Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes.
Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes.
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DOI：
10.1038/s41467-023-35808-6
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发表时间：
2023-01-12
影响因子：
16.6
通讯作者：
Huang, R. Stephanie
中科院分区：
文献类型：
--
作者：
Huang, Yingbo;Shan, Yuting;Zhang, Weijie;Lee, Adam M.;Li, Feng;Stranger, Barbara E.;Huang, R. Stephanie
性别差异在人类健康中被广泛观察到。然而，人们对这些观察到的性别差异背后的潜在机制知之甚少。我们假设性别分化的遗传效应是这些表型差异的贡献者。通过对一组药物代谢酶和转运蛋白(DMET)基因的研究，我们发现这些基因与人类复杂性状之间存在性别差异的遗传调控机制。在这里，我们表明，性别分化的遗传效应存在于基因组水平和DMET基因区域的许多人类复杂的特征。这些性别分化的调节机制反映在基因表达水平和内源性血清生物标志物上。通过孟德尔随机化分析，我们分别确定了假设的性别差异的因果效应在每个性别。此外，我们鉴定并验证了人类肝脏样本中DMET基因子集的性别差异基因表达。我们观察到在男性来源的肝微粒体中，CYP1A2的蛋白丰度和酶活性较高，这导致了氯氮平的活性代谢物形成水平较高，氯氮平是一种常用的抗精神病药物。综上所述，我们的结果证明了性别分化的遗传效应在DMET基因调控中的存在，这体现在包括疾病风险和药物反应在内的各种表型特征上。人们对疾病患病率和治疗结果性别差异的原因知之甚少。在这里，作者研究了复杂人类性状中药物代谢酶与转运蛋白基因和性别之间的相互作用，以揭示在基因表达、血清生物标志物和药物代谢的遗传调控方面的性别差异。
Sex differences have been widely observed in human health. However, little is known about the underlying mechanism behind these observed sex differences. We hypothesize that sex-differentiated genetic effects are contributors of these phenotypic differences. Focusing on a collection of drug metabolism enzymes and transporters (DMET) genes, we discover sex-differentiated genetic regulatory mechanisms between these genes and human complex traits. Here, we show that sex-differentiated genetic effects were present at genome-level and at DMET gene regions for many human complex traits. These sex-differentiated regulatory mechanisms are reflected in the levels of gene expression and endogenous serum biomarkers. Through Mendelian Randomization analysis, we identify putative sex-differentiated causal effects in each sex separately. Furthermore, we identify and validate sex differential gene expression of a subset of DMET genes in human liver samples. We observe higher protein abundance and enzyme activity of CYP1A2 in male-derived liver microsomes, which leads to higher level of an active metabolite formation of clozapine, a commonly prescribed antipsychotic drug. Taken together, our results demonstrate the presence of sex-differentiated genetic effects on DMET gene regulation, which manifest in various phenotypic traits including disease risks and drug responses. Little is known about the causes of sex differences in disease prevalence and treatment outcomes. Here, the authors study the interaction between drug metabolism enzymes and transporters genes and sex in complex human traits to uncover sex differences in the genetic regulation of gene expression, serum biomarkers, and metabolism of drugs.
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影响因子：
6.5
作者：
GERSON, SL;ARCE, C;MELTZER, HY
通讯作者：
MELTZER, HY
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
DOI：
10.1038/s41568-021-00348-y
发表时间：
2021-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Haupt S;Caramia F;Klein SL;Rubin JB;Haupt Y
通讯作者：
Haupt Y
影响因子：
5.8
作者：
Imamichi, Yoshitaka;Yuhki, Koh-ichi;Yazawa, Takashi
通讯作者：
Yazawa, Takashi
影响因子：
6.1
作者：
Ceylan-Isik, Ashli F.;McBride, Shawna M.;Ren, Jun
通讯作者：
Ren, Jun