A Polygenic Risk Score for Predicting Racial and Genetic Susceptibility to Prurigo Nodularis.

Area of Science:

• Genetics
• Dermatology
• Population Health

Background:

• Prurigo nodularis (PN) is an understudied inflammatory skin disease characterized by intensely itchy, hyperkeratotic nodules.
• Understanding the genetic underpinnings of PN is crucial for developing targeted therapies and elucidating disease etiology.

Purpose of the Study:

• To identify genetic factors contributing to prurigo nodularis (PN).
• To develop a predictive polygenic risk score for PN diagnosis.
• To investigate the role of genetic ancestry and race in PN development and disparities.

Main Methods:

• Development and validation of a polygenic risk score for PN in independent populations.
• Genome-wide association studies (GWAS) to identify associated genetic variants.
• Analysis of genetic risk in relation to self-reported race and genetic ancestry.

Main Results:

• A polygenic risk score significantly predicted PN diagnosis (OR = 1.41, P = 1.6 × 10⁻⁵).
• GWAS identified significant PN-associated variants near PLCB4 (rs6039266) and TXNRD1 (rs34217906, rs7134193).
• Black patients exhibited over a two-fold greater genetic risk for PN (OR = 2.63, P = 7.8 × 10⁻⁴), with combined PRS and race being highly predictive.

Conclusions:

• Genetic factors, including variants near PLCB4 and TXNRD1, contribute to PN susceptibility.
• Significant racial disparities in PN genetic risk suggest a complex interplay of genetics, environment, and social determinants of health.
• The findings highlight the need to consider genetic predisposition and social factors in understanding and addressing PN, particularly observed racial disparities.