A deCIDEdly New Germline Mutation That Protects Against Liver Disease

Verweij N, Haas ME, Nielsen JB, et al. Germline mutations in CIDEB and protection against liver disease. N Engl J Med 2022;387:332–344. Li JZ, Ye J, Xue B, et al. Cideb regulates diet-induced obesity, liver steatosis, and insulin sensitivity by controlling lipogenesis and fatty acid oxidation. Diabetes 2007;56:2523–2532. Genetic and environmental factors mediate progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) and cirrhosis. However, specific genetic determinants driving this transition are not well-understood. Rapid, high-throughput whole-exome sequencing technology now affords the opportunity to identify rare disease-relevant coding variants in large patient cohorts. This is critical because no therapies approved by the US Food and Drug Administration exist to treat or prevent NASH and because such novel methods can reveal new NASH target candidates. Furthermore, the precise means by which to stratify high-risk populations toward early, aggressive metabolic therapy are currently lacking. Verweij et al applied whole-exome sequencing and genetic association analysis to over 500,000 patients (24,944 with liver disease) in the UK Biobank and Geisinger Health System MyCode cohorts to identify protein-coding variants associated with liver disease. They used a multistage approach to identify four gene variants associated with high transaminases: APOB, ABCB4, SLC30A10, and TM6SF2. Interestingly, 1 putative loss-of-function coding variant in Cell death-inducing DFF45-like effector B (CIDEB) associated with lower transaminases and milder histological NAFLD Activity Scoring. Three CIDE isoforms comprise a family of lipid droplet–associated proteins that regulate lipid droplet homeostasis. CIDEB is of particular interest, because CIDEB-deficient mouse models have lower plasma triglycerides and are protected from diet-induced obesity, insulin resistance, and hepatic steatosis. These new data now implicate pathophysiological functions for CIDEB in liver disease in people. The primary strengths of this study include its multistage analytical approach; applying exome sequencing to a large, well-characterized study population; and validation of the CIDEB function using a cell-based assay system. Subsequent work should validate these associations in non–European-predominant populations, define further insight into precisely how this CIDEB variant is protective, and determine if targeting this protein will indeed prove beneficial in liver disease. The data nevertheless advance the field by nominating CIDEB as a novel NAFLD and NASH target, by uncovering a potential risk allele by which to stratify patients for aggressive, early NASH-specific treatment, and by providing a novel genetic approach to identify targets in other diseases using large-cohort exome sequencing. Each of these advances represents exciting steps toward precision treatment of NAFLD, NASH, and beyond.