Podoconiosis, Susceptibility To
Description
Podoconiosis, or endemic nonfilarial elephantiasis, is a noninfectious geochemical disease characterized by edema of the foot and lower leg that progresses to severe elephantiasis. It is a chronic and debilitating disorder that is a public health problem in at least 10 countries in tropical Africa, Central America, and northern India. Podoconiosis occurs among subsistence farmers and other occupational groups whose feet are exposed over many years to red clay soil derived from alkalic volcanic rock. However, podoconiosis develops only in a subgroup of exposed people, and studies have shown familial clustering with high heritability (summary by Davey et al. (2007) and Tekola Ayele et al. (2012)).
Clinical FeaturesPrice (1984) proposed the term podoconiosis (from the Greek 'podos,' for foot, and 'konia,' for dust) to describe endemic nonfilarial elephantiasis of the lower legs. He noted that the disease was first described in the 9th century AD by the Persian physician, Rhazes. Davey et al. (2007) stated that podoconiosis was historically reported in Ireland, Scotland, and France before footwear was more widely adopted. Price (1976) cited reports from the 1930s through the 1950s from tropical highland areas (i.e., areas free of mosquito vectors) of Uganda, Kenya, and Tanzania documenting the existence of nonfilarial elephantiasis in feet and lower legs. A series of intensive studies of the risk factors for the disease in Ethiopia and other East African countries in the 1970s led Price (1976) to identify wet tropical highland (1,200 to 2,300 m, or 4,000 to 7,000 ft) environments where red clay soil derived from volcanic basalt is farmed by barefoot workers as the convergence of circumstances that lead to disease.
Davey et al. (2007) stated that most patients with podoconiosis manifest disease in their twenties or thirties. Price (1972) reported that patients with podoconiosis ranged in age from 5 to 65 years.
Price (1984) described the earliest signs and symptoms of podoconiosis as recognized in special clinics in Ethiopia and Cameroon.
PathogenesisNumerous studies have ruled out occult filarial infection as a cause for podoconiosis. Tekola Ayele et al. (2012) and Lapolla and Tyring (2011) summarized current knowledge. After typically long-term exposure of bare feet to red clay soil derived from volcanic rock, which is both slippery and sticky when wet, colloid particles in the dust are absorbed through the skin. These particles are taken up by macrophages in the lower limb lymphatic system, inducing an inflammatory response in the lymphatic vessels and resulting in fibrosis and obstruction of the vessel lumen. Although mineral particles can be seen in the lymphatic system and lymph nodes of both unaffected and affected people, only some of the exposed people develop disease, suggesting that a genetic factor is also involved in pathogenesis.
InheritancePrice (1972) studied 90 families in the Ethiopian highlands with index cases of elephantiasis of the lower legs. Dominant inheritance was excluded by the absence of disease in a parent in many families. X-linked inheritance was ruled out by equality of male and female patients and by father and son patients. Further ascertainment and Lenz-Hogben analysis suggested the possible existence of an autosomal recessive trait. Price (1972) calculated a gene frequency of approximately 30% in the general population.
By studying 59 multigenerational families in a highly affected area with volcanic soil in the highlands of southwestern Ethiopia, Davey et al. (2007) found that more than 25% of sibs of probands were also affected. They estimated a sib recurrence risk ratio of 5.07 (i.e., 5 times the risk of a member of the general population) and heritability of podoconiosis as 63%. Segregation analysis indicated that an autosomal codominant major gene fit the most parsimonious model. Davey et al. (2007) proposed that genetically determined abnormal reactions to mineral particles absorbed in the lymph system are involved in susceptibility to podoconiosis.
MappingTekola Ayele et al. (2012) conducted a genomewide association study of 194 podoconiosis patients (average age of 24 years) and 203 controls (age greater than 50 years to minimize potential misclassification of cases and controls) from an area of southern Ethiopia with a disease prevalence rate of 5%. They validated their findings through family-based association testing in 202 family trios and HLA typing in 94 patients and 94 controls. Tekola Ayele et al. (2012) found a genomewide significant association of podoconiosis with the intergenic SNP rs17612858, which is located between the HLA-DQA1 (146880) and HLA-DQB1 (604305) loci on chromosome 6p21.3. In the allelic model, rs17612858 had an odds ratio (OR) of 2.44 and P of 1.42 x 10(-9), and in the additive model, rs17612858 had an OR of 2.19 and P of 3.44 x 10(-8). Stepwise multivariate regression analysis showed that minor allele homozygotes (TT) had an OR of 4.58 compared with major allele homozygotes (AA), who were also less susceptible than TA heterozygotes (OR = 1.68). Suggestive associations with podoconiosis were observed with 7 other SNPs in or near HLA-DQB1, HLA-DQA1, and HLA-DRB1 (142857). HLA typing showed that alleles HLA-DRB1*0701 (OR = 2.00), DQA1*0201 (OR = 1.91), and DQB1*0202 (OR = 1.91), as well as the HLA-DRB1*0701-DQB1*0202 haplotype (OR = 1.92), were risk variants for podoconiosis. Tekola Ayele et al. (2012) noted the significant differences of minor allele frequencies and different haplotype structures among African populations and stressed that no single group in Africa can be taken as a proxy for predicting HLA alleles of other populations in the continent. They concluded that association of podoconiosis with variants in HLA class II loci suggests that the condition may be a T-cell-mediated inflammatory disease and is a model for gene-environment interactions that may be relevant for other complex genetic disorders.