Human Genetic Resistance toOnchocerca volvulus:Evidence for Linkage to Chromosome 2p from an Autosome‐Wide Scan

Abstract

Background. Human infections with the tissue nematode Onchocerca volvulus show strong interindividual variation in intensity, which cannot be explained by differences in exposure alone. Several lines of evidence suggest a relevant influence of human genetics.Methods. In a genome-wide search for genetic determinants of resistance, we studied 196 siblings from 51 families exposed to endemic O. volvulus transmission in the forest zone of Ghana, West Africa. The numbers of worm larvae in the skin (i.e., microfilariae), which are the established measure of O. volvulus infection intensity, were counted in 4 small skin biopsy specimens (i.e., skin snips), and the numbers of palpable subcutaneous worm nodules (i.e., onchocercomata) were assessed. Numbers were corrected for age and exposure and were analyzed for linkage to 377 autosomal microsatellite markers and additional markers in genomic regions of interest.Results. Linkage was detected between the numbers of microfilariae and chromosome 2p21-p14 (maximum multipoint log 10 of odds (LOD) score of 3.80 at marker position D2S2378; empirical P ϭ 2.9 ϫ 10 Ϫ5 ). Conclusions. This finding provides strong evidence that a human genetic factor influences the intensity of O. volvulus infection. The strength of the linkage signal may facilitate the identification of the decisive genetic variants.

Identifying sub-optimal responses to ivermectin in the treatment of River Blindness

“…Microfilarial load varies markedly between hosts according to their age, sex, and geographical location, suggesting that differences in microfilarial load observed before the start of chemotherapy are largely caused by heterogeneity in host exposure to vectors (20). Host microfilarial load may also be influenced by human genetic factors (21) as well as immunological responses (22), whose relative contribution has not yet been quantified. The expression presented in SI Text, Estimation of the Minimum ATP Required to Explain Rates of Skin Repopulation, is used to estimate the minimum annual transmission potential (ATP, the number of infective larvae potentially received per host per year) that would be required to explain the high rates of skin repopulation estimated in the 4 villages by acquisition of new parasites alone, taking into account the different sample sizes of each village and assuming a 0 to 20% hypothetical contribution of host factors to the variability in microfilarial loads (Table 2).…”

Pre-control relationship of onchocercal skin disease with onchocercal infection in Guinea Savanna, Northern Nigeria

“…There is a spectrum of immune response to infection, with some infected persons showing a minimal immune response to parasite antigens, allowing the proliferation of microfilariae in the absence of clinical symptoms, while others have an intact and symptomatic immune response [38]. An immunogenetic basis for this clinical spectrum has been suggested [29;39;40] and differing isotypic antibody responses [30] and cellular immune responses [31;41–45] may play a role. The endosymbiotic bacteria Wolbachia are essential for the pathogenesis of O .…”

Host genetics and parasitic infections

“…• AmT, CL An autosome-wide genome linkage scan of O. volvulus infection intensity, as measured by the number of microfilariae in skin nodules, was performed in Ghana, and showed a QTL, termed Ov1, in the 2p21-p14 region [102]. The authors reviewed the literature to compare Ov1 with the body of linkage and association data obtained for atopic diseases: linkage has been shown at regions proximal to Ov1 for asthma, IgE levels, and bronchial hyper-reactivity [103][104][105].…”