Patients with Genetic HS Susceptibility Predisposed to Coronary Artery Disease, Diabetes

Individuals with a genetic susceptibility to hidradenitis suppurativa (HS) are predisposed to coronary artery disease as well as diabetes, new findings suggest, and further research may be necessary regarding the identified proteins and their roles as potential drug targets.¹

This study was led by Valdemar Wendelboe Nielsen, BSc, from the Department of Dermato-Venereology and Wound Healing Centre at Copenhagen University Hospital–Bispebjerg and Frederiksberg in Denmark.

Nielsen et al. expressed that larger-scale and genome-wide association studies had previously advanced the collective awareness of HS’s genetic underpinnings. Nevertheless, they noted that the affected genetic pathways had still not been fully investigated.²

“In this study, we examined the genetic correlation of HS with coronary artery disease (CAD) and diabetes,” Nielsen and colleagues wrote. “Using publicly available summary statistics and individual genotype data from the UK Biobank, we constructed a (polygenic risk score) for HS to explore the potential of the PRS as a tool to determine risk of incident CAD and diabetes and to identify proteins associated with increased risk of these comorbidities in a large population-based cohort.”¹

Trial Design

For their research, the investigators would implement the UK Biobank, a large population-based repository in the UK containing clinical and genetic data from over 500,000 individuals. This was their source of participants for their analysis, during which they enrolled participants between January 2006 - December 2010.

The research team’s cohort study involved an examination of the genetic correlation (genetic r) between genetic variants which had been linked to HS and those linked to such cardiometabolic conditions as CAD, atrial fibrillation, type 2 diabetes. They also assessed associations with blood lipids such as high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides.

Additionally, the team looked into subjects’ blood pressure (both systolic and diastolic) and their C-reactive protein (CRP). Linkage disequilibrium score regression was employed by the investigators for the purposes of estimating the genetic correlation.

A polygenic risk score (PRS) was used by the investigators for HS to examine the risk of subjects’ development of diabetes and coronary artery disease, specifically for those of European ancestry who were featured in the UK Biobank. Changes in the plasma proteome were also assessed.

The research team concluded their follow-up period in January 2023. The risk of developing CAD and diabetes was analyzed using time-to-event models which had specifically been designed for cause-related survival analyses.

The team’s main endpoints were the diagnosis of CAD and diabetes assessed using logistic regression, as well as the incidence of such conditions. These were determined through Cox proportional hazards models, with the models adjusted for factors like age, sex, body mass index (BMI), and smoking status.

Significant Findings

Overall, there were 391 481 participants included in the investigators’ analysis, with a median age of 58 years and 53% being reported as female. The team concluded that genetic variants for HS were shown to correlate significantly with variants linked to diabetes, CAD, and plasma levels of high-density lipoprotein cholesterol, C-reactive protein, and triglycerides.

In their comparison with the low-risk cohort, the research team reported a high PRS for HS conferred odds ratios of 1.13 (95% CI, 1.10-1.17; P < .001) for diabetes. It had been 1.09 (95% CI, 1.06-1.12; P < .001) for CAD.

The team highlighted the consistency of estimates that remained when they looked into incident CAD and diabetes exclusively. HS’s PRS was found to be associated substantially with altered expression of 58 plasma proteins.

The investigators added that the integration of such a proteomic profile and the PRS for HS in their machine learning model had led to prediction improvements for diabetes and CAD compared to a reference model based on factors such as patients’ sex, BMI, and age.

“The results of this cohort study suggest a correlation between genetic variants for HS, CAD, and diabetes and that genetic susceptibility to HS was associated with increased risk of incident CAD and diabetes,” they concluded.¹

References

1. ^{Nielsen VW, Bundgaard Vad O, Holgersen N, et al. Genetic Susceptibility to Hidradenitis Suppurativa and Predisposition to Cardiometabolic Disease. JAMA Dermatol. Published online October 09, 2024. doi:10.1001/jamadermatol.2024.3779.}
2. ^{Sun Q, Broadaway KA, Edmiston SN, et al. Genetic variants associated with hidradenitis suppurativa. JAMA Dermatol. 2023;159(9):930-938. doi:10.1001/jamadermatol.2023.2217.}