A luteinizing hormone receptor intronic variant is significantly associated with decreased risk of Alzheimer's disease in males carrying an apolipoprotein E ε4 allele

Genetic and biochemical studies support the apolipoprotein E (APOE) ε4 allele as a major risk factor for late-onset Alzheimer's disease (AD), though ~50% of AD patients do not carry the allele. APOE transports cholesterol for luteinizing hormone (LH)-regulated steroidogenesis, and both LH and neurosteroids have been implicated in the etiology of AD. Since polymorphisms of LH beta-subunit (LHB) and its receptor (LHCGR) have not been tested for their association with AD, we scored AD and age-matched control samples for APOE genotype and 14 polymorphisms of LHB and LHCGR. Thirteen gene-gene interactions between the loci of LHB, LHCGR, and APOE were associated with AD. The most strongly supported of these interactions was between an LHCGR intronic polymorphism (rs4073366; lhcgr2) and APOE in males, which was detected using all three interaction analyses: linkage disequilibrium, multi-dimensionality reduction, and logistic regression. While the APOE ε4 allele carried significant risk of AD in males [p = 0.007, odds ratio (OR) = 3.08(95%confidence interval: 1.37, 6.91)], ε4-positive males carrying 1 or 2 C-alleles at lhcgr2 exhibited significantly decreased risk of AD [OR = 0.06(0.01, 0.38); p = 0.003]. This suggests that the lhcgr2 C-allele or a closely linked locus greatly reduces the risk of AD in males carrying an APOE ε4 allele. The reversal of risk embodied in this interaction powerfully supports the importance of considering the role gene-gene interactions play in the etiology of complex biological diseases and demonstrates the importance of using multiple analytic methods to detect well-supported gene-gene interactions

The effect of oestradiol implants on regional and total bone mass: a three year longitudinal study

Objective: Although there is evidence from cross-sectional studies that percutaneous oestrogen administration protects against menopausal bone loss, few longitudinal data are available. We have examined the effect of 3 years' treatment with percutaneous oestradiol on total body calcium, spinal trabecular bone mineral density and radial bone mineral content in post-menopausal women. Design and patients: Twenty-nine post-menopausal women, aged 37–55 years, who had undergone hysterectomy and had experienced the onset of menopausal symptoms within the previous 2 years, were studied before and for 3 years during hormone replacement with oestradiol implants, given at approximately 6-monthly intervals. Measurements: Total body calcium was measured by prompt gamma neutron activation analysis, spinal trabecular bone mineral density by quantitative computed tomography and radial bone mineral content by single-photon absorptiometry. Results: There was a significant increase in the mean total body calcium, spinal trabecular bone mineral density and radial bone mineral content over the 3 years of the study. The mean (± SEM) percentage change per annum was +2 4% (±0.8) for total body calcium (P <0 01), + 3.3% (±0.6) for spinal trabecular bone mineral density (P < 0.001) and +12% (± 0.6) for radial bone mineral content (P < 0 05). Conclusions: Percutaneous oestradiol replacement therapy prevents menopausal bone loss and is associated with a sustained and significant increase in total body calcium, spinal trabecular bone mineral density and radial bone mineral content over a 3-year treatment period. Oestradiol implants thus have skeletal effects comparable to those of oral or transdermal oestrogens