, and Dr. Owen Parkes for his help with the English text edition.

Received March 9, 1998.

Revised July 2, 1998.

Accepted July 13, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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