Epistasis in Steroidogenic Genes in the Prediction of Alzheimer's Disease

描述（由申请人提供）： 支持性类固醇对正常认知健康至关重要的证据包括：1）12项研究表明，认知健康的绝经后妇女服用17 <$-雌二醇（E2）（主要的女性雌激素）后，认知能力得到改善，2）接受生理相关性类固醇治疗的受试者认知能力得到改善：接受E2治疗的女性（3项对照/1项非对照研究）和接受睾酮治疗的男性（T; 2项对照研究），3）在绝经前妇女接受“化学阉割”后观察到的突然认知缺陷，同时给予E2可逆转的缺陷，4）在已进行双侧卵巢切除术的绝经前妇女中痴呆的风险增加，5）妇女中认知疾病的患病率增加，这与性腺功能的突然早期丧失相关，6）与循环相比，脑中E2浓度升高; 7）在患有AD的女性和男性中，血清性类固醇之间呈负相关，但血清促性腺激素之间呈正相关。上述研究结果不应与广泛报道的妇女健康倡议研究混淆，该研究发现使用非生理性结合马雌激素的负面后果。 上述数据表明，在绝经期和男性更年期期间，循环中生理性类固醇的下降将极大地影响大脑功能，并且那些在绝经后和男性更年期期间具有较高合成能力的个体更有可能免于低性类固醇浓度引起的衰老变化。因此，我们假设那些具有较低神经类固醇合成能力的个体更有可能发展为AD，而那些具有较高神经类固醇合成能力的个体将更长时间地避免由年龄相关的外周性类固醇损失引起的神经变性。重要的是，APOE？4，AD的主要危险因素，和ABCA 7，最近与来自GWAS的AD相关，改变胆固醇的神经元转运，胆固醇是合成所有性类固醇的前体。 我们的初步研究通过检查调节性类固醇合成的类固醇生成途径家族成员（SPFM）基因中的单核苷酸多态性（SNP）来评估性类固醇合成能力。SPFM成员中那些累积降低正常途径功能（即导致性类固醇合成降低）的遗传变异的鉴定预期与认知缺陷相关。在这方面，我们发现APOE 4、lhcgr 2和fsh 1中的任何2个之间的基因-基因相互作用与女性性别一起显著增加了AD的发病风险至> 90%。这些数据非常有希望，但迄今为止，我们只分析了240个病例对照样本。因此，这项资助旨在在更大的样本量中进行基因型和激素分析，以获得更大的信心，这些相互作用是AD的重要预测因子。为此，在具体目标1中，我们将对另外2760个年龄和性别匹配的病例对照样本进行基因分型，并使用分析工具（逻辑回归、多维降维和递归分割）来鉴定预测AD的得到充分支持的基因-基因相互作用。在具体目标2中，我们将测量1）来自200个AD和年龄匹配的对照脑的匹配血浆、CSF和海马中的促黄体生成素、促卵泡激素、E2、孕酮（P5）、孕酮（P4）和T的浓度。将分析该数据，以确定AD患者的血浆、CSF和脑中性类固醇浓度是否较低，血浆、CSF和脑性类固醇之间的关系，以及特定目标1基因分型数据，与AD相关的特定基因-基因相互作用是否可预测血浆、CSF和脑性类固醇浓度。 这些实验将确定SPFM中的遗传变异调节循环和大脑性类固醇的合成并预测AD。这些研究的成功完成将使AD的预后和诊断测试的发展，并提供深入了解AD的神经内分泌机制。

DESCRIPTION (provided by applicant): Evidence supporting sex steroids as being essential for normal cognitive health includes: 1) 12 studies demonstrating improvements in cognitive performance of cognitively healthy postmenopausal women taking 17¿-estradiol (E2), the major female estrogen, 2) improvements in cognition in subjects treated with physiologically relevant sex steroids: women treated with E2 (3 controlled/1 uncontrolled studies) and men treated with testosterone (T; 2 controlled studies), 3) the abrupt cognitive deficits observed in premenopausal women following 'chemical castration', deficits that are reversible with simultaneous administration of E2, 4) the increased risk of dementia in premenopausal women who have had a bilateral oophorectomy, 5) the increased prevalence of cognitive disease in women, which correlates with the abrupt earlier loss of gonadal function, 6) the elevated concentration of E2 in the brain compared to the circulation, and 7) the negative correlation between serum sex steroids, but positive correlation between serum gonadotropins, in women and men with AD. The above findings should NOT be confused with the widely reported Women's Health Initiative study which found a negative consequence of using UNPHYSIOLOGICAL conjugated equine estrogens. The above data indicate that the decline in circulating physiological sex steroids at menopause and during andropause would greatly impact brain functioning, and that those individuals with a higher synthetic capacity post-menopause and during andropause would be more likely to be spared the senescent changes induced by low sex steroid concentrations. We therefore hypothesize that those individuals with a lower neurosteroid synthetic capacity are more likely to develop AD, while those with a higher neurosteroid synthetic capacity will be spared longer the neurodegeneration induced by the age-related loss of peripheral sex steroids. Importantly, APOE ?4, the major risk factor for AD, and ABCA7, recently associated with AD from GWAS, alter the neuronal transport of cholesterol, the precursor from which all sex steroids are synthesized. Our preliminary studies have assessed sex steroid synthetic capacity by examining single nucleotide polymorphisms (SNPs) in genes of steroidogenic pathway family members (SPFMs) that regulate sex steroid synthesis. Identification of those genetic variations in members of the SPFM that cumulatively lower normal pathway function, i.e. that result in lower sex steroid synthesis are expected to associate with cognitive deficits. In this respect, we have found that gene-gene interactions between any 2 of APOE ¿4, lhcgr2 and fsh1 together with female gender significantly increases the risk of developing AD to >90%. This data is very promising, but to date we have analyzed only 240 case-control samples. This grant therefore aims to perform genotype and hormone analyses in a larger sample size to gain greater confidence that these interactions are important predictors of AD. To this end, in Specific Aim 1 we will genotype a further 2760 age- and sex- matched case-control samples and use analytic tools (logistic regression, multi-dimensionality reduction and recursive partitioning) to identify well supported gene-gene interactions that predict AD. In Specific Aim 2, we will measure 1) the concentrations of luteinizing hormone, follicle-stimulating hormone, E2, pregnenolone (P5), progesterone (P4) and T in matched plasma, CSF and hippocampus from 200 AD and age-matched control brains. This data will be analyzed to determine if plasma, CSF and brain concentrations of sex steroids are lower in AD, the relationship between plasma, CSF and brain sex steroids, and together with Specific Aim 1 genotyping data, if specific gene-gene interactions associated with AD are predictive of plasma, CSF and brain sex steroid concentrations. These experiments will determine that genetic variants in SPFMs regulate circulating and brain sex steroid synthesis and predict AD. Successful completion of these studies would enable the development of prognostic and diagnostic tests for AD, and provide insights into the neuroendocrine mechanisms of AD.