P93 The impact of central adiposity and genetic factors on psoriasis risk: insights from the UK Biobank

Abstract Genetic and environmental factors contribute to both psoriasis risk and severity. Adiposity is highly prevalent in people with psoriasis and is associated with an increased risk of both the onset and severity of the disease. Central adiposity measures are strongly associated with adverse cardiometabolic outcomes; however, it remains uncertain whether this trend is similarly observed in psoriasis. Understanding which measures of adiposity predispose individuals to psoriasis, and the relationship between genetic factors and adiposity’s effect on psoriasis, can facilitate better risk stratification and guide targeted weight management interventions. This study aimed to characterize the body fat topography in people with psoriasis and their relationships with known psoriasis genetic risk factors in a large population-based cohort (UK Biobank, 336 806 participants of white British ancestry, including 9305 psoriasis cases). The relationship between known measures of adiposity and psoriasis genetic risk factors was explored using interaction testing. Mendelian Randomization (MR) was conducted to determine if the causal influence of adiposity on psoriasis risk differed in (i) HLA-C*06:02-stratified subgroups and (ii) psoriasis polygenic risk score (PRS) quartiles. Measures of central adiposity, assessed through multiple modalities (including magnetic resonance imaging, dual energy X-ray absorptiometry and bioelectric impedance measures) were most strongly associated with the risk of psoriasis. Sex-specific differences were observed, with stronger associations in females compared with males. A significant interaction between psoriasis PRS and adiposity measures on psoriasis risk was identified, which was not observed when HLA-C*06:02 (the psoriasis primary susceptibility allele) was excluded from the PRS. This finding is consistent with previous studies that observed a stronger association between adiposity measures and psoriasis in HLA-C*06:02-negative vs. HLA-C*06:02-positive participants. No significant differences in risk-increasing MR estimates were found between HLA-C*06:02-stratified subgroups for the effects of BMI, waist circumference, or waist-to-hip ratio on psoriasis risk. No differences in MR estimates for the effect of adiposity measures on psoriasis risk were observed across quartiles of psoriasis PRS. These findings underscore the importance of central adiposity in influencing psoriasis risk. The lack of differences in MR effects between HLA-C*06:02-stratified subgroups supports the notion that a collider bias may explain the epidemiological observation of higher adiposity levels in HLA-C*06:02-negative psoriasis, rather than a biological difference in adiposity’s effect on psoriasis between HLA-C*06:02-stratified subgroups. The magnitude of risk-increasing causal effects was consistent in HLA-C*06:02-stratified subgroups suggesting that adiposity is important to psoriasis risk independent of HLA status. The lack of difference in association or MR effect between adiposity and psoriasis across strata of psoriasis polygenic risk emphasizes the importance of optimizing weight management irrespective of psoriasis genetic risk.