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Professor Richard Trembath



  • East London Genes & Health
  • Pulmonary arterial hypertension
  • Adams-Oliver syndrome
  • Psoriasis and Inflammatory skin disease
  • Cluster headache

East London Genes & Health (ELGH)

East London Genes & Health ( is an exciting population genomics initiative in partnership with Queen Mary University of London (co-PI: Prof. David van Heel), to examine the genetic profiles of people of Bangladeshi and Pakistani origin. Through this programme, we aim to sequence the genomes of up to 100,000 volunteers from the local East London population, to support studies into how genes influence health and disease.

East London has world class NHS and research facilities, with excellence in biomedical research and electronic health records, yet people of Bangladeshi and Pakistani ethnicity have some of the highest rates of diabetes and heart disease and suffer poorer health than the rest of the UK population by a number of other measures.

The aims of the study include: a) comprehensive assessment of genetic variation in Bangladeshi and Pakistani communities; b) identification and characterization of naturally occurring gene knock-outs in humans (Narasimhan et al., 2016); c) evaluation of genetic susceptibility to rare forms of diabetes and related health conditions in this population; d) investigation of the genetic contribution to differential treatment response. Together, these studies will correlate genetic data with electronic records, providing unique insights into gene function and facilitating the development of new medicines and treatments.


Pulmonary Arterial Hypertension (PAH)

PAH is a devastating vascular disorder typified by a sustained elevation of arterial pressure due to the occlusion of the pulmonary arterioles. It is a condition of significant morbidity and mortality with death resulting as a consequence of right heart failure.

Using a positional cloning strategy we were successful in isolating BMPR2, a member of the transforming growth factor beta (TGF-beta) family of signalling molecules, as the major genetic determinant of this condition (Lane et al., 2000). The importance of this signalling pathway in maintenance of the pulmonary architecture was highlighted by our subsequent discovery that ALK1, also a TGF-beta receptor, was implicated in the pathogenesis of PAH (Trembath et al., 2001). We have also isolated variants of the SMAD family of TGF-beta signalling intermediaries as a rare cause of the disorder (Nasim et al., 2011).

Intriguingly, BMPR2 mutation demonstrates reduced penetrance within families indicating that other genetic or environmental triggers are required to trigger full-blown disease (Machado et al., 2005; Machado et al., 2006). To determine the genetic factors important in modulating the disease phenotype we are presently employing genome-wide association studies (GWAS) in a substantial cohort of idiopathic PAH. In addition, we have undertaken a programme of whole-genome sequencing through the NIHR BioResource for Rare Diseases (BRIDGE) consortium (PI: Prof. Nick Morrell, University of Cambridge) to comprehensively examine the BMPR2 locus and to identify novel genetic determinants for this condition.


Adams-Oliver Syndrome (AOS)

Adams-Oliver syndrome is a rare developmental disorder of limb and scalp defects, with a significant proportion of patients also demonstrating cardiovascular and/or neurological abnormalities. AOS is typically inherited as an autosomal dominant Mendelian trait, with reduced penetrance and clinical variability common within families. Autosomal recessive and sporadic cases have also been reported.

In 2011, we identified the first AOS gene, encoding the Rho GTPase-activating protein ARHGAP31, using a combination of whole-genome linkage analysis and targeted exome sequencing. Gain-of-function truncating mutations lead to dysregulation of the actin cytoskeleton and defects in cell growth and motility (Southgate et al., 2011). By contrast, loss-of-function mutations of the guanine nucleotide exchange factor DOCK6 underlie an autosomal recessive subtype of AOS associated with an increased incidence of neurological and ophthalmological anomalies (Sukalo et al., 2015).

Most recently, we have identified pathogenic mutations of the NOTCH1 and DLL4 genes, highlighting a key role for the Notch signalling pathway in AOS, particularly in association with cardiovascular defects (Southgate et al., 2015; Meester et al., 2015). We are actively engaged in the detection of novel AOS genes by exome sequencing and further investigation of the impact of mutations on this key signalling pathway.


Psoriasis and Inflammatory skin disease

Over the last 20 years, our group has played a leading role in the search for the genes that predispose to psoriasis, an inflammatory skin disorder that affects 2-4% of Caucasians. We have been major contributors to the identification and refinement of the main psoriasis susceptibility locus, known as PSORS1 (Trembath et al., 1997; Veal et al., 2002). Subsequent genetic and functional characterisation of PSORS1 positional candidates highlighted corneodesmosin, an adhesive protein that is specifically expressed in keratinocytes (Capon et al., 2003). We are also interested in the identification of disease susceptibility loci mapping outside of the PSORS1 interval (Veal et al., 2001; Capon et al., 2004) and are currently exploring novel research strategies for the identification of low penetrance susceptibility genes, including the integrated use of whole genome association analysis, transcription profiling and high-throughput sequencing.

With the move to King’s, we formed a multidisciplinary team including internationally renowned clinical dermatologists (Prof Jonathan Barker) and experimental immunologists (Prof Adrian Hayday and Prof Frank Nestle). The close association with these investigators has generated an exceptionally competitive environment for the identification and functional characterisation of psoriasis susceptibility genes. This work has highlighted a shared genetic aetiology across inflammatory disorders such as Crohn’s disease, atopic dermatitis and type II diabetes (Capon et al., 2007; Wolf et al., 2008; Quaranta et al., 2009) and identified a significant number of novel loci predisposing to psoriasis (Strange et al., 2010; Knight et al., 2012; Tsoi et al., 2012; Tsoi et al., 2015).


Cluster Headache (CH)

Cluster headache is a primary headache syndrome characterised by recurrent, unilateral, relatively short-lived attacks of excruciating pain, often occurring with regular periodicity. Recent estimates suggest a disease prevalence of ~1 per 500 of the adult population, and although the etiology and pathophysiology of CH are poorly characterised, it is widely considered to be a neurovascular disorder.

We have undertaken genome-wide linkage scans across a large cohort of Northern European families with CH, to identify loci harbouring the gene or genes predisposing to this disorder (Baumber et al., 2006). These data have identified multiple loci generating statistical evidence suggestive of linkage, providing evidence of possible phenotypic and genetic heterogeneity, suggesting CH to be a complex genetic disorder, and we now seek to examine these regions of putative linkage in more detail.

In addition, we have completed a whole-exome sequencing study in familial and sporadic cases of CH, in collaboration with the Pain Genetics team at Pfizer Inc. This comprehensive combined dataset is presently being analysed to better dissect the genetic mechanisms of this condition.

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