Human Molecular Genetics Advance Access originally published online on July 13, 2005
Human Molecular Genetics 2005 14(16):2405-2413; doi:10.1093/hmg/ddi242
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Tobacco smoking, estrogen receptor 
gene variation and small low density lipoprotein level
1Center for Cancer Research, E17-536, Massachusetts Institute of Technology, Cambridge, MA 02139, USA, 2The Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA, 3Biostatistics Research Center, Institute for Clinical Research and Health Policy Studies, Tufts-New England Medical Center, Boston, MA 02111, USA, 4Nutrition and Genomics Laboratory, USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA and 5The Molecular Cardiology Research Institute, Department of Medicine, New England Medical Center and Tufts University School of Medicine, Boston, MA 02111, USA
* To whom correspondence should be addressed. Tel: +617 2533015; Fax: +617 2535202; Email: shearman{at}mit.edu
Received February 26, 2005; Revised June 23, 2005; Accepted July 1, 2005
High levels of small low density lipoprotein (LDL) particles are a major risk factor for cardiovascular morbidity and mortality. Both estrogens and smoking, with known anti-estrogenic effects, alter the atherogenic lipid profile. We tested for a role of interaction between smoking and estrogen receptor 
gene (ESR1) variation in association with plasma concentration of atherogenic small LDL particles and LDL particle size. We studied 1727 unrelated subjects, 854 women and 873 men, mean age 51 years (SD 10), from the population-based Framingham Heart Study. After covariate adjustment, women who smoked and had the common ESR1 c.454-397 TT genotype (in 30% of women, T was present on both chromosomes at position 397 prior to the start of exon 2) had >1.7-fold higher levels of small LDL particles than women with the alternative genotypes (P-value for smoking–genotype interaction was 0.001). Similar results were obtained for three other ESR1 variants including c.454–351A>G, in the same linkage disequilibrium block. A similar substantial gender-specific result was also evident with a fifth variant, in a separate linkage disequilibrium block, in exon 4 (P=0.003). Women who smoked and had specific, common ESR1 genotypes had a substantially higher plasma concentration of atherogenic small LDL particles. Significant results revealed a dose-dependent effect of smoking and were evident in both pre- and postmenopausal women. The reported association has the potential to explain the risks associated with estrogen use in certain women and a recent report of association between an ESR1 haplotype comprised of c.454–397 T and c.454–351 A alleles with increased myocardial infarction and ischaemic heart disease, independent of the standard, established cardiovascular risk factors.
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