NTD Highlight Notice: Discovering podoconiosis susceptibility genes: from molecules to disease control for a 'neglected' NTD

Podoconiosis (from the Greek for 'foot' and 'dust') is a severely neglected non-infectious form of elephantiasis which is found in at least ten countries across tropical Africa and central America. It affects more than 4 million people in Africa, a quarter of whom live in Ethiopia where most of our research has been conducted. Despite being more common than HIV, malaria or tuberculosis in the areas where it is common, very little detailed study on the disease has been done.

Our research to date has demonstrated that podoconiosis is a chronic disease that occurs as a result of interactions between inherited factors (genes) and the environment, in this case the soil. Irritant particles from volcanic clay soils are thought to cause lymph vessel damage in the lower leg, resulting in unsightly swelling (lymphoedema) in about 1 in 20 people who work this soil barefoot. We hypothesised that affected individuals inherit genetic abnormalities that make them more likely to develop the disease when they have prolonged barefoot contact with the soil. Our studies of families with multiple cases of podoconiosis supported this theory. However, it is not known how many or which genes are involved, and we do not know what component of the soil triggers the disease in susceptible individuals.

Having shown there was a genetic basis to podoconiosis we carried out a study in southern Ethiopia to map the genes involved. We have generated strong evidence that the main gene or genes conferring susceptibility to podoconiosis lie within a region on one of our chromosomes (number 6) where a group of genes that play an important role in immunity are located. This region is known as the Human Leukocyte Antigen region (HLA) and these HLA genes control our responses to foreign molecules whether derived from infectious agents (e.g. viruses) or organs such as kidneys transplanted from unrelated people. The HLA region is already known to plays a role in susceptibility to infectious diseases and autoimmune diseases such as rheumatoid arthritis. We now want to study the HLA region in more detail in the original Ethiopian population and three other populations affected by podoconiosis in order to find the gene abnormalities that cause podoconiosis. We will sequence the DNA from the HLA region in 100 subjects from southern Ethiopia to identify all the genetic variation in the region. The new variants we discover will be typed in a larger number of cases and controls from south Ethiopia (500 of each) to see if they are more common in people with disease. We will also use a new technique called whole exome sequencing to identify other genetic changes that are associated with podoconiosis. This method allows us to test across the whole genome (i.e. cover all the chromosomes) and detect variants outside the HLA region that may also contribute to podoconiosis.

Although the disease can be prevented by wearing shoes, this is not feasible as most people who live in the areas where podoconiosis is common live in extreme poverty and cannot afford to buy shoes. The cost of providing and distributing robust shoes on a sustainable basis is prohibitive and the logistics challenging: there are estimated to be 15 million people at risk in Ethiopia alone, living in geographically remote regions. Identification of the genes that predispose people to podoconiosis will potentially identify key pathways in the disease process, which is still poorly characterised. This may in turn lead to new approaches to treatment for people already living with podoconiosis, and for other conditions characterised by lymphoedema and fibrosis. Understanding the science has already contributed to public health initiatives towards controlling podoconiosis (e.g. distributing shoes to children with an affected relative) and has provided training for Ethiopian scientists.

Podoconiosis is a non-infectious geochemical disease that results in swelling of the lower legs. It is caused by long term exposure of bare feet to clay soil derived from volcanic rock. Podoconiosis is an important yet neglected public health problem particularly in tropical African countries. This proposal is underpinned by our programme of research on podoconiosis developed over the last 6 years, which has brought together a multidisciplinary team comprising expertise in clinical tropical diseases, epidemiology, public health, molecular genetics, bioinformatics and statistics.
Having demonstrated that podoconiosis is heritable (63%) we have used a genetics approach towards identification of the molecular pathways involved in disease pathogenesis, which is a prerequisite for the development of better treatment for this stigmatising and debilitating disease. This proposal builds on the results of a genome wide association study (GWAS) that showed convincing association between variants in the class II HLA region and podoconiosis (P=1.42 x 10-9, OR=2.44). Suggestive association was identified in three non-HLA regions.
In this proposal we intend to identify new population specific DNA variants both from the HLA region and across the exome to test for association in a larger cohort from the GWAS population and to replicate our findings in three new ethnically distinct populations from other regions in Ethiopia and Cameroon where podoconiosis is endemic. Experimental work will be undertaken at the Wellcome Trust Sanger Institute, making use state of the art core sequencing and genotyping facilities.
In addition to the discovery of podoconiosis susceptibility genes, our work could shed light on mechanisms of disease pathogenesis for other HLA-associated diseases, and will generate large amounts of HLA data specific to African populations that will be valuable to the wider research community, for example those developing vaccines for important infectious diseases.

Who will benefit from this research?
In common with other research projects that we have taken forward, we anticipate that this project will contribute demonstrably to societies affected by podoconiosis. Podoconiosis is a stigmatising and debilitating disease that affects poor, rural communities. Remote, marginalized groups like podoconiosis patients are often underserved by research; this project will continue our work to bring the benefits of excellent research to a part of society often overlooked.
Beneficiaries of our research will include patients, their families and communities; health workers who care for patients with podoconiosis and other forms of lymphoedema; policy makers in the countries where we work and other endemic countries; governmental health agencies (local, national and international); non-governmental agencies such as the patients' association we work with; and the private sector.

How will they benefit?
Patients, their families and communities: although only recently recognised as an NTD by WHO podoconiosis is very common in endemic areas. Not usually fatal, podoconiosis reduces the health and wellbeing of an estimated 4 million people in Africa and constrains economic development in a number of countries. It causes pain and disfigurement. Patients are highly stigmatised, excluded from social and religious gatherings and marriage. Our research brings patients in contact with skilled health workers whose clinical care directly benefit patients by improving health. Improved physical health brings huge psychological health benefits to patients and their families. Our research will also have an impact in disease prevention through education and promoting the use of shoes where feasible. Our genetics research has already provided a robust scientific rationale to targeting shoes to children with a family history. Future work could lead to more refined risk estimation by modelling HLA gene alleles, family health history, and environmental risk factors so that cost-effective population screening and prevention methods against the disease can be developed. It is possible that a diagnostic point of care test could be a future outcome from this work.
Patients are disabled during their most economically productive years. Better health and wellbeing will lead to economic benefits for patients, their families and dependants, through increased productivity, that will also benefit the wider community. The impact of this work extends beyond individuals and families with podoconiosis. Better population-specific understanding of the HLA locus could lead to better understanding of other HLA-associated diseases and contribute to the development of vaccines for common infectious diseases.

Public sector: through education and training, clinicians and patient associations will look after podoconiosis patients more effectively. MFTPA has benefited from a raised profile as a result of this research which has increased support for their programme of activities. The hallmark of our podoconiosis research group is high calibre research relevant to improving health outcomes. Evidence of translation of our earlier research into practice, or use in advocacy fora, include the formal adoption as a NTD by WHO and inclusion of podoconiosis in the Ethiopian Federal Ministry of Health Integrated Management of NTD Strategy.

Private Sector: our research could provide innovation opportunities for pharmaceutical and genetic technology companies through identification of host targets suitable for the development of diagnostic tools and therapies for lymphoedema due to other diseases with overlapping pathological processes (e.g. fibrosis).

Transferable skills and training: the project proposed will develop capacity to investigate a priority endemic disease in Ethiopia and Cameroon, and demonstrates how progress in international health research may be accelerated through partnerships between individuals and institutions.