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不明原因的慢性ALT升高可作为非酒精性脂肪肝替代指标
2022-06-05 21:34
来源：小柯机器人

美国宾夕法尼亚大学Kyong-Mi Chang、Benjamin F. Voight等研究人员合作发现，不明原因的慢性ALT升高可作为非酒精性脂肪肝替代指标。这一研究成果于2022年6月2日在线发表在国际学术期刊《自然—遗传学》上。

通过使用替代的非酒精性脂肪肝（NAFLD）定义，即丙氨酸氨基转移酶（cALT）水平长期升高而没有其他肝脏疾病，研究人员在百万退伍军人计划（MVP）中进行了一项多种族全基因组关联研究（GWAS），包括90408个cALT病例和128187个对照。有77个基因座超过了全基因组的意义，包括25个事先没有NAFLD或丙氨酸氨基转移酶关联的基因座，在仅有欧裔美国人和仅有非裔美国人的分析中还发现了一个额外的基因座（P<5×10-8）。
 
在组织学定义的NAFLD队列（7397例和56785例对照）或放射学成像队列（n=44289）中的外部重复重现了17个单核苷酸多态性（SNP）（P<6.5×10-4），其中9个是新的（TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH和IFI30）。Pleiotropy分析显示，77个多种族中的61个和所有17个重复的SNP与代谢和/或炎症性状共同相关，这揭示了一个复杂的遗传结构模型。这个整合cALT、组织学和影像学的方法揭示了对NAFLD遗传易感性的新见解。
 
据悉，NAFLD是慢性肝病的一个日益增长的原因。
 
附：英文原文
 
Title: A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

Author: Vujkovic, Marijana, Ramdas, Shweta, Lorenz, Kim M., Guo, Xiuqing, Darlay, Rebecca, Cordell, Heather J., He, Jing, Gindin, Yevgeniy, Chung, Chuhan, Myers, Robert P., Schneider, Carolin V., Park, Joseph, Lee, Kyung Min, Serper, Marina, Carr, Rotonya M., Kaplan, David E., Haas, Mary E., MacLean, Matthew T., Witschey, Walter R., Zhu, Xiang, Tcheandjieu, Catherine, Kember, Rachel L., Kranzler, Henry R., Verma, Anurag, Giri, Ayush, Klarin, Derek M., Sun, Yan V., Huang, Jie, Huffman, Jennifer E., Townsend Creasy, Kate, Hand, Nicholas J., Liu, Ching-Ti, Long, Michelle T., Yao, Jie, Budoff, Matthew, Tan, Jingyi, Li, Xiaohui, Lin, Henry J., Chen, Yii-Der Ida, Taylor, Kent D., Chang, Ruey-Kang, Krauss, Ronald M., Vilarinho, Silvia, Brancale, Joseph, Nielsen, Jonas B., Locke, Adam E., Jones, Marcus B., Verweij, Niek, Baras, Aris, Reddy, K. Rajender, Neuschwander-Tetri, Brent A., Schwimmer, Jeffrey B., Sanyal, Arun J., Chalasani, Naga, Ryan, Kathleen A., Mitchell, Braxton D., Gill, Dipender, Wells, Andrew D., Manduchi, Elisabetta, Saiman, Yedidya, Mahmud, Nadim, Miller, Donald R., Reaven, Peter D., Phillips, Lawrence S., Muralidhar, Sumitra

Issue&Volume: 2022-06-02

Abstract: Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic elevation of alanine aminotransferase (cALT) levels without other liver diseases, we performed a multiancestry genome-wide association study (GWAS) in the Million Veteran Program (MVP) including 90,408 cALT cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance, including 25 without prior NAFLD or alanine aminotransferase associations, with one additional locus identified in European American-only and two in African American-only analyses (P<5 × 108). External replication in histology-defined NAFLD cohorts (7,397 cases and 56,785 controls) or radiologic imaging cohorts (n=44,289) replicated 17 single-nucleotide polymorphisms (SNPs) (P<6.5 × 104), of which 9 were new (TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH and IFI30). Pleiotropy analysis showed that 61 of 77 multiancestry and all 17 replicated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD.

DOI: 10.1038/s41588-022-01078-z

Source: https://www.nature.com/articles/s41588-022-01078-z

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex


本期文章：《自然—遗传学》：Online/在线发表

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