* Causal Relationship and Shared Genetic Loci between Psoriasis and Type 2 Diabetes through Trans-Disease Meta-Analysis. J Invest Dermatol.141(6): 1493-1502, 06/2021.
This study investigates the genetic overlap and causal relationships between psoriasis and type 2 diabetes (T2D). Using trans-disease meta-analysis (TDMA), we identified shared genetic loci that suggest a potential common pathophysiological pathway between the two diseases. This pioneer work highlights a clear genetic link between T2D and psoriasis independent of confounding factors, such as BMI. Applying robust statistical techniques for TDMA to data from over one million individuals, we identified four shared genetic signals, two of which are new findings for each disease, and we then evaluated them in a hospital-based dataset (42,112 individuals). Our study confirmed the significance of these loci using five different TDMA techniques, in addition to rigorous selection criteria. These findings suggest potential roles of NFκB mediator TRAF6 as a hub protein connecting the 4 identified loci. The findings of this work can serve as a starting point for developing new, more effective medicine for T2D and psoriasis, as well as other immune-mediated diseases. Moreover, we applied multi-variable Mendelian randomization techniques to demonstrate psoriasis has a significant causal effect on T2D, independent of BMI and other confounders.
* Retrospective pharmacogenetic study of psoriasis highlights the role of KLK7 in tumour necrosis factor signalling. Br J Dermatol.190(1): 70-79, 12/2023.
Treatment responses for psoriasis can vary, and it is important to understand factors associated with this variation. Linking to our Michigan psoriasis genetic cohort, we have collected the drug responses of six different treatment options, enabling us to conduct retrospective genome-wide pharmacogenetic studies. We associated genetic markers with self-evaluated treatment responses from six different options using linear regression. We further utilized an integrative approach incorporating epigenomic, transcriptomic, and a longitudinal clinical cohort to provide biological implications for the top signals associated with treatment response. We identified two novel genetic markers, one associated with anti-TNF biologics, and the other associated with methotrexate. These two markers are also associated with cutaneous mRNA expression levels of two known psoriasis-related genes: KLK7 and CD200. We further confirmed that the expression level of KLK7 is increased in the psoriatic epidermis and responses to anti-TNF treatment. We also found that keratinocytes have decrease in pro-inflammatory responses to TNF, by inhibiting the expression of KLK7. These findings highlight the role of KLK7 in modulating TNF signaling in keratinocytes, offer valuable insights for personalizing treatment in psoriasis patients, and present potential targets for loci and genes for future psoriasis drug development.