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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 |
HS, Hidradenitis suppurativa.
Methods
A literature search of PubMed and Embase databases was conducted for the terms “hidradenitis suppurativa” or “acne inversa” and “genes” or “genetics” or “genomics” or “mutations” or “epigenetics” or “DNA methylation.” Our search was limited to English-language articles and/or those published prior to January 20, 2020. For review, the authors manually identified the relevant articles discussing the genetics of HS specifically. Duplicate articles were excluded. In total, we identified 42 primary research studies analyzing the genetics of HS patients and two analyzing the epigenetics of HS. An additional 48 studies related to HS, its genetic basis, and the biology or functional significance of implicated genes were also included.
Family-Based Linkage Analysis
To date, six linkage analysis studies have been performed in HS patients. Linkage analysis is an unbiased, systematic method of identifying the chromosomal location of a heritable condition’s susceptibility genes. To perform linkage analysis, genome-wide or local chromosomal markers are tested in pedigrees to examine for segregation of these markers within a disease of interest. Loci exhibiting the strongest evidence of linkage, surpassing a predefined significance value of a logarithm of odds (LOD) score of 3 or greater, localize susceptibility genes to chromosome segments inhabited by those markers. The first seminal genome-wide linkage analysis (GWLA) study, performed by Gao et al. in 2006, was the first to identify a 76 Mb susceptibility locus at chromosome 1p21.1–1q25.3, with a maximum LOD score of 3.26 at marker D1S2624, in a large four-generation Han Chinese family demonstrating autosomal dominant HS ( n = nine affected and six unaffected family members). This region includes the NCSTN (nicastrin) gene, with subsequent exome sequencing of three of these family members identifying a splice site mutation in NCSTN later confirmed in remaining family members. Following this, researchers sequenced NCSTN in another HS family ( n = five affected and eight unaffected family members), identifying a splice site and frameshift mutation in NCSTN. Along with this work by Liu et al., 30 different mutations in NCSTN have been identified in HS and determined to be likely pathogenic (see Table 12.1 ).
In 2010, Wang et al. collected samples from six Han Chinese families exhibiting autosomal dominant HS, performing a combined linkage analysis in two HS families. They identified a 5.5 Mb susceptibility locus at chromosome 19q13 spanning 200 genes. Sequencing revealed two unique frameshift mutations in PSENEN (presenilin enhancer 2), resulting in a premature termination codon in family 1 and a delayed termination codon in family 2. Since PSENEN is one of four γ-secretase subunits, the researchers went on to sequence the remaining γ-secretase subunits in three other HS families, finding a single PSEN1 (presenilin 1) truncating mutation and three different NCSTN mutations (splicing, nonsense, and frameshift). The researchers observed reduced mRNA transcripts for all mutant alleles, suggesting the later substantiated involvement of γ-secretase haploinsufficiency in a subset of familial HS.
HS family-based linkage analyses have also been done in multigenerational African American, Iranian, and Japanese families demonstrating autosomal dominant HS, together identifying one nonsynonymous and two nonsense NCSTN mutations.
Genome Wide Association Studies
As of yet, only one GWAS has been published in the HS literature. This study by Liu et al. (2019) was not looking to identify HS susceptibility genes, but rather genes associated with HS response to adalimumab, a tumor necrosis factor (TNF) inhibitor that is FDA-approved to treat moderate to severe HS. Researchers performed a GWAS in adalimumab-treated subjects from the most extensive HS clinical trials to date (PIONEER I and II) ( n = 307). In their analysis, five single-nucleotide polymorphisms, all located within gene BCL2 , significantly associated with a positive adalimumab response and high BCL2 gene expression and protein abundance in hair follicles. The minor allele frequencies of these variants are low in Caucasian populations, at 0.04, but are somewhat common in Asian and African populations, at 0.12 and 0.27, respectively.
BCL-2, an anti-apoptotic regulatory protein, is involved in preventing cellular death and maintaining skin homeostasis in outer root sheath cells of hair follicles. TNF knockdown in human outer root sheath cells by Liu et al. resulted in significantly reduced BCL2 mRNA expression ( P = .000171), suggesting that a pathway involving BCL-2 may play a role in adalimumab response in HS patients.
γ-Secretase Target Candidate Gene Studies
To date, 22 target candidate gene studies have been done identifying mutations in two of the four γ-secretase subunits, NCSTN and PSENEN, in pure HS (see Table 12.1 ), as compared to HS presenting as part of or along with a medical syndrome. γ-secretase is an intramembranous complex capable of cleaving an excess of 30 type-1 transmembrane proteins, including amyloid precursor protein (APP), Notch, N-cadherin, and E-cadherin. The complex is composed of four hydrophobic proteins: presenilin, presenilin enhancer-2, nicastrin, and anterior pharynx defective encoded by PSEN1/PSEN 2 , PSENEN , NCSTN, and APH1A/APH1B , respectively.
Pink et al. in 2011 reported the first PSENEN mutation in Caucasian individuals by studying 53 individuals of seven multi-generational British families with HS as an autosomal dominant trait. Sequencing revealed a heterozygous single nucleotide insertion in PSENEN (c.66_67insG) predicted to cause a frameshift and altered protein product (p.Phe23ValfsX98). The mutation was absent in unaffected family members and 200 control chromosomes of European ancestry. Since this work by Pink et al., a total of 15 PSENEN mutations, including frameshift, nonsense, splicing, and missense mutations, have been reported in HS literature. In their review, Tricarico et al. recognized that PSENEN mutations result in one of three phenotypes: (1) HS, (2) Dowling-Degos disease, or (3) HS and Dowling-Degos disease, with Dowling-Degos disease involving reticulate hyperpigmentation in flexural areas. Of the 15 PSENEN mutations that they identified, only four are regarded as likely pathogenic in pure HS phenotype and seven are regarded as likely pathogenic in HS and Dowling-Degos disease phenotype.
With regard to nicastrin, more than 30 unique likely pathogenic NCSTN mutations have been identified to date in 16 target candidate gene studies in HS patients of many different ethnicities, including Chinese, Japanese, French, British, and others. They have also been found in HS patients with both familial and sporadic disease. NCSTN mutations identified in these studies include 2 frameshift, 5 splice site, 7 missense, and 10 truncating mutations (see Table 12.1 ). These mutations have been linked to haploinsufficiency and altered protein product. Many have been predicted to lead to loss of function, loss of transmembrane domain, modulation of substrate recruitment sites, reduced synthesis of additional ligand binding sites, and alteration of post-translational modifications and disulfide bonds. Examining the distribution of NCSTN sequence variants in HS patients, researchers have not been able to identify a strong predilection pertaining to specific protein domains or components. Four of seven identified missense variants are located adjacent to or within the Lid protein domain, a vital binding site for nicastrin, including the singular missense variant associated with a decrease in Notch, a signaling molecule implicated in HS pathogenesis.
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