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

足病是一种严重被忽视的非传染性象皮病，在热带非洲和中美洲的至少十个国家都有发现。它影响了400多万非洲人，其中四分之一生活在埃塞俄比亚，我们的大部分研究都是在那里进行的。尽管在常见的地区比艾滋病毒、疟疾或结核病更常见，但对这种疾病的详细研究很少。到目前为止，我们的研究表明，足癣是一种慢性疾病，是遗传因素(基因)和环境(在这种情况下是土壤)相互作用的结果。来自火山粘土土壤的刺激性颗粒被认为会导致小腿淋巴管受损，导致每20个赤脚工作的人中就有1人出现难看的肿胀(淋巴水肿)。我们假设，受影响的人遗传了基因异常，当他们长时间赤脚接触土壤时，他们更有可能患上这种疾病。我们对患有多发性足癣的家庭的研究支持了这一理论。然而，目前还不知道有多少或哪些基因参与其中，我们也不知道土壤中的什么成分会在易感个体中引发这种疾病。为了证明足病存在遗传基础，我们在埃塞俄比亚南部进行了一项研究，绘制了相关基因的图谱。我们已经产生了强有力的证据，表明致病的一个或多个主要基因位于我们的一条染色体(编号6)上的一个区域内，在该区域中有一组在免疫中起重要作用的基因。这一区域被称为人类白细胞抗原区(人类白细胞抗原区)，这些基因控制着我们对外来分子的反应，无论是来自感染性病原体(例如病毒)还是来自无关人移植的肾脏等器官。已知的是，人类白细胞抗原区域在感染疾病和自身免疫性疾病(如类风湿性关节炎)的易感性中起作用。我们现在想要更详细地研究原始埃塞俄比亚人群和其他三个受足病影响的人群的人类白细胞抗原区域，以找出导致足病的基因异常。我们将对来自埃塞俄比亚南部的100名受试者的人类白细胞抗原区域的DNA进行测序，以确定该地区的所有遗传变异。我们发现的新变种将在埃塞俄比亚南部的更多病例和对照中进行分型(每个病例500个)，以确定它们是否在有疾病的人中更常见。我们还将使用一种名为完整外显子组测序的新技术来识别与足锥虫病相关的其他基因变化。这种方法允许我们对整个基因组进行测试(即覆盖所有染色体)，并检测也可能导致足锥虫病的人类白细胞抗原区域以外的变异。虽然这种疾病可以通过穿鞋来预防，但这是不可行的，因为大多数生活在脚癣常见地区的人生活在极端贫困中，买不起鞋子。在可持续的基础上提供和分发坚固耐用的鞋子的成本令人望而却步，而后勤工作也具有挑战性：据估计，仅在埃塞俄比亚就有1500万人生活在地理上偏远的地区，处于危险之中。识别使人们易患足病的基因可能会识别疾病过程中的关键途径，目前仍没有得到很好的描述。这反过来可能会导致新的治疗方法，用于已经患有足癣以及以淋巴水肿和纤维化为特征的其他疾病的患者。对这一科学的了解已有助于公共卫生倡议，以控制足癣(例如，向患病亲属的儿童分发鞋子)，并为埃塞俄比亚科学家提供培训。

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.