Polymorphisms Associated With Metabolic Dysfunction-Associated Steatotic Liver Disease Influence the Progression of End-Stage Liver Disease.
Polymorphisms Associated With Metabolic Dysfunction-Associated Steatotic Liver Disease Influence the Progression of End-Stage Liver Disease.
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DOI：
10.1016/j.gastha.2023.09.011
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Tafaleng, Edgar N
中科院分区：
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作者：
Kocas-Kilicarslan, Zehra N;Cetin, Zeliha;Faccioli, Lanuza A P;Motomura, Takashi;Amirneni, Sriram;Diaz-Aragon, Ricardo;Florentino, Rodrigo M;Sun, Yiyue;Pla-Palacin, Iris;Xia, Mengying;Miedel, Mark T;Kurihara, Takeshi;Hu, Zhiping;Ostrowska, Alina;Wang, Zi;Constantine, Robert;Li, Albert;Taylor, D Lansing;Behari, Jaideep;Soto-Gutierrez, Alejandro;Tafaleng, Edgar N
导致肝硬化和终末期肝病 (ESLD) 的慢性肝损伤每年导致全球超过 100 万人死亡。尽管之前已经研究了遗传因素对代谢功能障碍相关脂肪肝病 (MASLD) 和酒精相关肝病 (ALD) 严重程度的影响，但它们对 ESLD 发展的贡献在很大程度上仍未被探索。我们对健康人群 (n = 123)、代谢功能障碍相关脂肪性肝炎 (MASH) (n = 145)、MASLD 相关 ESLD (n = 72) 和 ALD 相关 ESLD (n = 57) 队列中的 6 个 MASLD 相关多态性进行了基因分型，并进行了多项 Logistic 回归以确定遗传、人口统计学和临床因素对 ESLD 进展的综合贡献。一系列不同的因素与 ESLD 的进展相关。 PNPLA3 rs738409:G 和 TM6SF2 rs58542926:T 等位基因、体重指数 (BMI)、年龄和女性性别与从健康状态进展为 MASH 呈正相关。 PNPLA3 rs738409:G 等位基因、年龄、男性和患有 2 型糖尿病呈正相关，而 BMI 与从 MASH 进展到 MASLD 相关 ESLD 呈负相关。 PNPLA3 rs738409:G 和 GCKR rs780094:T 等位基因、年龄和男性性别呈正相关，而 BMI 与从健康状态进展为 ALD 相关 ESLD 呈负相关。研究结果表明，无论病因如何，PNPLA3 rs738409:G 等位基因都会增加对 ESLD 的易感性，TM6SF2 rs58542926:T 等位基因会增加对 MASH 的易感性，GCKR rs780094:T 等位基因会增加对 ALD 相关 ESLD 的易感性。 PNPLA3、TM6SF2 和 GCKR 小等位基因影响 MASLD 相关或 ALD 相关 ESLD 的进展。对 MASLD 和 ALD 患者的这些变异进行基因分型可以增强风险评估，促进早期干预以预防 ESLD。
Chronic liver injury that results in cirrhosis and end-stage liver disease (ESLD) causes more than 1 million deaths annually worldwide. Although the impact of genetic factors on the severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease (ALD) has been previously studied, their contribution to the development of ESLD remains largely unexplored. We genotyped 6 MASLD-associated polymorphisms in healthy (n = 123), metabolic dysfunction-associated steatohepatitis (MASH) (n = 145), MASLD-associated ESLD (n = 72), and ALD-associated ESLD (n = 57) cohorts and performed multinomial logistic regression to determine the combined contribution of genetic, demographic, and clinical factors to the progression of ESLD. Distinct sets of factors are associated with the progression to ESLD. The PNPLA3 rs738409:G and TM6SF2 rs58542926:T alleles, body mass index (BMI), age, and female sex were positively associated with progression from a healthy state to MASH. The PNPLA3 rs738409:G allele, age, male sex, and having type 2 diabetes mellitus were positively associated, while BMI was negatively associated with progression from MASH to MASLD-associated ESLD. The PNPLA3 rs738409:G and GCKR rs780094:T alleles, age, and male sex were positively associated, while BMI was negatively associated with progression from a healthy state to ALD-associated ESLD. The findings indicate that the PNPLA3 rs738409:G allele increases susceptibility to ESLD regardless of etiology, the TM6SF2 rs58542926:T allele increases susceptibility to MASH, and the GCKR rs780094:T allele increases susceptibility to ALD-associated ESLD. The PNPLA3, TM6SF2, and GCKR minor alleles influence the progression of MASLD-associated or ALD-associated ESLD. Genotyping for these variants in MASLD and ALD patients can enhance risk assessment, prompting early interventions to prevent ESLD.