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Impact of estrogen receptor gene polymorphisms and mRNA levels on obesity and lipolysis--a cohort study.

Nilsson M, Dahlman I, Jiao H, Gustafsson JA, Arner P, Dahlman-Wright K - BMC Med. Genet. (2007)

Bottom Line: No ESR1 SNP was associated with obesity.ESR1 rs532010 was associated with lipolytic sensitivity to noradrenaline (nominal P value 0.012), and ESR1 rs1884051 with responsiveness to the non-selective beta-adrenoceptor agonist isoprenaline (nominal P value 0.05).These associations became non-significant after Bonferroni correction.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departments of Biosciences and Nutrition, Karolinska Institutet, S-141 57 Huddinge, Sweden. ilsson_anna_maria@yahoo.se

ABSTRACT

Background: The estrogen receptors alpha and beta (ESR1, ESR2) have been implicated in adiposity, lipid metabolism and feeding behaviour. In this report we analyse ESR1 and ESR2 gene single nucleotide polymorphisms (SNPs) for association with obesity. We also relate adipose tissue ESR1 mRNA levels and ESR1 SNPs to adipocyte lipolysis and lipogenesis phenotypes.

Methods: 23 ESR1 and 11 ESR2 tag-SNPs, covering most of the common haplotype variation in each gene according to HAPMAP data, were analysed by Chi2 for association with obesity in a cohort comprising 705 adults with severe obesity and 402 lean individuals. Results were replicated in a cohort comprising 837 obese and 613 lean subjects. About 80% of both cohorts comprised women and 20% men. Adipose tissue ESR1 mRNA was quantified in 122 women and related to lipolysis and lipogenesis by multiple regression. ESR1 SNPs were analysed for association with adipocyte lipolysis and lipogenesis phenotypes in 204 obese women by simple regression.

Results: No ESR1 SNP was associated with obesity. Five ESR2 SNPs displayed nominal significant allelic association with obesity in women and one in men. The two ESR2 SNPs associated with obesity with nominal P value < 0.01 were genotyped in a second cohort where no association with obesity was observed. There was an inverse correlation between ESR1 mRNA levels in abdominal subcutaneous (sc) adipose tissue and basal lipolysis, as well as responsiveness to adrenoceptor agonists independent of age and BMI (P value 0.009-0.045). ESR1 rs532010 was associated with lipolytic sensitivity to noradrenaline (nominal P value 0.012), and ESR1 rs1884051 with responsiveness to the non-selective beta-adrenoceptor agonist isoprenaline (nominal P value 0.05). These associations became non-significant after Bonferroni correction.

Conclusion: ESR1 gene alleles are unlikely to be a major cause of obesity in women. A minor importance of ESR2 on severe obesity cannot be excluded. The inverse correlation between ESR1 mRNA levels and lipolytic responsiveness to adrenoceptor agonists implies that low adipose tissue ESR1 levels attenuate catecholamine resistance in sc fat cells of obese women hereby contributing to loss of sc and gain of visceral fat. There is no evidence for a genetic impact of ESR1 on lipolysis or lipogenesis.

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LD (D') between ESR1 SNP and haploblocks according to Caucasian HAPMAP data.
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Figure 1: LD (D') between ESR1 SNP and haploblocks according to Caucasian HAPMAP data.

Mentions: To investigate if ESR1 and ESR2 alleles contribute to susceptibility to obesity, polymorphisms covering the common variation in these genes were genotyped in sample 1, Table 2. For ESR1, 6 out of 29 (21%) Illumina genotyping assays failed, which is higher than the expected 10% failure rate. The majority represented Golden-gate validated assays indicating, according to the supplier, that the failure is due to interference between different SNP assays under the employed multiplex conditions. LD between ESR gene SNPs is shown in Figure 1 and 2, in which haploblock limits according to Caucasian HAPMAP data have been labeled. Genotyped ESR1 SNPs built 25 haplotypes, Table 3. These SNPs unambiguously identified 67% (20/30) of the common (> 5%) haplotypes in the ESR1 region in HAPMAP, representing 75% of the common haplotype variation in ESR1 according to HAPMAP data. Remaining ten ESR1 haplotypes in HAPMAP could in our sample not be separated from another haplotype, that is they were merged into five haplotypes. For ESR2, all genotyped assays were called successfully although one SNP, rs7154455, displayed a low genotyping call rate, 83%, Table 2. Thus there was 100% coverage of the common Caucasian ESR2 haplotypes in HAPMAP, Figure 2. All SNPs were in HWE.


Impact of estrogen receptor gene polymorphisms and mRNA levels on obesity and lipolysis--a cohort study.

Nilsson M, Dahlman I, Jiao H, Gustafsson JA, Arner P, Dahlman-Wright K - BMC Med. Genet. (2007)

LD (D') between ESR1 SNP and haploblocks according to Caucasian HAPMAP data.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2238734&req=5

Figure 1: LD (D') between ESR1 SNP and haploblocks according to Caucasian HAPMAP data.
Mentions: To investigate if ESR1 and ESR2 alleles contribute to susceptibility to obesity, polymorphisms covering the common variation in these genes were genotyped in sample 1, Table 2. For ESR1, 6 out of 29 (21%) Illumina genotyping assays failed, which is higher than the expected 10% failure rate. The majority represented Golden-gate validated assays indicating, according to the supplier, that the failure is due to interference between different SNP assays under the employed multiplex conditions. LD between ESR gene SNPs is shown in Figure 1 and 2, in which haploblock limits according to Caucasian HAPMAP data have been labeled. Genotyped ESR1 SNPs built 25 haplotypes, Table 3. These SNPs unambiguously identified 67% (20/30) of the common (> 5%) haplotypes in the ESR1 region in HAPMAP, representing 75% of the common haplotype variation in ESR1 according to HAPMAP data. Remaining ten ESR1 haplotypes in HAPMAP could in our sample not be separated from another haplotype, that is they were merged into five haplotypes. For ESR2, all genotyped assays were called successfully although one SNP, rs7154455, displayed a low genotyping call rate, 83%, Table 2. Thus there was 100% coverage of the common Caucasian ESR2 haplotypes in HAPMAP, Figure 2. All SNPs were in HWE.

Bottom Line: No ESR1 SNP was associated with obesity.ESR1 rs532010 was associated with lipolytic sensitivity to noradrenaline (nominal P value 0.012), and ESR1 rs1884051 with responsiveness to the non-selective beta-adrenoceptor agonist isoprenaline (nominal P value 0.05).These associations became non-significant after Bonferroni correction.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departments of Biosciences and Nutrition, Karolinska Institutet, S-141 57 Huddinge, Sweden. ilsson_anna_maria@yahoo.se

ABSTRACT

Background: The estrogen receptors alpha and beta (ESR1, ESR2) have been implicated in adiposity, lipid metabolism and feeding behaviour. In this report we analyse ESR1 and ESR2 gene single nucleotide polymorphisms (SNPs) for association with obesity. We also relate adipose tissue ESR1 mRNA levels and ESR1 SNPs to adipocyte lipolysis and lipogenesis phenotypes.

Methods: 23 ESR1 and 11 ESR2 tag-SNPs, covering most of the common haplotype variation in each gene according to HAPMAP data, were analysed by Chi2 for association with obesity in a cohort comprising 705 adults with severe obesity and 402 lean individuals. Results were replicated in a cohort comprising 837 obese and 613 lean subjects. About 80% of both cohorts comprised women and 20% men. Adipose tissue ESR1 mRNA was quantified in 122 women and related to lipolysis and lipogenesis by multiple regression. ESR1 SNPs were analysed for association with adipocyte lipolysis and lipogenesis phenotypes in 204 obese women by simple regression.

Results: No ESR1 SNP was associated with obesity. Five ESR2 SNPs displayed nominal significant allelic association with obesity in women and one in men. The two ESR2 SNPs associated with obesity with nominal P value < 0.01 were genotyped in a second cohort where no association with obesity was observed. There was an inverse correlation between ESR1 mRNA levels in abdominal subcutaneous (sc) adipose tissue and basal lipolysis, as well as responsiveness to adrenoceptor agonists independent of age and BMI (P value 0.009-0.045). ESR1 rs532010 was associated with lipolytic sensitivity to noradrenaline (nominal P value 0.012), and ESR1 rs1884051 with responsiveness to the non-selective beta-adrenoceptor agonist isoprenaline (nominal P value 0.05). These associations became non-significant after Bonferroni correction.

Conclusion: ESR1 gene alleles are unlikely to be a major cause of obesity in women. A minor importance of ESR2 on severe obesity cannot be excluded. The inverse correlation between ESR1 mRNA levels and lipolytic responsiveness to adrenoceptor agonists implies that low adipose tissue ESR1 levels attenuate catecholamine resistance in sc fat cells of obese women hereby contributing to loss of sc and gain of visceral fat. There is no evidence for a genetic impact of ESR1 on lipolysis or lipogenesis.

Show MeSH
Related in: MedlinePlus