IMPACT OF SEX-RELATED HORMONE LEVELS AND GENETIC VARIATION ON ALCOHOL USE DISORDERS AND RELATED PHENOTYPES IN MALES AND FEMALES

以前曾报道过与性别有关的差异在易感性和进展， 酒精使用障碍、存在或不存在共病状况和治疗反应。 例如，酒精消费量较高，酒精依赖在男性中更为常见， 而女性在经历不愉快的情绪时更容易大量饮酒， 努力减轻心理压力。我们之前的研究表明遗传变异 可能导致了这些性别差异。具体来说，我们已经表明，在变异的 PDYN基因增加了男性酒精依赖的风险，但增加了阴性酒精依赖的风险。 （救济）女性的渴望。我们已经观察到，遗传变异的性别依赖效应是 也是表型特异性的，表明与内源性表型，合并症， 或其他生物因素（如性激素）。然而，生物学机制 这些遗传关联和其他与酒精相关的特征的性别特异性差异 并没有得到很好的理解。这是合理的建议，性别相关激素的差异， 不同性别之间的水平和/或不同性别之间的遗传差异可能在 在这些生物性别差异中的作用。然而，缺乏系统的研究， 性相关激素水平对酒精使用障碍风险的影响 也没有尝试全面调查酗酒、性相关 男性和女性酗酒者的激素水平和遗传变异。重要的是，我们的试点研究 表明，血浆中的一些性相关激素水平之间的差异显着 酒精依赖病例和非酒精对照。我们假设这两种与性有关的 激素水平和遗传因素与酗酒的性别差异有关， 相关特征。在235名男性和118名女性酗酒者的样本中， 女性非酒精对照组，我们将1）研究血浆中 性相关激素（睾酮、雌激素、孕酮、LH、FSH和SHBG）和酒精 依赖性; 2）研究血浆性相关激素水平与 酒精中毒相关表型，如饮酒、渴望、戒断、共病 酒精依赖男性和女性的抑郁和焦虑;以及3）检查 遗传变异和性相关激素水平之间的关联 没有酒精依赖。这项研究的结果将有助于更好地了解 酒精使用障碍的性别差异的生物学，促进发展更有效的 和个体化治疗策略。

Sex-related differences have been previously reported in the susceptibility and progression of alcohol use disorders, presence or absence of comorbid conditions, and treatment response. For example, alcohol consumption is higher and alcohol dependence is more common in males, whereas females are more likely to drink heavily when experiencing unpleasant emotions or in effort to relieve psychological distress. Our previous research suggests that genetic variation may contribute to these sex-related differences. Specifically, we have shown that variants in the PDYN gene increased risk for alcohol dependence in males, but increased the risk for negative (relief) craving in females. We have observed that sex-dependent effects of genetic variants are also phenotype-specific, suggesting complex relationships with endophenotypes, comorbidities, or other biological factors (such as sex hormones). However, the biological mechanisms underlying these genetic associations and other sex-specific differences in alcohol-related traits are not well understood. It is reasonable to suggest that differences in sex-related hormone levels across the sexes and/or genetic differences between the sexes may play an important role in these biological sex differences. Yet, there is a lack of systematic research addressing the impact of sex-related hormone levels on the risk of development of alcohol use disorders and no attempts to comprehensively investigate associations between alcoholism, sex-related hormone levels and genetic variation in male and female alcoholics. Importantly, our pilot study indicates that plasma levels of some of the sex-related hormones differ significantly between alcohol dependent cases and non-alcoholic controls. We hypothesize that both sex-related hormone levels and genetic factors are associated with sex differences in alcoholism and related traits. In a sample of 235 male and 118 female alcoholics matched to 235 male and 118 female non-alcoholic controls, we will 1) investigate the association between plasma levels of sex-related hormones (testosterone, estrogens, progesterone, LH, FSH and SHBG) and alcohol dependence; 2) investigate associations between plasma levels of sex-related hormones with alcoholism-related phenotypes, such as alcohol consumption, craving, withdrawal, comorbid depression and anxiety among alcohol-dependent males and females; and 3) examine the association between genetic variation and sex-related hormone levels in subjects with and without alcohol dependence. The findings of this study will lead to a better understanding of the biology of sex differences in alcohol use disorders, facilitating development of more effective and individualized treatment strategies.