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

NTD亮点预告：发现脚足病易感基因：从分子到“被忽视”的NTD疾病控制

• 批准号: MR/J008621/1
• 负责人: Melanie Newport
• 金额: $ 64.77万
• 依托单位: University of Sussex
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ008621%2F1
• 关键词: NTD; Highlight; Notice; Discovering; podoconiosis

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.

足癣病（源自希腊语，意为“脚”和“灰尘”）是一种被严重忽视的非传染性象皮病，在热带非洲和中美洲至少十个国家都有发现。它影响了非洲400多万人，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。尽管在该病常见的地区，该病比艾滋病毒、疟疾或结核病更为常见，但对该病进行的详细研究却很少。迄今为止，我们的研究表明，足癣病是一种慢性疾病，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。火山粘土中的刺激性颗粒被认为会导致小腿的淋巴管损伤，赤脚在这种土壤中工作的人，每20人中就有1人会出现难看的肿胀（淋巴水肿）。我们假设受影响的个体遗传了基因异常，这使得他们在长时间赤脚与土壤接触时更有可能患上这种疾病。我们对多例足癣家庭的研究支持了这一理论。然而，目前尚不清楚有多少基因或哪些基因参与其中，我们也不知道土壤的什么成分会在易感个体中引发这种疾病。在证明足癣病有遗传基础之后，我们在埃塞俄比亚南部进行了一项研究，绘制了相关基因图谱。我们已经获得了强有力的证据，证明导致足癣病易感性的主要基因或基因位于我们的一条染色体（6号）上的一个区域内，该区域内有一组在免疫中起重要作用的基因。这个区域被称为人类白细胞抗原区（HLA），这些HLA基因控制着我们对外来分子的反应，无论是来自感染因子（如病毒）还是来自非亲属移植的肾脏等器官。已知HLA区域在感染性疾病和自身免疫性疾病（如类风湿关节炎）的易感性中起作用。我们现在想在埃塞俄比亚原始人群和其他三个受足癣影响的人群中更详细地研究HLA区域，以找到导致足癣病的基因异常。我们将对来自埃塞俄比亚南部的100名受试者的HLA区域DNA进行测序，以确定该地区的所有遗传变异。我们发现的新变异将在埃塞俄比亚南部的大量病例和对照（各500例）中进行分类，以确定它们是否在患病人群中更常见。我们还将使用一种称为全外显子组测序的新技术来鉴定与足癣病相关的其他遗传变化。这种方法使我们能够测试整个基因组（即覆盖所有染色体），并检测HLA区域之外可能导致足癣病的变异。虽然这种疾病可以通过穿鞋来预防，但这是不可行的，因为生活在足癣病常见地区的大多数人生活在极端贫困中，买不起鞋。在可持续的基础上提供和分发耐用鞋的成本高得令人望而却步，物流也很困难：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。鉴定使人易患足癣病的基因将潜在地确定疾病过程中的关键途径，这一过程的特征仍然很差。这可能反过来为已经患有足癣病的人以及以淋巴水肿和纤维化为特征的其他疾病带来新的治疗方法。了解这一科学已经促进了控制足癣病的公共卫生举措（例如，向有患病亲属的儿童分发鞋子），并为埃塞俄比亚科学家提供了培训。

项目成果

Poster abstract: Gene-set analysis of Podoconiosis Genome-Wide Association dataset reveal enrichment of immune-related pathways

海报摘要：足足病全基因组关联数据集的基因组分析揭示了免疫相关通路的富集

• 发表时间: 2017
• 作者: Gebresilase TT

Global epidemiology of podoconiosis: A systematic review.

• DOI: 10.1371/journal.pntd.0006324
• 发表时间: 2018-03
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Deribe K;Cano J;Trueba ML;Newport MJ;Davey G
• 通讯作者: Davey G

Investigating the immunopathogenesis of Podoconiosis

研究脚足病的免疫发病机制

• 发表时间: 2019
• 作者: Alcanatara, D

The global atlas of podoconiosis.

• DOI: 10.1016/s2214-109x(17)30140-7
• 发表时间: 2017-05
• 期刊: The Lancet. Global health
• 作者: Deribe K;Cano J;Newport MJ;Pullan RL;Noor AM;Enquselassie F;Murray CJL;Hay SI;Brooker SJ;Davey G
• 通讯作者: Davey G

Mapping the geographical distribution of podoconiosis in Cameroon using parasitological, serological, and clinical evidence to exclude other causes of lymphedema.

• DOI: 10.1371/journal.pntd.0006126
• 发表时间: 2018-01
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Deribe K;Beng AA;Cano J;Njouendo AJ;Fru-Cho J;Awah AR;Eyong ME;Chounna Ndongmo PW;Giorgi E;Pigott DM;Golding N;Pullan RL;Noor AM;Enquselassie F;Murray CJL;Brooker SJ;Hay SI;Enyong P;Newport MJ;Wanji S;Davey G
• 通讯作者: Davey G