Molecular genetic analysis of hidradenitis suppurativa
Lead Research Organisation:
King's College London
Department Name: Genetics and Molecular Medicine
Abstract
Hidradenitis suppurativa is an aggressive chronic inflammatory skin disease that affects 1% of the population. It presents with painful and often discharging boils, cysts and abscesses most commonly in the armpits, groin and buttocks. The resulting pain, discharge, smell and restricted movement inflicts lasting damage on the psychosocial wellbeing of sufferers and can dramatically affect relationships with family and friends. Current treatments are limited, often ineffective and associated with numerous unpleasant side effects.
Although the cause of this debilitating disease remains unclear it has been recognised that it runs in families. The aim of our research is to identify the responsible gene or genes and the mechanism through which they result in disease. Our research group at King‘s College London, led by Professors Richard Trembath and Jonathan Barker, has extensive experience at investigating and discovering the causative gene behind familial conditions. We have identified a number of families with hidradenitis suppurativa and have collected blood from all family members. This will provide DNA from which to perform our work. By discovering the causative genes and eliciting their function we hope to stimulate the production of new, more effective treatments with fewer side effects.
Although the cause of this debilitating disease remains unclear it has been recognised that it runs in families. The aim of our research is to identify the responsible gene or genes and the mechanism through which they result in disease. Our research group at King‘s College London, led by Professors Richard Trembath and Jonathan Barker, has extensive experience at investigating and discovering the causative gene behind familial conditions. We have identified a number of families with hidradenitis suppurativa and have collected blood from all family members. This will provide DNA from which to perform our work. By discovering the causative genes and eliciting their function we hope to stimulate the production of new, more effective treatments with fewer side effects.
Technical Summary
Hidradenitis suppurativa, HS (acne inversa), is an aggressive inflammatory skin disease that affects 1% of the population. It is characterised by painful cysts, abscesses and sinuses in flexural areas. It remains unclear whether it is a disorder of the hair follicle, apocrine gland or an intrinsic defect of the host response. The efficacy of anti-TNF? therapy indicates an underlying chronic inflammatory response. Several studies have demonstrated a strong genetic component. 34% of first degree relatives of probands with HS are affected and multiple pedigrees have been published demonstrating an autosomal dominant inheritance pattern. I phenotyped, bled and extracted DNA from three families demonstrating autosomal dominant inheritance. A genomewide linkage screen revealed linkage of a ~32Mb region on chromosome three in the largest pedigree (14 affected individuals), subsequently confirmed in the remaining two pedigrees. The region contains approximately 340 genes including several genes encoding proteins whose functional role highlights them as candidates in HS.
Aims and Objectives
The aim of the project is to identify causative gene(s) for HS, to determine the contribution to familial and sporadic cases of HS and to define the physiological and pathological function of the HS gene product.
Objectives:
1) To identify the gene(s) determining HS
2) To explore the genetic epidemiology of HS
3) To understand the biology of the causative gene(s) and the consequences of the identified
mutation(s)
Design and methodology
Twelve candidate genes within the region defined by linkage analysis will be sequenced in two family members (Sanger methodology). If no mutation is detected within the candidate genes then the remaining genes in the region will be sequenced with a next generation sequencing approach. The potential pathogenicity of any sequence variants will be determined via bioinformatic investigation of the variant within genomic databases, genotyping additional family members to confirm cosegregation with disease status and assessment of population frequency. The causative gene will then be sequenced in more affected pedigrees and sporadic cases. Methods used to determine the function of the gene and the resulting mutation(s) will include bioinformatic analysis, gene expression studies, fluorescently tagged expression constructs, antibodies targeted against the protein product and the development of model based assays.
Scientific and medical opportunities
This project has the potential to identify key genetic and molecular mechanisms underlying HS and other related disorders such as acne vulgaris and Crohn‘s disease. The identification of new therapeutic targets could stimulate the development of novel, more effective therapies.
Aims and Objectives
The aim of the project is to identify causative gene(s) for HS, to determine the contribution to familial and sporadic cases of HS and to define the physiological and pathological function of the HS gene product.
Objectives:
1) To identify the gene(s) determining HS
2) To explore the genetic epidemiology of HS
3) To understand the biology of the causative gene(s) and the consequences of the identified
mutation(s)
Design and methodology
Twelve candidate genes within the region defined by linkage analysis will be sequenced in two family members (Sanger methodology). If no mutation is detected within the candidate genes then the remaining genes in the region will be sequenced with a next generation sequencing approach. The potential pathogenicity of any sequence variants will be determined via bioinformatic investigation of the variant within genomic databases, genotyping additional family members to confirm cosegregation with disease status and assessment of population frequency. The causative gene will then be sequenced in more affected pedigrees and sporadic cases. Methods used to determine the function of the gene and the resulting mutation(s) will include bioinformatic analysis, gene expression studies, fluorescently tagged expression constructs, antibodies targeted against the protein product and the development of model based assays.
Scientific and medical opportunities
This project has the potential to identify key genetic and molecular mechanisms underlying HS and other related disorders such as acne vulgaris and Crohn‘s disease. The identification of new therapeutic targets could stimulate the development of novel, more effective therapies.