Division of GastroenterologyDepartment of MedicineDuke UniversityDurhamNCUSA.
Duke Molecular Physiology InstituteDuke UniversityDurhamNCUSA.
Hepatol Commun. 2021 Jan 18;5(4):598-607. doi: 10.1002/hep4.1668. eCollection 2021 Apr.
The development of fibrosis in nonalcoholic fatty liver disease (NAFLD) is influenced by genetics, sex, and menopausal status, but whether genetic susceptibility to fibrosis is influenced by sex and reproductive status is unclear. Our aim was to identify metabolism-related single nucleotide polymorphisms (SNPs), whose effect on NAFLD fibrosis is significantly modified by sex and menopausal status. We performed a cross-sectional, proof-of-concept study of 616 patients in the Duke NAFLD Clinical Database and Biorepository. The primary outcome was nonalcoholic steatohepatitis-Clinical Research Network (NASH-CRN) fibrosis stage. Menopause status was self-reported; age 51 years was used as a surrogate for menopause in patients with missing menopause data. The Metabochip was used to obtain 98,359 SNP genotypes in known metabolic pathway genes for each patient. We used additive genetic models to characterize sex and menopause-specific effects of SNP genotypes on NAFLD fibrosis stage. In the main effects analysis, none of the SNPs were associated with fibrosis at < 0.05 after correcting for multiple comparisons. Twenty-five SNPs significantly interacted with sex/menopause to affect fibrosis stage (interaction < 0.0001). After removal of loci in linkage disequilibrium, 10 independent loci were identified. Six were in the following genes: (potassium voltage-gated channel interacting protein 4), (psoriasis susceptibility 1 candidate 1), (Kelch-like family member 8), (glycine receptor alpha 1), (notch receptor 2), and (protein kinase C eta), and four SNPs were intergenic. In stratified models, four SNPs were significant in premenopausal and postmenopausal women, three only in postmenopausal women, two in men and postmenopausal women, and one only in premenopausal women. We identified 10 loci with a significant sex/menopause interaction with respect to fibrosis. None of these SNPs were significant in all sex/menopause groups, suggesting modulation of genetic susceptibility to fibrosis by sex and menopause status. Future studies of genetic predictors of NAFLD progression should account for sex and menopause.
非酒精性脂肪性肝病 (NAFLD) 纤维化的发展受遗传、性别和绝经状态的影响，但遗传易感性是否受性别和生殖状态的影响尚不清楚。我们的目的是确定代谢相关的单核苷酸多态性 (SNP)，这些 SNP 对 NAFLD 纤维化的影响明显受到性别和绝经状态的修饰。我们对杜克大学 NAFLD 临床数据库和生物库中的 616 名患者进行了横断面、概念验证研究。主要结局是非酒精性脂肪性肝炎临床研究网络 (NASH-CRN) 纤维化分期。绝经状态为自我报告；对于绝经数据缺失的患者，使用 51 岁作为绝经的替代指标。对每位患者使用代谢芯片获得 98359 个已知代谢途径基因的 SNP 基因型。我们使用加性遗传模型来描述 SNP 基因型对 NAFLD 纤维化分期的性别和绝经特异性影响。在主要效应分析中，在对多重比较进行校正后，没有一个 SNP 与纤维化相关，差异具有统计学意义 （<0.05）。25 个 SNP 与性别/绝经显著相互作用，影响纤维化分期 （相互作用 < 0.0001）。去除连锁不平衡的基因座后，确定了 10 个独立的基因座。其中 6 个位于以下基因： （钾电压门控通道相互作用蛋白 4）， （银屑病易感 1 候选基因 1）， （Kelch 样家族成员 8）， （甘氨酸受体 alpha 1）， （Notch 受体 2）和 （蛋白激酶 C eta），4 个 SNP 位于基因间。在分层模型中，4 个 SNP 在绝经前和绝经后妇女中具有显著性，3 个仅在绝经后妇女中具有显著性，2 个在男性和绝经后妇女中具有显著性，1 个仅在绝经前妇女中具有显著性。我们确定了 10 个与纤维化有显著性别/绝经相互作用的基因座。这些 SNP 均不在所有性别/绝经组中具有显著性，提示性别和绝经状态对纤维化遗传易感性有调节作用。未来研究 NAFLD 进展的遗传预测因子时，应考虑到性别和绝经状态。
