Journal
CLINICAL AND MOLECULAR HEPATOLOGY
Volume 28, Issue 2, Pages 183-195Publisher
KOREAN ASSOC STUDY LIVER
DOI: 10.3350/cmh.2021.0301
Keywords
Non-alcoholic fatty liver disease; Klotho proteins; Vitamin D; Polymorphism; Single nucleotide
Categories
Funding
- National Natural Science Foundation of China [82070588]
- High Level Creative Talents from Department of Public Health in Zhejiang Province [S2032102600032]
- Project of New Century 551 Talent Nurturing in Wenzhou
- Erasmus Medical Center, Rotterdam
- Netherlands Organization for the Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
- Erasmus University, Rotterdam
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The KL rs495392 polymorphism has a protective effect against hepatic steatosis in patients with NAFLD, and carriers of the rs495392 A allele are associated with serum vitamin D levels and the impact of PNPLA3 rs738409 G allele on severe hepatic steatosis risk.
Background/Aims: Non-alcoholic fatty liver disease (NAFLD) is closely associated with metabolic dysfunction. Among the multiple factors, genetic variation acts as important modifiers. Klotho, an enzyme encoded by the klotho (KL) gene in human, has been implicated in the pathogenesis of metabolic dysfunctions. However, the impact of variants in KL on NAFLD risk remains poorly understood. The aim of this study was to investigate the impact of KL rs495392 C>A polymorphism on the histological severity of NAFLD. Methods: We evaluated the impact of the KL rs495392 polymorphism on liver histology in 531 Chinese with NAFLD and replicated that in the population-based Rotterdam Study cohort. The interactions between the rs495392, vitamin D, and patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 polymorphism were also analyzed. Results: Carriage of the rs495392 A allele had a protective effect on steatosis severity (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.42-0.89; P=0.010) in Chinese patients. After adjustment for potential confounders, the A allele remained significant with a protective effect (OR, 0.66; 95% CI, 0.45-0.98; P=0.040). The effect on hepatic steatosis was confirmed in the Rotterdam Study cohort. Additional analysis showed the association between serum vitamin D levels and NAFLD specifically in rs495392 A allele carriers, but not in non-carriers. Moreover, we found that the rs495392 A allele attenuated the detrimental impact of PNPLA3 rs738409 G allele on the risk of severe hepatic steatosis. Conclusions: The KL rs495392 polymorphism has a protective effect against hepatic steatosis in patients with NAFLD.
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