Non-alcoholic fatty liver disease is not a causal risk factor for psoriasis: A Mendelian randomization study of 108,835 individuals

Background: Psoriasis is observationally associated with a higher risk of non-alcoholic fatty liver disease (NAFLD); however, the causal relationship between the two diseases remains unclear.

Objective: We hypothesized that individuals with NAFLD or elevated liver fat content have higher risk of psoriasis and that NAFLD is a causal risk factor for psoriasis. We tested this using a Mendelian randomization approach.

Methods: We included 108,835 individuals from the Danish general population, including 1,277 individuals with psoriasis and 802 individuals with NAFLD according to ICD codes. To estimate liver fat content, a subset of the participants (N = 7,416) also had a CT scan performed. First, we tested whether a diagnosis of NAFLD or elevated liver fat content was observationally associated with risk of psoriasis. Subsequently, we used the genetic variants <i>PNPLA3</i> and <i>TM6SF2</i>, both strongly associated with NAFLD and high liver fat content, to test whether NAFLD was causally associated with increased risk of psoriasis.

Results: Observationally, individuals with vs. without a diagnosis of NAFLD had higher risk of psoriasis with an odds ratio of 2.03 (95% confidence interval 1.28-3.21). The risk of psoriasis increased in a stepwise manner with increasing liver fat content with an odds ratio of 5.00 (2.63-9.46) in individuals in the highest quartile of liver fat content compared to individuals in the lowest quartile. In genetic analyses, <i>PNPLA3</i> and <i>TM6SF2</i> were both associated with increased risk of NAFLD but not with increased risk of psoriasis.

Conclusion: Observationally, a diagnosis of NAFLD or elevated liver fat content was associated with higher risk of psoriasis. However, using genetic variants as a proxy for NAFLD, we did not find evidence of a causal relationship between NAFLD and psoriasis. Thus, the observational association between NAFLD and psoriasis is presumably a result of shared confounding factors or reverse causation.