High Copy Numbers of β-Defensin Cluster on 8p23.1, Confer Genetic Susceptibility, and Modulate the Physical Course of Hidradenitis Suppurativa/Acne Inversa

Abstract

Hidradenitis suppurativa/acne inversa (HS) has a multifactorial pathogenesis, with many patients reporting positive family history. Nine β-defensin genes (among them DEFB4 and DEFB103, encoding for proinflammatory mediators human β-defensin-2 and human β-defensin-3, respectively) exist as a cluster (DEFB) affected by copy number (CN). We hypothesized that CNs are greater in patients with HS and that they are linked to genetic susceptibility. CNs of DEFB were studied in two independent patient cohorts: 163 patients from Greece and 98 from Germany. CNs were greater in patients than control subjects in both studied cohorts. Carriage of more than six CNs was associated with a 7.53 odds ratio for HS in the Greek cohort and a 5.76 odds ratio for HS in the German cohort. The common odds ratio after meta-analysis was 6.72 (P < 0.0001). However, presence of fewer than six copies was linked with disease onset at an earlier age (P = 0.048), less frequent presentation of permanent purulence of the affected skin lesions (P = 0.036), and fewer skin localizations (P = 0.042). A robust genetic trait for susceptibility to HS is provided, and this is confirmed in two independent cohorts. Susceptibility arises from carriage of more than six DEFB copies, which interferes directly with the HS phenotype.

Alterations in innate immunity and epithelial cell differentiation are the molecular pillars of hidradenitis suppurativa

“…In a study of skin biopsy specimens and sweat collected from 36 HS patients and 57 healthy control subjects, deficient constitutive production of ribonuclease 7 and, in severe HS, reduced HBD3 induction was suggested to contribute to impaired immunity within the hair follicle and thereby boost HS inflammation and severity . Interestingly, a robust genetic trait for HBD susceptibility to HS has been confirmed in two independent cohorts, namely in German and Greek HS patients . Susceptibility was shown to arise from carriage of more than six HBD copies, which interferes directly with the HS phenotype.…”

“…11 Interestingly, a robust genetic trait for HBD susceptibility to HS has been confirmed in two independent cohorts, namely in German and Greek HS patients. 46 Susceptibility was shown to arise from carriage of more than six HBD copies, which interferes directly with the HS phenotype. Whereas the role of bacteria in HS seems to be important, HS is not considered to be primarily an infectious disease.…”

A retrospective study of the characteristics of patients with early‐onset compared to adult‐onset hidradenitis suppurativa

“…It seems that the disease onset demonstrates two discrete risk periods; for early-onset HS, it is identified after puberty and before adulthood, while for adult HS at 19 Carriage of fewer than six copies of b-defensin genes was linked with HS onset at an earlier age. 20 A limitation of our study is recall bias, as patients were asked to recall the age of onset of hidradenitis, which may have accounted for possible misclassification in the age categories. However, as the onset of HS is a major event in life, it is expected that patients remember their age at onset correctly.…”

Copy Number Variation Disorders

“…CNVs involving some genes like the β-defensin cluster on 8p23.1 have been associated with multiple diseases including, Crohn’s disease and several skin disorders including Psoriasis, Hidradenitis Supparativa/Acne Inversa [37] and dermatophytosis [38]. Similarly, CNVs of the Fc gamma receptor (FCGR) gene cluster on 1q23.3 have been associated with SLE [39], RA [40] and many other autoimmune disorders.…”