Sex and Menopause Modify the Effect of Single Nucleotide Polymorphism Genotypes on Fibrosis in NAFLD.
Sex and Menopause Modify the Effect of Single Nucleotide Polymorphism Genotypes on Fibrosis in NAFLD.
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DOI：
10.1002/hep4.1668
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发表时间：
2021-04
影响因子：
5.1
通讯作者：
Suzuki A
中科院分区：
文献类型：
--
作者：
Wegermann K;Garrett ME;Zheng J;Coviello A;Moylan CA;Abdelmalek MF;Chow SC;Guy CD;Diehl AM;Ashley-Koch A;Suzuki A
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，但纤维化的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），其对NAFLD纤维化的影响受性别和绝经状态的影响。我们对杜克NAFLD临床数据库和生物储存库中的616例患者进行了一项横断面、概念验证研究。主要结局为非酒精性脂肪性肝炎-临床研究网络（NASH-CRN）纤维化分期。绝经状态是自我报告的;在绝经数据缺失的患者中，年龄51岁被用作绝经的替代。Metabochip用于获得每个患者已知代谢途径基因中的98，359个SNP基因型。我们使用加性遗传模型来表征SNP基因型对NAFLD纤维化阶段的性别和绝经特异性影响。在主效应分析中，校正多重比较后，在P < 0.05时，没有SNP与纤维化相关。25个SNP与性别/绝经显著相互作用以影响纤维化分期（相互作用P < 0.0001）。在去除连锁不平衡位点后，鉴定出10个独立的位点。6个位于以下基因中：KCNIP 4（钾电压门控通道相互作用蛋白4），PSORS 1C 1（银屑病易感性1候选者1），KLHL 8（Kelch样家族成员8），GLRA 1（甘氨酸受体α 1），NOTCH 2（notch受体2）和PRKCH（蛋白激酶C eta），4个SNP是基因间的。在分层模型中，4个SNP在绝经前和绝经后妇女中有显著性，3个仅在绝经后妇女中有显著性，2个在男性和绝经后妇女中有显著性，1个仅在绝经前妇女中有显著性。结论：我们确定了10个基因座与纤维化有显著的性别/绝经相互作用。这些SNPs在所有性别/绝经组中均不显著，表明性别和绝经状态对纤维化的遗传易感性的调节。未来NAFLD进展的遗传预测因子的研究应该考虑性别和绝经。
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 P < 0.05 after correcting for multiple comparisons. Twenty‐five SNPs significantly interacted with sex/menopause to affect fibrosis stage (interaction P < 0.0001). After removal of loci in linkage disequilibrium, 10 independent loci were identified. Six were in the following genes: KCNIP4 (potassium voltage‐gated channel interacting protein 4), PSORS1C1 (psoriasis susceptibility 1 candidate 1), KLHL8 (Kelch‐like family member 8), GLRA1 (glycine receptor alpha 1), NOTCH2 (notch receptor 2), and PRKCH (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. Conclusion: 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.
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影响因子：
4.8
作者：
Corbin, Karen D.;Abdelmalek, Manal F.;Zeisel, Steven H.
通讯作者：
Zeisel, Steven H.
影响因子：
3.8
作者：
Ballestri S;Nascimbeni F;Baldelli E;Marrazzo A;Romagnoli D;Lonardo A
通讯作者：
Lonardo A
影响因子：
7
作者：
Blekhman, Ran;Marioni, John C.;Gilad, Yoav
通讯作者：
Gilad, Yoav
DOI：
10.1073/pnas.1323785111
发表时间：
2014-06-17
影响因子：
11.1
作者：
Mahdessian, Hovsep;Taxiarchis, Apostolos;van't Hooft, Ferdinand
通讯作者：
van't Hooft, Ferdinand
影响因子：
29.4
作者：
Chalasani N;Guo X;Loomba R;Goodarzi MO;Haritunians T;Kwon S;Cui J;Taylor KD;Wilson L;Cummings OW;Chen YD;Rotter JI;Nonalcoholic Steatohepatitis Clinical Research Network
通讯作者：
Nonalcoholic Steatohepatitis Clinical Research Network