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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-2447
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 6 2286-2291
Copyright © 2007 by The Endocrine Society

Effect of an Estrogen Receptor-{alpha} Intron 4 Polymorphism on Fat Mass in 11-Year-Old Children

J. H. Tobias, C. D. Steer, C. Vilarino-Güell and M. A. Brown

Clinical Science at South Bristol (J.H.T.), Community Medicine (C.D.S.), University of Bristol, Bristol BS2 8HW, United Kingdom; Botnar Research Centre (C.V.-G., M.A.B.), University of Oxford, Oxford OX1 3QX, United Kingdom; and Centre for Immunology and Cancer Research (M.A.B.), University of Queensland, Brisbane QLD 4072, Australia

Address all correspondence and requests for reprints to: Dr. J. Tobias, Rheumatology Unit, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom. E-mail: jon.tobias{at}bristol.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Polymorphisms in the ESR1 gene encoding estrogen receptor (ER)-{alpha} may be associated with fat mass in adults.

Objectives: The objective of the study was to establish whether ESR1 polymorphisms influence fat mass in childhood.

Design: This was a cross-sectional analysis after genotyping of rs9340799, rs2234693, and rs7757956 ESR1 polymorphisms.

Setting: The Avon Longitudinal Study of Parents and Children (ALSPAC) was a population-based prospective study.

Participants: Participants included 3097 11-yr-old children with results for ESR1 genotyping, puberty measures, and dual-energy x-ray absorptiometry results.

Outcomes: Relationships between ESR1 polymorphisms and indices of body composition were measured.

Results: The rs7757956 polymorphism was associated with fat mass (P = 0.002). Total body fat mass (adjusted for height) was reduced by 6% in children with TA/AA genotypes, and risk of being overweight (≥85th centile of fat mass) was decreased by 20%. This genetic effect appeared to interact with puberty in girls (P = 0.05 for interaction): in those with the TT genotype, total body fat mass (adjusted for height) was 18% higher in Tanner stages 3–5 vs. stages 1–2; the equivalent difference was 7% in those with TA/AA genotypes. Furthermore, the risk of being overweight was 36% lower in girls with TA/AA genotypes in Tanner stages 3–5, but no reduction was seen in those in stages 1–2. Neither rs9340799 nor rs2234693 polymorphisms were associated with body composition measures.

Conclusions: Fat mass in 11-yr-old children was related to the rs7757956 ESR1 polymorphism. This association was strongest in girls in more advanced puberty, in whom the risk of being overweight was reduced by 36% in those with the TA/AA genotype.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE PREVALENCE OF childhood obesity is increasing in several Western countries including the United Kingdom, Europe, and the United States (1, 2, 3), which has important implications for both immediate and long-term health (4, 5). Diet survey data suggest that population levels of obesity have increased in the face of declining energy intake, implying that inactivity may be more important than overconsumption (6, 7). Although these environmental influences are likely to exert the strongest effects in genetically predisposed individuals, to date, relatively few genetic factors have been implicated as causative agents in childhood obesity. However, in recent genetic association studies, polymorphisms in the adiponectin, INSIG2, and melanocortin-4 receptor genes have been reported to be associated with obesity in child populations (8, 9, 10).

In terms of other endocrine pathways that may potentially be involved in childhood obesity, sex steroids and the GH-IGF-I axis are both recognized as major regulators of body composition in childhood (11). For example, male estrogen receptor (ER)-{alpha} knockout mice have previously been reported to develop obesity after sexual maturity (12, 13). This finding is consistent with the report that adipocytes express relatively high levels of ER{alpha}, which is thought to be the major ER subtype involved in functional responses of adipocytes to estrogen (14, 15, 16). Evidence of a possible link between genetic variation in ESR1 (the gene encoding ER{alpha}) and obesity is provided by the observation that the ESR1 rs2234693 (PvuII) polymorphism is associated with fat mass in women but not men (17). Moreover, this polymorphism was associated with waist to hip ratio, consistent with evidence that estrogen helps to determine body fat distribution in women before the menopause (17).

As for a possible link between genetic variation in the ESR1 gene and obesity in childhood, in a small group of 147 children, adolescents, and young adults, no association was observed between PvuII and rs9340799 (XbaI) polymorphisms and body mass index (BMI) (18). However, this investigation was based on relatively few children, and was probably too small to detect genetic influences of the magnitude that are likely to have been present. Furthermore, this study was restricted to analysis of PvuII and XbaI polymorphisms, which represent a relatively small component of the overall genetic heterogeneity of the ESR1 gene. For example, in a recent investigation in which we examined the association between ESR1 polymorphisms and pubertal changes in bone mass in the Avon Longitudinal Study of Parents and Children (ALSPAC), we identified an intron 4 polymorphism as being related to bone mass independently of the PvuII and XbaI polymorphisms (19).

Because the ER is a ligand-activated transcription factor, ESR1 gene polymorphisms may exert differing effects in childhood according to prevalent levels of estradiol, which rise appreciably during puberty, reaching adult levels in girls at menarche. In addition, strong interactions exist between sex steroids and the GH-IGF-I axis in terms of their effects on body composition in childhood (11), and so effects of ESR1 gene polymorphisms on body composition in childhood may also depend on the concurrent level of somatotrophic hormones. Therefore, to investigate the influence of ESR1 gene polymorphisms on body composition in childhood, in the present study, we examined associations between the three ESR1 polymorphisms analyzed in the ALSPAC cohort as described above, and indices of body composition as measured at 11.8 yr. At this age, girls are well distributed across all Tanner stages, providing an opportunity to examine the influence of puberty on genetic associations with dual-energy x-ray absorptiometry (DXA)-derived variables (19).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study population

ALSPAC is a geographically based cohort that recruited pregnant women residing in Avon with an expected date of delivery between April 1, 1991, and December 31, 1992. A total of 14,541 pregnancies were initially enrolled, with 14,062 children born. This represented 80–90% of the eligible population (see www.alspac.bris.ac.uk for further details on the ALSPAC cohort) (20). Of these births, 13,988 were alive at 12 months. Ethical approval was obtained from the ALSPAC Law and Ethics Committee and local research ethics committees. Parental consent and child’s assent were obtained for all measurements made.

Genotyping

Genotyping was performed by Kbiosciences (Hoddesdon, Herts, UK), using DNA extracted from cord blood, peripheral blood, and mouthwash samples in all available children (n = 9804) (21). ESR1 single nucleotide polymorphisms (SNPs) were first identified from the International HapMap Project database (www.hapmap.org) (phase 2). Using these data, we defined all possible haplotypes of ESR1 using the program Phase (22), which defined all haplotypes with greater than 90% posterior probability. The proportion of genetic diversity (entropy) in the gene and the amount that could be tagged by individual SNPs and combinations thereof was then determined using the program Entropy (www.gmap.net/perl/marker/markerentry). This study identified 11 tagSNPs accounting for 90% of the genetic diversity of the ESR1 gene. Based on suggestive association data with DXA measures of bone mass in a previous study of in the ALSPAC children-in-focus group (a 10% subsample of the cohort studied in more detail in early childhood) at 9 yr of age (our unpublished observations), four of these ESR1 SNPs were selected for further study in the whole cohort. Because the genotypes of one of these four SNPs, rs2228480, were not in Hardy-Weinberg equilibrium (P = 0.007), it was excluded from further analysis. Genotype frequencies for the three remaining SNPs on which this study is based are shown in Table 1Go. The frequency of genotyping failures for these three SNPs ranged from 6.4 to 8.6%. Error rates as measured by analysis of duplicate samples were less than 1%. Haplotypes were analyzed using the program WHAP, which employed the EM-algorithm to determine haplotype frequencies (http://www.genome.wi.mit.edu/~shaun/whap/). Subjects in whom the probability of correct assignment of haplotype was less than 0.95 were excluded. Only haplotypes with frequency greater than 5% were analyzed.


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  		TABLE 1. Genotyping frequencies for rs2234693, rs9340799, and rs7757956, as ascertained in all available samples (5081 boys and 4723 girls)

 
Measurement of height, weight, and DXA-derived parameters

The present study was based on results for total body DXA scans obtained at research clinics to which the whole cohort was invited at mean age of 11.8 yr. On attendance at research clinics, sitting and standing height were measured using a Harpenden stadiometer, as was weight using a body fat analyzer (Tanita Corp., Arlington Heights, IL). Total body DXA scans were performed using a Prodigy (Lunar, Madison, WI) with pediatric scanning software. Of the 7159 children who attended the clinic at age 11 yr, 7057 underwent a whole-body DXA scan; results were available for 7006 children after exclusion of anomalies. All scans were subsequently evaluated and reanalyzed as necessary to ensure that borders between adjacent subregions were optimally placed. DXA variables analyzed in the present study consisted of total body fat and lean mass and total body less head bone area.

Other variables

Gender was obtained from birth notifications. At the time of the DXA scan and measurement of the anthropometric variables, the child’s age was calculated from the date of birth and date of attendance at the research clinic. Puberty was assessed by self-completion questionnaires using diagrams based on Tanner staging of pubic hair distribution for boys and pubic hair and breast development for girls. Results were limited to the subgroup of children in whom pubertal stage information was available within 16 wk of the clinic visit.

Statistical analysis

Associations between each ESR1 polymorphism and height, weight, BMI (weight divided by height squared), total body lean and fat mass, and total body less head bone area, as measured by DXA, were examined using linear regression to test different hypotheses for genotype effects. To test for a rare allele recessive/common allele dominant effect, results for common allele homozygotes and heterozygotes were combined and compared with rare allele homozygotes; for a rare allele dominant/common allele recessive effect, those homozygous for the common allele were compared with combined results for heterozygotes and rare allele homozygotes (models for gene-dose effects were also employed but yielded no further information). Analyses, which were based on boys and girls combined, were adjusted for age, gender, Tanner stage height, and also height squared to account for the quadratic relationship with fat mass. To take account of multiple comparisons, P value for statistical significance for these initial analyses was taken as 0.01 [assuming two independent genetic effects in light of previous linkage disequilibrium (LD) analyses (19), and two independent phenotypes]. Post hoc analyses (for which threshold for statistical significance was taken as P = 0.05) were used to explore associations between fat mass and rs7757956 by examining relationships with fat distribution (from trunk to leg fat ratio), interactions with puberty (using interaction tests performed separately in boys and girls), and risk of obesity [odds ratios calculated from logistic regression analyses, based on top quartile of fat mass in ALSPAC, adjusted for height and height squared; 85th and 95th centiles for fat mass as percentage of body weight in 11–12 yr old U.K. children (23)].


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Genotype data were available from 9804 children (Table 1Go). Of these children, fat mass as measured by DXA was available at age 11 yr in 5754 children, for whom matching Tanner stage results were available in 3097. As expected, boys in Tanner stage 4 were considerably taller and heavier than those in early puberty (Table 2Go). Advanced Tanner stage was also associated with a higher BMI and lean and fat mass, of which lean mass showed the greatest difference. In girls, the difference in height and weight across puberty was somewhat greater, in part reflecting the fact that at their age of inclusion, unlike boys, girls were distributed across all five Tanner stages (Table 2Go). Relatively large differences in BMI according to Tanner stage were also present, contributing significantly to the associated differences in body weight. The higher BMI in late pubertal girls appeared to predominantly reflect substantial changes in fat mass, which was 93.5% greater in girls in Tanner stage 5, compared with those in Tanner stage 1. In contrast, lean mass was 34.9% higher in Tanner stage 5 vs. Tanner stage 1 girls.


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  		TABLE 2. Mean ± SD age, height, weight, and DXA results in 1283 boys and 1814 girls with ESR1 genotyping data

 
No association was observed between intron 1 polymorphisms and measures of body composition, in analyses performed on boys and girls combined (Table 3Go). On the other hand, the rs7757956 polymorphism located within intron 4 was weakly associated with weight in analyses based on the rare allele dominant model, although this failed to reach statistical significance. Moreover, using this model, statistically significant associations were observed between rs7757956 and BMI and particularly fat mass. No relationship was evident between the intron 4 polymorphism and lean mass, and adjusting for lean mass had little effect on the relationship with fat mass, suggesting the intron 4 polymorphism primarily influences body composition through an effect on fat mass.


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  		TABLE 3. P value for associations between ESR1 SNPs and height, weight, BMI, and total lean and fat mass as measured at age 11 yr, adjusted for age, gender, and puberty (maximum n = 3097)

 
In further analyses, we examined whether the intron 4 polymorphism affects fat distribution. Although this polymorphism was not related to fat mass of the arms, legs, or trunk as a proportion of total fat mass, a weak relationship was observed with the ratio of trunk to leg fat mass based on the rare allele dominant genetic model (Table 4Go). Similar associations with the ESR1 polymorphism were observed in analyses performed in all 5754 children with genotype and fat mass data, compared with those seen in the subgroup with pubertal stage information as described above, but the strength of associations was somewhat weaker, presumably reflecting the lack of adjustment for pubertal stage (P = 0.007, 0.03, 0.02, and 0.02 for associations between rs7757956 and arm, leg, trunk, and total fat mass, respectively; rare allele dominant model adjusted for age, gender, height, and lean mass).


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  		TABLE 4. P value for associations between regional fat mass at age 11 yr and ESR1 rs7757956 polymorphism, adjusted for age, gender, puberty, height, and height squared ± total body fat mass (n = 3024)

 
The extent of LD between these three ESR1 SNPs was explored by haplotype analysis. As expected, the two intron 1 SNPs showed a high level of LD (D' = 0.80), whereas there was no evidence of linkage between either intron 1 SNP and the intron 4 polymorphism (D' < 0.05). No associations were found between measures of body composition and haplotypes formed from the two intron 1 polymorphisms based on the five most common haplotypes (frequencies > 0.05). We then explored the association between the intron 4 polymorphism and fat mass by comparison of mean fat mass according to genotype, after adjustment for age, gender, pubertal stage, height, and height squared. TA/AA genotype was associated with a 6.0, 6.3, and 6.4% reduction in fat mass, compared with the TT genotype as assessed in the whole population, boys, and girls, respectively (Table 5Go). In contrast, the association between the intron 4 polymorphism and trunk to leg fat ratio was largely attributable to a relationship in girls, in whom the TA/AA genotype was associated with a reduction in trunk to leg fat ratio of approximately 3%.


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  		TABLE 5. Total fat mass (kilograms) and trunk to leg fat ratio according to rs7757956 genotype at age 11 yr

 
Subsequently we examined whether these associations with the intron 4 polymorphism were related to pubertal stage, after categorizing children as pre/early pubertal (Tanner stages 1 and 2) or pubertal (Tanner stages 3–5). In the case of fat mass, a significant interaction was observed in respect of puberty in girls (P = 0.05) but not boys (P = 0.3). Analysis of mean fat mass (adjusted for age, height and height squared) according to intron 4 polymorphism and Tanner stage in girls revealed that in pre/early pubertal girls, little or no difference was evident according to intron 4 genotype, whereas in pubertal girls, TA/AA genotypes were associated with a 9% lower fat mass (Fig. 1Go). Furthermore, in girls with the TT genotype, height-adjusted fat mass was 18% higher in those in Tanner stages 3–5 vs. stages 1–2; in contrast, in those with TA/AA genotypes, this difference according to Tanner stage was only 7%. In contrast, the relationship between intron 4 polymorphism and trunk to leg fat ratio showed no evidence of an interaction with puberty (P = 0.4 and 0.5 for puberty interaction in boys and girls, respectively).


Figure 1
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  		FIG. 1. Mean total body fat mass according to ESR1 rs7757956 genotype and Tanner stage in 11-yr-old girls, adjusted for height and height squared, for numbers of girls as shown.

 
Finally, we examined whether the intron 4 polymorphism is related to obesity risk in childhood by comparing the proportion of children with an adjusted fat mass in the upper quartile of fat mass between different genotypes. Additional analyses were performed based on the proportion of children whose fat mass was above thresholds for overfat and obese as recently determined in a UK population (23). Irrespective of which threshold was used, TA/AA genotypes were associated with a reduced risk of being overweight of approximately 20% as assessed in boys and girls combined (Table 6Go). The strongest risk reduction was in relation to the risk of being overfat in girls in Tanner stages 3–5, in whom risk was reduced by 36% in the presence of TA/AA genotypes. In contrast, in Tanner stage 1–2 girls, the risk of being overfat was unaffected by intron 4 genotype.


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  		TABLE 6. Risk of obesity in children with TA/AA genotypes of the ESR1 rs7757956 polymorphism (rare allele dominant genetic model) for the whole population combined, boys, and girls, of whom the latter are further subdivided according to pubertal stage

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We found an ESR1 intron 4 polymorphism to be related to fat mass, after analysis of associations between ESR1 polymorphisms and body composition as measured in 3097 11-yr-old children. In those with one or two copies of the rare allele (TA/AA genotype), total body fat mass was reduced by 6%, whereas the risk of being overweight decreased by 20%. Results of analyses of associations with regional fat mass suggested that this finding reflected an influence on total body fat mass rather than fat distribution. Although changes in fat mass during rapid growth are strongly correlated with changes in other parameters such as height and lean mass, the relationship reported in the present study appeared to be confined to fat mass; the intron 4 polymorphism was also associated with BMI, but this solely reflected a relationship with fat mass. In contrast, intron 1 polymorphisms were not associated with indices of body composition as assessed at age 11 yr, consistent with previous findings from studies in children (18) and the fact that these intron 1 polymorphisms are independent of the intron 4 polymorphism as judged by results of linkage disequilibrium analysis.

Differences in fat mass according to intron 4 genotype were similar in boys and girls, suggesting that fat deposition in childhood is influenced by ER{alpha} in both genders. Interestingly, an interaction was observed between this genetic effect and puberty in girls because the difference in fat mass between early and late pubertal girls was 60% less in those with the TA/AA, compared with the TT genotype (i.e. 7.2 vs. 18%, respectively). Furthermore, the risk of being overfat differed according to Tanner stage, such that this risk was reduced by 36% in the presence of the TA/AA genotype in girls in Tanner stages 3–5, whereas no protective effect was observed in girls in Tanner stages 1–2. Interpretation of results for risk of overfat or obese is complicated by concerns over the validity of applying percentage fat thresholds as calculated previously (23) because their application led to an unexpectedly large proportion of the ALSPAC cohort being defined as overfat or obese. A possible explanation for this apparent discrepancy is that these thresholds were calculated based on fat mass derived from impedance measures as opposed to DXA as in the present study.

The interaction among ESR1 genotype, fat mass, and puberty in girls that we observed is consistent with our observation that girls showed a significantly greater gain in fat mass with puberty, compared with boys. Presumably this gender difference in fat mass gain during puberty reflects a stimulatory effect of rising estrogen levels in girls on fat deposition. This role may be distinct to that in adulthood, in which if anything estrogen appears to reduce total body fat (24), in which ER{alpha} has been implicated from animal models (12, 13). On the other hand, our observation that intron 4 genotype is associated with trunk to leg fat mass ratio is consistent with previous suggestions that ER{alpha} plays a role in regulating fat distribution in adulthood (17). However, although the latter study reported a relationship between ER{alpha} genotype and waist to hip ratio, this was in relation to the rs9340799 polymorphism, whereas we saw no association between trunk to leg ratio and either intron 1 polymorphism.

Although we are not aware of equivalent data relating fat mass to Tanner stage, our findings are consistent with previous observations that fat mass increases with age in girls across a similar age range (11, 23). However, the increase in fat content with puberty in girls (21.7 vs. 28.2% in Tanner stages 1 and 5, respectively) appears to be somewhat greater than age-related changes reported previously. In view of the cross-sectional study design that we used, the relatively high fat mass that we observed in late pubertal girls may have in part been due to confounding, resulting from an inverse relationship between fat mass and age of onset of puberty as previously been reported (25). Age of puberty onset may also have been influenced by ESR1 genotype, which could have contributed to interactions described above, but our previous analyses based on the same study population suggested this was not the case because the proportion of girls in different Tanner stages was found to be unaffected by ESR1 intron 4 genotype (19).

Because estrogen may promote fat deposition during puberty, our observation that the difference in fat mass according to pubertal stage is lower in girls with the TA/AA genotype suggests the latter is associated with less efficient activation of ER{alpha}-dependent pathways in adipocytes. This finding is consistent with our recent observation that the TA/AA genotype is associated with a lesser increase in volumetric bone density in late pubertal girls, reflecting a similar interaction between rs7757956 genotype and puberty in girls to that reported here (19). The intron 4 polymorphism rs7757956 does not affect coding sequence. HapMap phase 2 data (www.hapmap.org, July 2006 build) indicates that of 637 SNPs identified in ESR1, this SNP is only in significant LD with one SNP with an r2 > 0.8 (rs9340944, r2 = 0.95) and five other SNPs with r2 greater than 0.5 (rs 6916218, rs1569788, rs6905370, rs722208, and rs9340954). All of these SNPs lie within intron 4 and are therefore noncoding, implying that the association operates by affecting ESR1 splicing or expression levels rather than protein sequence.

Because ESR1 expression varies between different tissues, the attendant mechanisms involved in regulating expression also presumably vary accordingly, suggesting that a given intronic polymorphisms might affect ESR1 expression to a different extent in different tissues. This offers a potential explanation for an apparent inconsistency with our previous observation that intron 1 ESR1 polymorphisms if anything showed a stronger association with skeletal development, compared with the intron 4 polymorphism (19), whereas no association was evident between intron 1 ESR1 polymorphisms and fat mass in the same group of children.

This study represents the largest genetic association study of the relationship between ESR1 polymorphisms and body composition in childhood. Furthermore, girls included in our study were evenly distributed across the different Tanner stages, reflecting the normal distribution of age of puberty onset; this provided an opportunity to examine interactions among body composition, puberty, and ESR1 polymorphisms using a cross-sectional study design. Although genotyping was performed on the majority of the cohort, analyses were confined to the subgroup with DXA scans, although this is unlikely to have introduced significant bias.

In summary, we investigated the relationship between ESR1 polymorphisms and body composition as measured in 3097 children at a mean of 11.8 yr of age. In analyses of boys and girls combined, total body fat mass was associated with a novel ESR1 intron 4 polymorphism, such that fat mass was 6% lower in children with TA/AA genotypes, and the risk of being overweight was reduced by 20%. Furthermore, an interaction with puberty was observed in girls because whereas fat mass adjusted for height was 18% higher in those with the TT genotype when comparing girls in Tanner stages 3–5 vs. stages 1–2, the equivalent difference for the TA/AA genotype was 7%. These findings suggest that the gain in total body fat mass in children, and particularly pubertal girls, is influenced by genetic variations in ESR1 and provide a justification for further studies intended to examine whether rs7757956 is associated with fat mass and risk of obesity in older child, as well as adult, populations.


   Acknowledgments
 
We are extremely grateful to all the families who took part in this study; the midwives for their help in recruiting them; and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The U.K. Medical Research Council, the Wellcome Trust, and the University of Bristol provide core support for ALSPAC. This publication is the responsibility of J.H.T. and C.D.S., who also serve as guarantors for the contents of this paper.


   Footnotes
 
This work was supported by Wellcome Trust and the National Osteoporosis Society. C.V.-G. and M.A.B. were supported by the Arthritis Research Campaign (United Kingdom).

Disclosure Statement: The authors have nothing to disclose.

First Published Online April 3, 2007

Abbreviations: ALSPAC, Avon Longitudinal Study of Parents and Children; BMI, body mass index; DXA, dual-energy x-ray absorptiometry; ER, estrogen receptor; LD, linkage disequilibrium; SNP, single nucleotide polymorphism.

Received November 8, 2006.

Accepted March 22, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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