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Available evidences suggest that podoconiosis is triggered by long term exposure of bare feet to volcanic red clay soil particles. Previous genome-wide studies in Ethiopia showed association between the HLA class II region and disease susceptibility. However, functional relationships between the soil trigger, immunogenetic risk factors and the immunological basis of the disease are uncharted. Therefore, we aimed to characterise the immune profile and gene expression of podoconiosis patients relative to endemic healthy controls. Peripheral blood immunophenotyping of T cells indicated podoconiosis patients had significantly higher CD4 and CD8 T cell surface HLA-DR expression compared to healthy controls while CD62L expression was significantly lower. The levels of the activation markers CD40 and CD86 were significantly higher on monocytes and dendritic cell subsets in patients compared to the controls. RNA sequencing gene expression data indicated higher transcript levels for activation, scavenger receptors, and apoptosis markers while levels were lower for histones, T cell receptors, variable, and constant immunoglobulin chain in podoconiosis patients compared to healthy controls. Our finding provides evidence that podoconiosis is associated with high levels of immune activation and inflammation with over-expression of genes within the pro-inflammatory axis. This offers further support to a working hypothesis of podoconiosis as soil particle-driven, HLA-associated disease of immunopathogenic aetiology., (© 2024. The Author(s).)

Introduction: Engaging youth as peer educators has yet to be considered to promote literacy concerning conjoint genetic and environmental (G × E) influences on health conditions. Whether youth living in low- and middle-income countries (LMICs) could and would be willing to serve as lay educators of G × E education is unclear., Methods: A cross-sectional survey of youth living in Southern Ethiopia was conducted from August to September 2017. Trained data collectors administered the survey on 377 randomly selected youth who ranged in age from 15 to 24; 52% were female and 95% reported having some formal education. Self-reported willingness and a constructed competency score were assessed. Bivariate analyses tested for factors associated with willingness and competency to serve as lay G × E literacy builders., Results: Competency and willingness were significantly greater (p < 0.05) for youth who were male, had some formal education, and had civic or leadership experience. Differences in median willingness were significant for youth who scored as more competent versus those who scored as less competent (p < 0.001). There were no characteristics that moderated the association of competency with willingness., Conclusion: Youth peer educator programs hold promise for disseminating improved G Χ E literacy and reducing stigma associated with deterministic misunderstandings. Thoughtful recruitment and training strategies will be needed to ensure that the broadest representation of youth in LMIC contexts has the opportunity to serve in this role, particularly girls and those without formal education., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Podoconiosis, a debilitating lymphoedema of the leg, results from barefoot exposure to volcanic clay soil in genetically susceptible individuals. A previous genome-wide association study (GWAS) conducted in the Wolaita ethnic group from Ethiopia showed association between single nucleotide polymorphisms (SNPs) in the HLA class II region and podoconiosis. We aimed to conduct a second GWAS in a new sample (N = 1892) collected from the Wolaita and two other Ethiopian populations, the Amhara and the Oromo, also affected by podoconiosis. Fourteen SNPs in the HLA class II region showed significant genome-wide association (P < 5.0 × 10 -8 ) with podoconiosis. The lead SNP was rs9270911 (P = 5.51 × 10 -10 ; OR 1.53; 95% CI 1.34-1.74), located near HLA-DRB1. Inclusion of data from the first GWAS (combined N = 2289) identified 47 SNPs in the class II HLA region that were significantly associated with podoconiosis (lead SNP also rs9270911 (P = 2.25 × 10 -12 ). No new loci outside of the HLA class II region were identified in this more highly-powered second GWAS. Our findings confirm the HLA class II association with podoconiosis suggesting HLA-mediated abnormal induction and regulation of immune responses may have a direct role in its pathogenesis.

Brugia malayi is a human filarial nematode responsible for elephantiasis, a debilitating condition that is part of a broader spectrum of diseases called filariasis, including lymphatic filariasis and river blindness. Almost all filarial nematode species infecting humans live in mutualism with Wolbachia endosymbionts, present in somatic hypodermal tissues but also in the female germline which ensures their vertical transmission to the nematode progeny. These α-proteobacteria potentially provision their host with essential metabolites and protect the parasite against the vertebrate immune response. In the absence of Wolbachia wBm, B. malayi females become sterile, and the filarial nematode lifespan is greatly reduced. In order to better comprehend this symbiosis, we investigated the adaptation of wBm to the host nematode soma and germline, and we characterized these cellular environments to highlight their specificities. Dual RNAseq experiments were performed at the tissue-specific and ovarian developmental stage levels, reaching the resolution of the germline mitotic proliferation and meiotic differentiation stages. We found that most wBm genes, including putative effectors, are not differentially regulated between infected tissues. However, two wBm genes involved in stress responses are upregulated in the hypodermal chords compared to the germline, indicating that this somatic tissue represents a harsh environment to which wBm have adapted. A comparison of the B. malayi and C. elegans germline transcriptomes reveals a poor conservation of genes involved in the production of oocytes, with the filarial germline proliferative zone relying on a majority of genes absent from C. elegans. The first orthology map of the B. malayi genome presented here, together with tissue-specific expression enrichment analyses, indicate that the early steps of oogenesis are a developmental process involving genes specific to filarial nematodes, that likely result from evolutionary innovations supporting the filarial parasitic lifestyle., Competing Interests: The authors have declared that no competing interests exist.

Background: Podoconiosis is a progressive swelling of the legs affecting genetically susceptible people who live in areas with irritant red clay soils and walk barefoot. The disease is a public health concern in many countries, including Rwanda., Methods: This retrospective study described individual and familial characteristics of patients with podoconiosis attending the Heart and Sole Africa (HASA) clinics in Rwanda. Data on patient characteristics and family history were retrieved from electronic medical records (January 2013 - August 2019). A multiple regression analysis was used to explore factors influencing age of onset of podoconiosis., Results: Among 467 patients with podoconiosis, the mean (standard deviation) age of onset was 34.4 (19.6) years, 139 (29.8%) patients developed podoconiosis at <20 years of age, 417 (89%) came from Musanze or neighboring Burera Districts, and 238 (51.0%) had a family history of podoconiosis. Increasing patient age was associated with older age at onset of disease (p<0.001), while an increased number of relatives with podoconiosis (p<0.002) was significantly associated with earlier disease onset., Conclusion: Most patients with podoconiosis were women, and more than half had a family history of podoconiosis. An increased number of relatives with podoconiosis was associated with a significantly younger age at disease onset., (© The Author(s) 2020. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Background: Podoconiosis is a tropical lymphoedema of the leg resulting from barefoot exposure to irritant volcanic soils. Approximately 4 million people are affected, mainly in African highland regions. The pathogenesis of this neglected tropical disease is still largely unknown, although HLA class II (HLAII) polymorphisms are associated with the disease., Methods: NanoString technology was used to assess expression of 579 immune-related genes in formalin-fixed and paraffin-embedded lymph node archival samples from podoconiosis patients and unaffected controls., Results: Forty-eight genes were upregulated and 21 downregulated in podoconiosis samples compared with controls. Gene ontology analysis showed differentially expressed genes to be closely related to major histocompatibility complex protein, cytokine and TNF receptor binding genes. Pathway enrichment analysis revealed involvement of lymphocyte activation, adaptive immunity, cytokine signalling, antigen processing and the IL-12 pathways., Conclusions: This exploratory study reports a multiplex gene expression analysis in podoconiosis and shows upregulation of pro-inflammatory transcripts compatible with the notion of local, chronic immune activation in this HLAII-associated disease. Implicated pathways will inform future research into podoconiosis immunopathogenesis., (© The Author(s) 2020. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Rationale: Follicular occlusion triad (FOT) is an autosomal recessive inherited disease and no more than 3 variants of the triad have been reported. We give a report in which scrotal elephantiasis is a variant of FOT and further perform a literature review., Patient Concerns: A 41-year-old man came to us because of a large scrotal cyst and generalized skin lesions that had occurred over the past 10 years. The generalized skin lesions consisted of hidradenitis suppurativa on the perineum and back, acne conglobata in the armpit, and dissecting cellulitis of the scalp. He took antibiotics for a long time but achieved poor effect. Furthermore, he told his father and elder brother also manifested such skin lesions., Diagnoses: Magnetic resonance showed a mass in the left scrotum with clear boundaries. A routine blood test showed a high leukocyte level of 12 × 10/L and a hemoglobin content of 78 g/L. C-reactive-protein increased. Series of autoimmune antibody tests were negative. The postoperative pathologic findings showed that the mass was an epidermoid cyst, and hematoxylin and eosin staining showed hyperkeratosis of the skin as well as inflammatory and edematous changes. A diagnosis of a variant of FOT was made., Interventions: We removed skin abscesses and lesioned the inner part with hydrogen peroxide. Then we performed an excision of the scrotal lesion., Outcome: The patient recovered well and had no evidence of recurrence at a 16-month follow-up., Lessons: We reported a case in which scrotal elephantiasis was a variant of FOT and surgical intervention played an important role in secondary urologic diseases.

Objectives: Assess the feasibility of engaging youth to disseminate accurate information about gene by environmental (GxE) influences on podoconiosis, a neglected tropical lymphedema endemic in southern Ethiopia., Methods: A cross sectional survey was conducted with 377 youth randomly selected from 2 districts of Southern Ethiopia. Measures included GxE knowledge (4 true/false statements), preventive action knowledge (endorse wearing shoes and foot hygiene), causal misconceptions (11 items related to contagion) and confidence to explain GxE (9 disagree/agree statements)., Results: Over half (59%) accurately endorsed joint contributions of gene and environment to podoconiosis and preventive mechanisms (e.g., wearing protective shoes and keeping foot hygiene). Multivariable logistic regression showed that youth with accurate understanding about GxE contributors reported having: some education, friends or kin who were affected by the condition, and prior interactions with health extension workers. Surprisingly, higher accurate GxE knowledge was positively associated with endorsing contagion as a causal factor. Accuracy of GxE and preventive action knowledge were positively associated with youth's confidence to explain podoconiosis-related information., Conclusions: Youth have the potential to be competent disseminators of GxE information about podoconiosis. Interventions to foster confidence among youth in social or kin relationships with affected individuals may be most promising. Efforts to challenge youth's co-existing inaccurate beliefs about contagion could strengthen the link of GxE explanations to preventive actions., Competing Interests: The authors have declared that no competing interests exist.

Background: Misunderstandings of the role of genetics in disease development are associated with stigmatizing behaviors and fatalistic attitudes about prevention. This report describes an evaluation of community understanding of an educational module about genetic and environmental influences on the development of podoconiosis, a neglected tropical disease endemic in highland Ethiopia., Methods: A qualitative process assessment was conducted as part of a large prospective intervention trial in August 2013, in Wolaita Zone, southern Ethiopia. Sixty five participants were purposively selected from 600 households randomized to receive the inherited susceptibility module. The educational module used pictorial representations and oral explanations of the interaction of inherited sensitivity and soil exposure and was delivered by lay health educators in participants' homes. Data were collected using semi-structured individual interviews (IDIs) or focus group discussions (FGDs)., Results: Qualitative analyses showed that most participants improved their understanding of inherited soil sensitivity and susceptibility to podoconiosis. Participants linked their new understanding to decreased stigma-related attitudes. The module also corrected misconceptions that the condition was contagious, again diminishing stigmatizing attitudes. Lastly, these improvements in understanding increased the perceived value of foot protection., Conclusions: Taken together, these improvements support the acceptability, feasibility and potential benefits of implementing gene-environment education in low and middle income countries., (© The Author 2016. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

The recent feasibility of genome-wide studies of adaptation in human populations has provided novel insights into biological pathways that have been affected by adaptive pressures. However, only a few African populations have been investigated using these genome-wide approaches. Here, we performed a genome-wide analysis for evidence of recent positive selection in a sample of 120 individuals of Wolaita ethnicity belonging to Omotic-speaking people who have inhabited the mid- and high-land areas of southern Ethiopia for millennia. Using the 11 HapMap populations as the comparison group, we found Wolaita-specific signals of recent positive selection in several human leukocyte antigen (HLA) loci. Notably, the selected loci overlapped with HLA regions that we previously reported to be associated with podoconiosis-a geochemical lymphedema of the lower legs common in the Wolaita area. We found selection signals in PPARA, a gene involved in energy metabolism during prolonged food deficiency. This finding is consistent with the dietary use of enset, a crop with high-carbohydrate and low-fat and -protein contents domesticated in Ethiopia subsequent to food deprivation 10 000 years ago, and with metabolic adaptation to high-altitude hypoxia. We observed novel selection signals in CDKAL1 and NEGR1, well-known diabetes and obesity susceptibility genes. Finally, the SLC24A5 gene locus known to be associated with skin pigmentation was in the top selection signals in the Wolaita, and the alleles of single-nucleotide polymorphisms rs1426654 and rs1834640 (SLC24A5) associated with light skin pigmentation in Eurasian populations were of high frequency (47.9%) in this Omotic-speaking indigenous Ethiopian population.

Little is known about how beliefs about heredity as a cause of health conditions might influence preventive and interpersonal behaviors among those individuals with low genetic and health literacy. We explored causal beliefs about podoconiosis, a neglected tropical disease (NTD) endemic in Ethiopia. Podoconiosis clusters in families but can be prevented if individuals at genetically high risk wear shoes consistently. Adults (N = 242) from four rural Ethiopian communities participated in qualitative assessments of beliefs about the causes of podoconiosis. Heredity was commonly mentioned, with heredity being perceived as (1) the sole cause of podoconiosis, (2) not a causal factor, or (3) one of multiple causes. These beliefs influenced the perceived controllability of podoconiosis and in turn, whether individuals endorsed preventive and interpersonal stigmatizing behaviors. Culturally informed education programs that increase the perceived controllability of stigmatized hereditary health conditions like podoconiosis have promise for increasing preventive behaviors and reducing interpersonal stigma.

Background: Podoconiosis is a tropical lymphedema resulting from long-term barefoot exposure to red-clay soil derived from volcanic rock. The World Health Organization recently designated it as a neglected tropical disease. Podoconiosis develops in only a subgroup of exposed people, and studies have shown familial clustering with high heritability (63%)., Methods: We conducted a genomewide association study of 194 case patients and 203 controls from southern Ethiopia. Findings were validated by means of family-based association testing in 202 family trios and HLA typing in 94 case patients and 94 controls., Results: We found a genomewide significant association of podoconiosis with the single-nucleotide polymorphism (SNP) rs17612858, located 5.8 kb from the HLA-DQA1 locus (in the allelic model: odds ratio, 2.44; 95% confidence interval [CI], 1.82 to 3.26; P=1.42×10(-9); and in the additive model: odds ratio, 2.19; 95% CI, 1.66 to 2.90; P=3.44×10(-8)), and suggestive associations (P<1.0×10(-5)) with seven other SNPs in or near HLA-DQB1, HLA-DQA1, and HLA-DRB1. We confirmed these associations using family-based association testing. HLA typing showed the alleles HLA-DRB1*0701 (odds ratio, 2.00), DQA1*0201 (odds ratio, 1.91), and DQB1*0202 (odds ratio, 1.79) and the HLA-DRB1*0701-DQB1*0202 haplotype (odds ratio, 1.92) were risk variants for podoconiosis., Conclusions: Association between variants in HLA class II loci with podoconiosis (a noncommunicable disease) suggests that the condition may be a T-cell-mediated inflammatory disease and is a model for gene-environment interactions that may be relevant to other complex genetic disorders. (Funded by the Wellcome Trust and others.).

Background: The consent process for a genetic study is challenging when the research is conducted in a group stigmatized because of beliefs that the disease is familial. Podoconiosis, also known as 'mossy foot', is an example of such a disease. It is a condition resulting in swelling of the lower legs among people exposed to red clay soil. It is a very stigmatizing problem in endemic areas of Ethiopia because of the widely held opinion that the disease runs in families and is untreatable. The aim of this study was to explore the impact of social stigma on the process of obtaining consent for a study on the genetics of podoconiosis in Southern Ethiopia., Methods: We adapted a rapid assessment tool validated in The Gambia. The methodology was qualitative involving focus-group discussions (n = 4) and in-depth interviews (n = 25) with community members, fieldworkers, researchers and staff of the Mossy Foot Treatment and Prevention Association (MFTPA) working on prevention and treatment of podoconiosis., Results: We found that patients were afraid of participation in a genetic study for fear the study might aggravate stigmatization by publicizing the familial nature of the disease. The MFTPA was also concerned that discussion about the familial nature of podoconiosis would disappoint patients and would threaten the trust they have in the organization. In addition, participants of the rapid assessment stressed that the genetic study should be approved at family level before prospective participants are approached for consent. Based on this feedback, we developed and implemented a consent process involving community consensus and education of fieldworkers, community members and health workers. In addition, we utilized the experience and established trust of the MFTPA to diminish the perceived risk., Conclusion: The study showed that the consent process developed based on issues highlighted in the rapid assessment facilitated recruitment of participants and increased their confidence that the genetic research would not fuel stigma. Therefore, investigators must seek to assess and address risks of research from prospective participants' perspectives. This involves understanding the issues in the society, the culture, community dialogues and developing a consent process that takes all these into consideration.

In this report, we describe a case of bilateral non-syndromic hereditary lymphedema praecox of lower legs. The patient was diagnosed at age 16. Ten years later, he was unable to ambulate due to increased bilateral lower leg volume, continuous pain, and recurrent episodes of cellulitis. He was treated at our tertiary-care center with compression therapy and circumferential liposuction of lower legs, ankles, and dorsum of feet in order to remove hypertrophic fat deposits, facilitate conservative therapy, and decrease further risk of cellulitis. No complications were seen and compression therapy was continued. Fourteen month follow-up reveals no increase in leg volume over time, absence of pain, and no further episodes of cellulitis with complete ability to ambulate and return to normal activities. Even when it does not eliminate the underlying cause of primary lymphedema, combined therapy consisting of compression and liposuction is safe and is able to achieve control, at least on a short term, of clinically disabling conditions associated with advanced stages.

Podoconiosis (endemic non-filarial elephantiasis) is a geochemical disease occurring in individuals exposed to red clay soil derived from alkalic volcanic rock. It is a chronic, debilitating disorder and a considerable public health problem in at least 10 countries in tropical Africa, Central America and northern India. Only a small proportion of individuals exposed to red clay develop disease and familial clustering of cases occurs, so we tested the hypothesis that disease occurs in genetically susceptible individuals on exposure to an environmental element in soil. Using multiple statistical genetic techniques we estimated sibling recurrence risk ratio (lambda(s)) and heritability for podoconiosis, and conducted segregation analysis on 59 multigenerational affected families from Wolaitta Zone, southern Ethiopia. We estimated the lambda(s) to be 5.07. The heritability of podoconiosis was estimated to be 0.629 (SE 0.069, P=1x10(-7)). Segregation analysis showed that the most parsimonious model was that of an autosomal co-dominant major gene. Age and use of footwear were significant covariates in the final model. Host genetic factors are important determinants of susceptibility to podoconiosis. Identification of the gene(s) involved will lead to better understanding of the gene-environment interactions involved in the pathogenesis of podoconiosis and other complex multifactorial conditions.

Mutations in the vascular endothelial growth factor receptor 3 gene, VEGFR3/FLT4, have been identified in a subset of families with hereditary lymphedema type I or Milroy disease (MIM 153100). Individuals carrying a VEGFR3 mutation exhibit congenital edema of the lower limbs, usually bilaterally and below the knees, sometimes associated with cellulitis, prominent veins, papillomatosis, upturned toenails, and hydrocele. In this study, we report the first de novo VEGFR3 mutation in a patient with sporadic congenital lymphedema. We also describe three other families with a VEGFR3 mutation. In each family, one individual had an atypical clinical presentation of hereditary lymphedema type I, whereas the others had the classical VEGFR3 mutation-caused phenotype. The atypical presentations included pre-natal pleural effusion, spontaneous resorption of lymphedema and elephantiasis. Three of the four identified mutations were novel. These data show that de novo VEGFR3 mutations may be present in patients without family history of congenital lymphedema. This has implications for follow-up care, as such individuals have nearly a 50% risk for occurrence of lymphedema in their children. Our findings also indicate that although most patients with a VEGFR3 mutation have the well-defined phenotype for hereditary lymphedema type I, there are exceptions that should be considered in genetic counseling. Because VEGFR3 mutation can cause generalized lymphatic dysfunction and can thus result in hydrops fetalis, VEGFR3 screening should be added to the investigation of cases of hydrops fetalis of an unknown etiology.

The underlying cause of primary lymphedema is a malformation of the lymph vessel system. Secondary lymphedemas can be due to infections, recurrent inflammation, hypoproteinemia, tumors, operations, or irradiation. As a reaction to persistent edema and interstitial macromolecules, fibrosis occurs. Recurrent inflammations of the indurated and edematous tissue are clinically impressive. The massive form of the scrotal lymphedema leads to painful tautness and sexual dysfunction. A concurrent penile edema can cause dysuria. The deformity of the affected extremities and organs not only leads to restriction of mobility but also to psychological stress due to the disfigurement, even as far as to social deprivation. We report on a surgical technique for treating pronounced scrotal edema by resection and neoscrotal reconstruction using ventral pedunculated scrotal skin flaps in cases of congenital hereditary elephantiasis of the Meige type.

The authors report the case of a 13-year-old neurofibromatosis (NF-I) patient who suffered a blunt trauma in 1993. The diagnosis of subperiosteal hematoma was made. The pathogenesis of subperiosteal hematoma is discussed.

The distribution of non-filarial elephantiasis of the lower legs in Rwanda and Burundi in Central Africa has been studied in order to test the previous observation of an association between the disease and the volcanic rocks and soils on which the people live. Using the method of market counts, a total of 26,602 adults were observed in 23 markets; 189 had elephantiasis. In addition, 264 cases were observed in specially arranged clinics and a further 77 while travelling. Prevalence per thousand adults varied from 0.0 to 20.7. It was noted that the areas of high prevalence corresponded with the areas of volcanic lava. A differential market count at the edge of the red soils in two of these areas showed a raised prevalence among people living on these soils, similar to that observed in Ethiopia. The observations confirm that the disease occurs in barefooted people who dig in soil developed from volcanic rocks, under tropical conditions, at altitudes around 1500 m. It is suggested that the high proportion of iron and other transitional metals may be important as irritant or toxic to the lymphatic vessels of the legs after absorption.

Secondary peripheral lymphedemas (all edemas based on pontine symptoms) are very much more frequent than primary edemas which are either congenital or due to a predisposition. Of the latter, only hereditary (essential) lymphedema and idiopathic lymphedema (lymphedema praecox) play a role in clinical practise with the regard to their incidence. The exceedingly rare hereditary lymphedemas, which differ from the primary noncongenital lymphedemas only with regard to the demonstrated heritability merely have a clinical significance. Thus for example only six such cases occurred amongst our patients in the last 20 years. Most primary lymphedemas occur at the time of puberty with a time span of 10 to 30 years. Primary lymphedemas can also occur within a genuine clinical picture (flat nevi, Recklinghausen disease etc.), so that underlying symptoms must be looked for when they occur.

Similar HLA association was found in patients with elephantiasis in Sri Lankans and Southern Indians. HLA-B15 was observed in 13/44 (30%) Sri Lankan patients with elephantiasis compared to 1/27 (4%) Sri Lankan controls (p = .0058; RR = 10.9) and in 5/8 (28%) Southern Indian elephantiasis compared to 10/101 (10%) Southern Indian controls (p = 0.04; RR = 3.5). In combining the data, the significance of the difference of the frequency of B15 between patients with elephantiasis and controls was even more marked (p = 0.00045; corrected p = 0.012; RR = 4.4).