Evidence of gene–gene interaction in hidradenitis suppurativa: a nationwide registry study of Danish twins

Abstract

Summary Background Hidradenitis suppurativa (HS) is a recurrent inflammatory skin disease that, apart from rare causative loss‐of‐function mutations, has a widely unknown genetic aetiology. Objectives To estimate the relative importance of genetic and environmental factors underlying susceptibility to HS. Methods Via the Danish Twin Registry and the Danish National Patient Registry we pulled together information on zygosity with that of HS status. Cases of HS were identified by the International Classification of Diseases (ICD)‐8 (705·91) and ICD‐10 (L73·2). Heritability was assessed by the classic biometric model and the possibility of gene–gene interaction via the multilocus modelling approach. Results Among 100 044 registered twins, we found 170 twins (from 163 pairs) diagnosed with HS. The seven concordant pairs were all monozygotic. Monozygotic twins had a case‐wise concordance rate of 28% [95% confidence interval (CI) 7–49], corresponding to a familial risk of 73 (95% CI 13–133) times that of the background population. The biometrical modelling suggested a heritability of 0·80 (95% CI 0·67–0·93), and the multilocus index estimate was 230 (95% CI 60–400). This is highly indicative of gene–gene interactions, with the possibility of up to six interacting loci. Conclusions This twin study was substantially larger and employed a more valid phenotype than previous studies. Genetics account for the majority of HS susceptibility, and HS is most likely caused by gene–gene interactions rather than monogenetic mutations or solely additive genetic factors. New approaches aimed at assessing potential interactions at a single‐nucleotide polymorphism (SNP)–SNP level should be implemented in future HS genome‐wide association studies.

The expected missing heritability of hidradenitis suppurativa in perspective

“…In this issue of the BJD , the study by Kjærsgaard Andersen et al . cross‐references Danish National Twin Registry data with International Classification of Diseases 8/10 codes for HS to provide a robust heritability estimate for HS of 80% [95% confidence interval (CI) 67–93] 1 . This estimate is in line with a previous twin study, which identified a heritability for HS of 77% (95% CI 54–90), despite using different methodologies 2 …”

“…also allows for nongenetic (e.g. environmental) contributions to HS 1,8 . Distinct HS phenotypes each seem to be associated with different environmental factors such as smoking or obesity, suggesting an important role for gene–environment (G × E) interactions 8 .…”

“…found an unusually high multilocus index, which is dependent on both the number of contributing genes and their degree of interaction (gene–gene interactions) 3 . This indicates a predicted discrepancy between the study’s heritability estimate and future genome‐wide association study (GWAS) results, a concept that is well recognized in complex traits and commonly known as ‘missing heritability’ 1,4 . How large this predicted gap might be can be illustrated by looking at the heritability of Crohn disease (CD).…”

The Genomic Architecture of Hidradenitis Suppurativa—A Systematic Review

“…Despite the high heritability estimates of HS (77–80%) only a minority of HS patients demonstrate a strong monogenic etiology in the context of familial or syndromic HS (5%) ( Kjaersgaard Andersen et al, 2021 ). Nevertheless, common forms of the disease demonstrate familial segregation.…”

Incidence and remission rates of self‐reported hidradenitis suppurativa ‐ A prospective cohort study conducted in Danish blood donors

“…Consequently, information on remission rate for this group may be of higher interest to physicians treating patients with HS. The prevalence of the subgroup with self‐reported HS from ≥3 areas was 0.3%, a figure that reflects both the cumulative incidence of diagnosed HS patients amongst Danish twins by age 40 years (female: 0.35%, male: 0.13%), 24 and the 0.19% prevalence found in a Danish nation‐wide register study on physician diagnosed HS 5 . Ultimately, this indicates that the ≥3 areas subgroup is similar to patients diagnosed with HS by a physician.…”