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Sex-Specific Association between Estrogen Receptor- Gene Variation and Measures of Adiposity: The Framingham Heart Study

National Heart, Lung, and Blood Institute’s Framingham Heart Study (C.S.F., J.M.M., D.L.), Framingham, Massachusetts 01702; Department of Endocrinology, Diabetes, and Hypertension (C.S.F.), the Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115; Department of Biostatistics (Q.Y., L.A.C., C.-Y.G., L.D.A.), School of Public Health, Boston University, Boston, Massachusetts 02118; Department of Neurology (Q.Y., L.D.A.) and Section of General Internal Medicine (J.M.M.), Boston University School of Medicine (D.L.), Boston, Massachusetts 02118; Center for Cancer Research (D.E.H., A.M.S.), Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; Department of Medicine (M.E.M.), Molecular Cardiology Research Institute, Tufts-New England Medical Center and Tufts-New England Medical Center Specialized Center of Research in Ischemic Heart Disease, Boston, Massachusetts 02111; and the National Heart, Lung, and Blood Institute (C.S.F., D.L.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Caroline S. Fox, M.D., M.P.H., 73 Mount Wayte Avenue, Suite 2, Framingham, Massachusetts 01702. E-mail: foxca{at}nhlbi.nih.gov.

	Abstract

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Background: Polymorphisms in estrogen receptor- (ESR1) may be associated with variation in body mass index and waist circumference. However, most prior studies have been limited by sample size and power.

Methods: DNA from 1763 unrelated men and women (mean age, 56 yr) from the Framingham Heart Study offspring cohort was genotyped for four ESR1 polymorphisms: T30C (rs2077647) in exon 1, PvuII (rs2234693), and XbaI (rs 9340799) in intron 1, and C1335G (rs 1801132) in exon 4.

Results: Men homozygous for the PvuII C allele (frequency, 0.45) had lower waist circumference (99.3 cm), compared with TT homozygous men (99.8 cm) and heterozygotes (100.6 cm) (P < 0.004). Similar results were obtained with XbaI, which lies in the same linkage disequilibrium block. C1335G also demonstrated a gender-specific association: men with CG or GG genotypes had lower mean body mass index, 27.7 and 27.9 kg/m², respectively, compared with 28.6 kg/m² among the CC homozygotes (P < 0.01). No significant associations were seen with T30C, nor were associations observed among women.

Conclusions: Polymorphisms in ESR1 are associated with measures of adiposity in men. These associations further support the hypothesis that the intron 1 region of ESR1 influences phenotypes important for cardiovascular risk.

	Introduction

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CARDIOVASCULAR DISEASE (CVD) is the leading cause of morbidity and mortality in the United States, affecting roughly 12 million people and accounting for nearly 1 million deaths per year (1). Although improvements in cardiovascular risk factor profiles have contributed to reductions in CVD mortality, an increasing prevalence of obesity may have slowed this rate of decline (2).

Obesity increases the risk of all-cause mortality, (3) vascular disease, (4), and nonvascular causes of death including certain cancers (5). Genetic and environmental factors contribute to obesity (6). We reported that a locus for body mass index (BMI) maps to chromosome 6q23–25, with a peak LOD score of 4.6 (7). We have also shown that waist circumference, a measure of visceral adiposity, maps to this same location with a peak LOD score of 3.7 (8), suggesting that one or more genes underlying BMI and visceral adiposity reside in this region.

Estrogen receptor- (ESR1) is a candidate gene that resides on 6q25, approximately 4 mB from the BMI peak LOD score, and 15 mB from the waist circumference peak LOD score. Candidate gene studies have suggested that polymorphisms in ESR1 may be associated with variation in BMI (9, 10) and waist circumference (9). However, most prior studies have been limited by sample size and power. Thus, we sought to test whether polymorphisms in ESR1 gene variants are associated with measures of adiposity, including BMI and waist circumference, in the Framingham Heart Study, a large, well-characterized sample.

	Subjects and Methods

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Study sample

The Framingham Heart Study began in 1948 with the enrollment of 5209 men and women, 28–62 yr of age at study entry, with subjects undergoing repeat exams every 2 yr (11, 12). In 1971, 5124 men and women were enrolled into the offspring cohort of the Framingham Heart Study, which included the children or spouses of the children of the original cohort. Offspring subjects underwent examinations approximately every 4 yr; the design and methodology of the offspring cohort has been previously described (13, 14).

Participants in the current study were drawn from a subset of individuals from the Framingham Heart Study offspring cohort who had DNA obtained between 1995 and 1998 (n = 2933). Of these, samples from 1811 participants underwent genotyping of the ESR1 gene. Participants had to be unrelated, and equivalent numbers of men and women were selected (15); 1739 had ESR1 c.454–397T>C genotypes (PvuII), 1755 had XbaI genotypes, 1712 had T30C genotypes, and 1687 had C1335G genotypes. Genotype data from these four polymorphisms along with BMI and waist circumference data from this examination cycle as well as two prior examination cycles (1987–1991 and 1991–1995) were used in the current study. To reduce measurement error, (16), we used the mean of BMI and waist circumference data from participants who attended at least two examinations over an 11-yr period (1987–1998). Among those with genotype data, 1719 attended an examination in 1987–1991, 1721 attended an examination in 1991–1995, and 1791 attended an examination in 1995–1998. A total of 1763 participants attended at least two examinations and were available for this analysis. For those with genotype data and available BMI data, 98 individuals attended only two examinations, and 1665 individuals attended three examinations. Similarly for waist circumference, 108 individuals attended only two exams, and 1654 individuals attended three examinations.

Data collection

Details regarding the methods of risk factor measurement and laboratory analysis have been described previously (17). Measured covariates for the current study were assessed at three examinations, from 1987–1991 (exam 4), 1991–1995 (exam 5), and 1995–1998 (exam 6). Weight and height were measured using standard procedures. BMI was defined as weight (kilograms) divided by the square of height (meters). Waist circumference was measured at the level of the umbilicus. Smoking status was defined as smoking one or more cigarettes per day in the year preceding the examination. Women were considered postmenopausal if their periods had stopped for at least 1 yr.

All subjects gave informed consent before each clinic visit, and the examination protocol was approved by the Institutional Review Board at Boston Medical Center (Boston, MA).

DNA extraction and genotyping

Standard methods were used for extraction of genomic DNA peripheral blood leukocytes. Detailed ESR1 genotyping methods have been described previously (15). Briefly, ESR1 c.30T>C (rs2077647), in exon 1, was genotyped by a TaqMan assay, c.454–397T>C (rs2234693) and c.454–351A>G (rs9340799), in intron 1, by PCR amplification and PvuII or XbaI by restriction fragment length hybridization and c.975C>G (rs1801132), in exon 4, by allele-specific oligohybridization.

Statistical analysis

For each participant, mean BMI and waist circumference were calculated by dividing the sum of BMI or waist circumference by the number of examinations attended and used as dependent variables in the subsequent analyses; the mean age was calculated similarly. Current smoking status (yes/no) was determined for each examination. Long-term smoking status (yes/no) was then defined for each participant by dividing the number of times smoking status was present by the total number of examinations attended. If this number was 0.5 or more, reflecting presence of the condition at half or more of the examinations attended, then subjects were considered to be smokers (smoking status of yes). Using SAS (18), general linear regression models were used to determine whether mean BMI or waist circumference varied according to ESR1 genotype. These methods require the fulfillment of the following assumptions: 1) the observations are independent, and 2) equal variability among the traits. These methods are robust to violations of normality and do not require a straight line assumption because all P values are based on 2 degree-of-freedom tests. BMI was adjusted for age, age squared, and long-term smoking status; waist circumference was additionally adjusted for BMI. A secondary analysis was performed in which the sample was restricted to those younger than 60 yr of age because of the observation that declines in obesity are often seen after age 60 yr (19).

Haplotype frequency was estimated using the expectation-maximization algorithm (20). A haplotype-specific score statistic, capturing the covariance between the number of copies of a haplotype and the trait value, was used to test the association between that haplotype and the trait. Because haplotype phase may be uncertain for some subjects, each of those subjects contributed a weighted average of score statistics for all haplotype configurations compatible with the observed genotype, with the weight being the likelihood of each configuration. The haplotype-specific score statistic compares a haplotype with all other haplotypes combined and is distributed as a ² with 1 degree of freedom. A global score statistic that is a summation of all the haplotype-specific score statistics was used to test the association of the trait with all haplotypes simultaneously. The global score statistic is distributed as a ² with degree of freedom being number of different haplotypes minus one. The haplotype frequency estimation and association analyses were conducted in haplotype score (21). Final results are presented as multivariable-adjusted least square means. To account for multiple testing, P < 0.01 was considered statistically significant; this was obtained by dividing the number of independent primary analyses (n = 4) into 0.05.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Overall, 1763 participants were available for analysis. Half of the sample subjects were women, and the mean age was 56 yr (Table 1). The mean BMI among women was 26.7 kg/m², whereas among men it was higher, at 28.3 kg/m². The mean waist circumference was 88.1 cm in women and 100.1 cm in men.

View this table: [in this window] [in a new window]   TABLE 2. Fully adjusted global P values of mean waist circumference and BMI of participants attending examinations 4, 5, and 6 in relation to the T30C, PvuII, XbaI, and V1335 polymorphisms in the ESRI- gene1

View larger version (22K): [in this window] [in a new window]   FIG. 1. Least square means of waist circumference and BMI by genotype among men. 1, 1, Common homozygotes; 1, 2, heterozygotes; 2, 2, rare homozygotes. Bars represent SE values.

View larger version (20K): [in this window] [in a new window]   FIG. 2. Least square means of waist circumference and BMI by genotype among women. 1, 1, Common homozygotes; 1, 2, heterozygotes; 2, 2, rare homozygotes. Bars represent SE values.

Haplotype analyses

Because both the XbaI and PvuII polymorphisms were associated with waist circumference, haplotype analyses were conducted between these polymorphisms and waist circumference (Table 3). No global tests were significant for the association between these haplotypes and waist circumference.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Epidemiologic evidence implicates estrogen in the pathogenesis of adiposity. The menopausal transition is associated with increases in body weight (22). Postmenopausal women have increased visceral (23) and central fat depots (24) and also increased BMI (24), compared with premenopausal women. Similarly, in the Women’s Health Initiative study, the group of women assigned to estrogen plus progestin had lower mean body weight and waist circumference in follow-up, compared with women who received placebo (25). Thus, data from both observational and clinical trials suggest a role for relative estrogen deficiency in the pathogenesis of increasing adiposity with menopause. Animal studies provide further support of this inference because delivery of estradiol to rats has been shown to result in weight loss (26) as well as a role for estrogen in energy balance and feeding behavior (27, 28).

To our knowledge, the only well-powered study of ESR1 and measures of adiposity was of 2238 Japanese men and women (9). In that study, men homozygous for the PvuII C allele had lower BMI values (22.0 vs. 22.9 kg/m²). Among women homozygous for the C allele of the XbaI polymorphism, BMI and waist circumference levels were higher, compared with those homozygous for the common alleles, but there were only 19 participants in this group, limiting the generalizability of their results. Although both PvuII and XbaI were not associated with BMI in our study, both were associated with waist circumference in men, with lower values among the homozygotes for the minor allele. Because both lower BMI and lower waist circumference may be considered characteristic of relative estrogen abundance, our findings, and those of the study among Japanese men, are not inconsistent. They are also consistent with a report suggesting that the PvuII C allele is associated with increased transcription of ESR1 when compared with the common allele and thus presumably associated with higher relative levels of functional ESR1 protein (29).

There have been three small studies that add further evidence to the association between ESR1 and measures of adiposity. Among a sample of 108 elderly Caucasian women (mean age 73 yr), those homozygous for the minor allele of PvuII had lower BMI; waist circumference was not investigated (10). Another small study of 49 participants with type 2 diabetes [29 with android obesity (BMI > 30 kg/m², waist to hip ratio > 0.9 in men and > 0.8 in women)] and 138 healthy controls showed participants with android obesity had a higher prevalence of the common allele of the XbaI genotype, compared with healthy controls (30); our results, although not directly comparable, are similar. Collectively, these results provide some corroboration for our data, suggesting that minor alleles for the PvuII and XbaI polymorphisms may play a role in determining adiposity.

In our haplotype analyses, the XbaI A allele was consistently associated with higher waist circumference, whereas the PvuII C allele was associated with lower waist circumference in the GC haplotype and with greater waist size in the AC haplotype of XbaI and PvuII. Although not conclusive, these results suggest that XbaI is responsible for the association and that the association between PvuII and waist size in men may be due to its tight linkage disequilibrium with XbaI. It may seem contradictory that the P value is more significant for PvuII in analyzing individual polymorphisms. But this could be because PvuII has a more balanced genotype frequency distribution than XbaI and thus offers better power to detect the association. Individual polymorphisms also have more balanced genotype distributions than haplotypes of the two polymorphisms, which may explain why we did not see significant results in the haplotype analyses. In summary, the haplotype analyses offer insight into the relation between the two polymorphisms together and waist circumference, which was not available from analyzing individual polymorphisms.

It may be surprising that our positive findings are among men only and that there is no evidence of association in women. In prior work we have shown that men homozygous for the ESR1 PvuII C allele had a 3-fold increase in the odds of myocardial infarction in this same study sample (15). In that investigation there were too few cardiovascular events to reach any conclusions among women; an association has since been identified among women from the larger Rotterdam Study (31). Alternative explanations for our null findings in women may be due to a smaller effect size among women. Paradoxically, this same genotype is associated with lower waist circumference in our study. This discrepancy may be due to the cross-sectional nature of our data, in which traditional risk factor relations can be obscured due to existing comorbidities. It is also important to consider that these are complicated processes, and the relation between adiposity and myocardial infarction is multifactorial, involving biologic pathways in addition to the ESR1 gene. In our study, the observed differences in mean waist circumference and BMI by genotype were not large. However, obesity is a complex disease trait, and multiple genes are likely involved. Therefore, it is not surprising that individual genes will not exert large effects. PvuII, XbaI, and V1335 displayed heterosis among men, a situation in which the heterozygote has a more extreme phenotype (i.e. higher values for waist circumference and the lowest values for BMI) than the homozygotes. On the surface, heterosis initially appears paradoxical and suggests that a dose-response effect of the rare allele is not present. In fact, molecular heterosis may be present in 50% of all gene associations (32). However, the exact mechanism in our study is uncertain, especially because the polymorphisms of interest are intronic. We did not observe an effect in men younger than 60 yr of age, countering our hypothesis that the effects of ESR1 would be most apparent in younger samples.

Strengths of this study include a large sample size and adequate power to address the role of ESR1 variation in relation to adiposity. Furthermore, we were able to assess long-term averaged measures of waist circumference and BMI because our study participants attended a series of examinations over a 12-yr period. Limitations include a predominantly Caucasian sample; our results will need to be verified in other ethnic groups. As with any association study, we cannot exclude the possibility of an effect of population stratification in generating our results. However, there is evidence that these theoretical effects may have been overestimated in population-based studies (33). Lastly, we need to consider the effect of multiple testing, of which there are no standardized approaches. For this reason, we have accepted a significant P < 0.01 to reduce the risk of reporting false-positive results. Additional evidence suggesting that these findings may not be spurious (i.e. false positive) stem from our prior research demonstrating linkage signals to BMI and waist circumference with peak LOD scores in the region of the ESR1 gene.

In conclusion, our results suggest that polymorphisms in ESR1 are associated with measures of BMI and waist circumference. These associations further support the hypothesis that the intron 1 region of ESR1 influences phenotypes important for CVD risk in men. Further confirmation and validation of our findings in other samples are warranted.

	Footnotes

 
This work was supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (N01-HC-25195).

First Published Online September 6, 2005

Abbreviations: BMI, Body mass index; CVD, cardiovascular disease; ESR1, estrogen receptor- gene.

Received March 28, 2005.

Accepted August 25, 2005.

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