Impact of Keratins 8 and 18 Genetic Variants on the Severity of Alcoholic Liver Disease

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Laboratory Investigation Pub Date : 2024-10-01 DOI:10.1016/j.labinv.2024.102133

Matthieu Tihy , Nathalie Lin-Marq , Thierry Berney , Laurent Spahr , Laura Rubbia-Brandt , Laure Elkrief

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Abstract

Alcohol-related liver disease (ALD) affects ∼30% of heavy drinkers and is characterized by liver steatosis, fibrosis, and steatohepatitis. The aggregation of keratins 8 (KRT8) and 18 (KRT18) plays a key role in the formation of Mallory–Denk bodies, a hallmark of ALD. Circulating levels of KRT18 fragments are elevated during ALD, and several KRT8/18 genetic variants have been linked to an increased risk of liver disease. In this study, we explored the relationship between the histologic features of ALD and genetic variants of KRT8/18 in 106 severe patients with ALD from the Hôpitaux Universitaires de Genève. We found a significant over-representation of several KRT8 (rs2070910, rs137898974, rs1065306) and KRT18 (rs17120866, rs1492241) variants located in the noncoding regions of these genes. Increased circulating level of keratins 18 fragments were associated with rs17120866 and alcoholic hepatitis. The combination of several KRT18 variants appeared associated with a poorer prognosis. These results highlight the possible role of KRT18 variants in ALD.

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角蛋白 8 和 18 基因变异对酒精性肝病严重程度的影响。

酒精相关肝病（ALD）影响着大约 30% 的重度饮酒者，其特征是肝脏脂肪变性、纤维化和脂肪性肝炎。角蛋白 8（KRT8）和 18（KRT18）的聚集在马洛里-登克体的形成中起着关键作用，而马洛里-登克体是 ALD 的特征之一。在 ALD 期间，循环中的角蛋白 18 片段水平会升高，而几种 KRT8/18 基因变异与肝病风险的增加有关。在这项研究中，我们以日内瓦大学医院的106名重度ALD患者为研究对象，探讨了ALD的组织学特征与KRT8/18基因变异之间的关系。我们发现，位于 KRT8（rs2070910、rs137898974、rs1065306）和 KRT18（rs17120866、rs1492241）基因非编码区的几个 KRT8（rs2070910、rs137898974、rs1065306）和 KRT18（rs17120866、rs1492241）变体的比例明显偏高。循环中角蛋白 18 片段水平的增加与 rs17120866 和酒精性肝炎有关。多个 KRT18 变异的组合似乎与较差的预后有关。这些结果突显了 KRT18 变体在 ALD 中可能扮演的角色。

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来源期刊

Laboratory Investigation 医学-病理学

CiteScore

8.30

自引率

0.00%

发文量

125

审稿时长

2 months

期刊介绍： Laboratory Investigation is an international journal owned by the United States and Canadian Academy of Pathology. Laboratory Investigation offers prompt publication of high-quality original research in all biomedical disciplines relating to the understanding of human disease and the application of new methods to the diagnosis of disease. Both human and experimental studies are welcome.