Genetics and Epigenetics of Hidradenitis Suppurativa

Introduction

Hidradenitis suppurativa (HS) is an inflammatory condition characterized by painful and sometimes purulent nodules, abscesses, and sinus tracts located in intertriginous regions. Lesions may progress to form hypertrophic scars or dermal tunnels. HS patients are regarded as having one of the worst qualities of life among the major dermatologic conditions. Comorbidities include obesity, asthma, acne, diabetes, dyslipidemia, hypertension, thyroid disease, rheumatoid arthritis, depression, psoriasis, and polycystic ovarian syndrome.

The hypothesized pathogenesis of HS is multifaceted. On a cellular level, it is characterized by follicular hyperkeratosis which leads to a deleterious pathway involving follicular occlusion, dilation, inflammation, and rupture. The etiology involves a complex interplay between a dysregulated immune system and genetic, environmental, and microbiological factors.

Given the morbid nature of this disease, its etiology is of great interest to both patients and clinicians alike. The question “to what extent is HS caused by genetic factors?” was recently identified as one of the top 10 most important uncertainties in a Priority Setting Partnership, in which patients and clinicians agreed on mutually important HS research questions. While poor quality of life greatly affects these patients, they are more often worried about passing this condition on to their offspring.

Many features of HS support a genetic basis. Thirty to 42% of HS patients report a family history of HS. Family history of HS is significantly higher in early onset HS, which is also associated with more widespread involvement. There is an increased incidence of HS in monogenic disorders such as Dowling-Degos disease, Down syndrome, and keratitis, ichthyosis, and deafness syndrome, among others. Different HS phenotypes (axillary–submammary, follicular, and gluteal) show preferences in regard to sex predominance, age of onset, lesion type, location affected, and disease severity suggesting genetic heterogeneity. ^17(p53) HS is also associated with many inflammatory diseases that have known polygenic etiologies, such as inflammatory bowel disease.

This chapter provides a general overview of the HS genetics and epigenetics literature. First, a review of HS investigational genetic studies is presented, describing mutations reported to be associated with HS susceptibility, phenotype, or treatment response ( Table 12.1 ). These studies are discussed according to study design: family linkage analyses, genome-wide association studies (GWAS), or target candidate gene studies. Genetic findings in syndromic HS—HS presenting as part of or along with a medical syndrome—are reviewed as well ( Table 12.2 ). Early work on HS epigenetics and microRNAs is discussed next. The chapter concludes by discussing the biological and clinical relevance of these findings as well as areas for future study.

Table 12.1

Mutations Associated With Hidradenitis Suppurativa Identified Through Family Linkage Analyses, One Genome-Wide Association Study, and Target Candidate Gene Studies

Study	Gene	Protein	Function	Identified Mutation(s)	Ethnicity	Familial/sporadic
Genome-Wide Linkage Analysis/Unbiased Linkage Analysis Studies
Gao et al., 2006	Susceptibility locus 1p211–1q25.3				Han Chinese	Familial
Wang et al., 2010	NCSTN PSENEN PSEN1	Nicastrin Presenelin enhancer 2 Presenelin 1	Cofactor subunit of γ-secretase, a glycoprotein transmembrane aspartyl protease cleaving over 30 type I integral membrane proteins, including Notch and Amyloid Precursor Protein Cofactor subunit of γ-secretase Catalytic subunit of γ-secretase	1 splice site, 1 truncating, 1 nonsense 1 truncating, 1 frameshift 1 truncating	Han Chinese	Familial
Liu et al., 2011	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 splice site, 1 truncating	Han Chinese	Familial
Chen et al., 2014	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 nonsense	African American	Familial
Faraji Zonooz et al. 2016	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 nonsense	Iranian	Familial
Takeichi et al., 2020	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 missense	Japanese	Familial
Genome-Wide Association Study
Liu et al., 2019	BCL2	BCL-2	Anti-apoptotic regulatory protein involved in skin homeostasis	5 single nucleotide polymorphisms associated with a positive response of HS to adalimumab	Not reported	Not reported
Target Candidate Gene Studies
NCSTN Mutations
Li et al., 2011	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 nonsense, 1 missense	Chinese	Familial
Pink et al., 2011	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 splice site	British	42% familial
Pink et al., 2012	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 missense, 2 splice site	Not reported	Sporadic
Haines et al., 2012	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 truncating	Singapore	Sporadic
Miskinyte et al., 2012	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 splice site, 2 truncating	French	Familial
Zhang et al., 2013	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	2 missense	Chinese	Familial
Nomura et al., 2013	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 splice site	Japanese	Familial
Jiao et al., 2013	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 missense	Han Chinese	Familial
Ma et al., 2013	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 truncating	Chinese	Familial
Nomura et al., 2014	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 truncating	Japanese	Familial
Yang et al., 2015	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 truncating	Chinese	Familial
Ratnamala et al., 2016	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 truncating	Indian	Familial
Zhang et al., 2016	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 missense	Chinese	Familial
Liu et al., 2016	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 truncating, 1 missense	Caucasian	Familial, Nonfamilial
Xiao et al., 2018	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 frameshift	Sporadic	Familial
Wu et al., 2018	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 truncating	Chinese	Familial
PSENEN
Pink et al., 2011	PSENEN	Presenelin enhancer 2	Cofactor subunit of γ-secretase	1 frameshift	British	Familial
Zhou et al., 2016 ^9(p20)	PSENEN	Presenelin enhancer 2	Cofactor subunit of γ-secretase	1 missense, 1 splice site	Chinese	Familial
Kan et al., 2018	PSENEN	Presenelin enhancer 2	Cofactor subunit of γ-secretase	1 frameshift	Japanese	Familial
Mutations in Other Genes
Savva et al., 2013	TNF	TNF-α	Pro-inflammatory cytokine elevated in HS lesional skin	SNP (-238G/A) in promoter region linked to HS susceptibility	Not reported	29% familial
Giatrakos et al., 2013	IL12Rβ1	IL12Rββ1 receptor subunit	Part of IL-12 receptor complex; IL-12/IL-23 pathway involved in antigen presentation in HS	Haplotype (h2) associated with more severe disease vs. haplotype (h1) associated with an older age of onset	Caucasian	Sporadic
Giamarellos-Bourboulis et al., 2016	DEFB (cluster of nine β—defensing genes)	β-defensin	Proinflammatory mediators; deposits of β-defensin-2 and -3 found in HS lesional skin	> 6 copy number of DEFB (cluster of 9 beta-defensin genes) associated with a 6.72 OR for HS ( P < .0001)	Greek (cohort 1), German (cohort 2)	20.9% and 37.1% familial in cohort one and two, respectively
Agut-Busquet et al., 2018	MYD88	Myeloid differentiation primary response protein	Involved in innate and adaptive immune response and Toll-like receptor and IL-1 receptor signaling	SNP (GG genotype of rs6853) associated with an increased risk of severe HS	Caucasian	Not reported

HS , Hidradenitis suppurativa; SNP , single nucleotide polymorphisms.

Table 12.2

Mutations Identified in Syndromic Cases of Hidradenitis Suppurativa

Study	Gene	Protein	Function	Identified Mutation(s)	Ethnicity	Familial/Sporadic
HS + Nevus Comedonicus Syndrome (NCS)
Higgins et al., 2017	FGFR2	Fibroblast growth factor receptor 2	Expressed in keratinocytes, hair follicles, and sebaceous glands; substrate-receptor binding results in cell division and differentiation	1 missense	Unknown	Unknown
HS + Familial Mediterranean Fever
Vural et al., 2019	MEFV	Pyrin	Involved in regulating inflammasome activity	Frequency of pathogenic MEFV variants associated with risk of severe and complex HS	Not reported	Not reported
HS + Darier’s Disease
Ornelas et al., 2016	ATP2A2	Sarcoplasmic reticulum calcium adenosine triphosphatase (SERCA) transport ATPase type 2 isoform pump	Important in maintaining calcium homeostasis; SERCA inhibition may affect Notch signaling	ATP2A2 mutation	Not reported	Not reported
HS + Dent Disease 2
Marzuillo et al., 2018	OCRLI	Inositol polyphosphate 5-phosphatase (OCRL1)	Forms a complex at maturing epidermal-dermal junction and regulates phosphoinositol-4,5-bisphosphate abundance (levels linked to inflammation)	OCRLI mutation	Not reported	Not reported
HS + Pachyonychia Congenita
Pedraz et al., 2008	KRT6A	Keratin 6A	Provides strength to skin, nails, and hair	1 missense	Not reported	Not reported
HS + Down Syndrome
Borbujo Martínez et al., 1992, Mengesha et al., 1999, Mebazaa et al., 2009, Blok et al., 2016	Chr 21	Primarily encodes Amyloid Precursor Protein	Integral membrane protein; competitive substrate for γ-secretase along with Notch	Trisomy 21	Not reported	Sporadic
HS + Keratitis-Ichthyosis-Deafness (KID)
Montgomery et al., 2004, Lazic et al., 2012	GJB2 gene, G12R gene	Connexin-26 protein	Forms gap junctions key for tissue homeostasis, growth, and development	2 missense	Not reported	Sporadic
HS + Dowling-Degos Disease (DDD)
Zhou et al., 2016	PSENEN	Presenelin enhancer 2	Cofactor subunit of γ-secretase	1 missense, 1 splice site	Chinese	Familial
Ralser et al., 2017	PSENEN	Presenelin enhancer 2	Cofactor subunit of γ-secretase	2 splice site, 2 nonsense	3 German, 2 Indian, 1 French patient	Not reported
Pavlovsky et al., 2018	PSENEN	Presenelin enhancer 2	Cofactor subunit of γ-secretase	1 missense	Ashkenazi Jewish	Familial
González-Villanueva et al., 2018	POFUT1	Protein O-Fucosyltransferase 1	Protein in endoplasmic reticulum; adds sugar moieties to Notch receptors	1 splice site	Not reported	Not reported
PASH (Pyoderma Gangrenosum, Acne, and Suppurativa Hidradenitis) and PAPASH Syndrome
Braun-Falco et al., 2012, Marzano et al., 2013, ^42(p201)Calderón-Castrat et al., 2016, Saito et al., 2018	PSTPIP1	Proline-serine-threonine phosphatase-interacting protein 1	Involved in regulating inflammasome activity	3 missense and 1 SNP with increased repetition of CCTG micro-satellite motif	Patient 1 Russian, Patient 2 German	Sporadic
Marzano et al., 2013	NLRP3 IL1RN MEFV NOD2 PSMB8	Cryopyrin IL-1 receptor antagonist Pyrin Nucleotide-binding oligomerization domain-containing protein 2 Proteasome 20S Subunit Beta 8	Initiates and regulates the immune system’s response to injury, invasion, or toxins Modulates the IL-1 mediated immune responses Regulates inflammasome activity Involved in autophagy; when triggered by a bacterial antigen, it activates NFkB that regulates the immune response Subunit of immunoproteosome important in detecting self v. non-self proteins in immune cells to guide immune response	1 missense 1 missense 2 missense 2 missense 1 missense	Not reported	Not reported
Duchatelet et al., 2015	NCSTN	Nicastrin	Cofactor subunit of γ-secretase	1 frameshift	Not reported	Two familial and one sporadic
Follicular Occlusion Triad
Musumeci et al., 2019	KR17	Keratin 17	Provides strength to skin, nails, and hair	1 missense	Not reported	Familial