PMC:6218809 / 22619-25659 JSONTXT

{"project":"2_test","denotations":[{"id":"30388403-28450586-2049239","span":{"begin":508,"end":509},"obj":"28450586"},{"id":"30388403-30033078-2049240","span":{"begin":511,"end":513},"obj":"30033078"},{"id":"30388403-11425164-2049241","span":{"begin":849,"end":851},"obj":"11425164"},{"id":"30388403-1511178-2049242","span":{"begin":1007,"end":1009},"obj":"1511178"},{"id":"30388403-19022401-2049243","span":{"begin":1343,"end":1345},"obj":"19022401"},{"id":"30388403-22484763-2049244","span":{"begin":1347,"end":1349},"obj":"22484763"},{"id":"30388403-9545414-2049245","span":{"begin":1351,"end":1353},"obj":"9545414"},{"id":"30388403-25423887-2049246","span":{"begin":1533,"end":1535},"obj":"25423887"},{"id":"30388403-19022401-2049247","span":{"begin":1537,"end":1539},"obj":"19022401"},{"id":"30388403-22484763-2049248","span":{"begin":1541,"end":1543},"obj":"22484763"},{"id":"30388403-28450586-2049249","span":{"begin":2095,"end":2096},"obj":"28450586"},{"id":"30388403-10631157-2049250","span":{"begin":2597,"end":2599},"obj":"10631157"}],"text":"Association of DUP4 with Malaria-Related Phenotypes\nThe DUP4 genotyping assay allowed us to investigate the association of DUP4 with three quantitative traits related to malaria: hemoglobin levels in peripheral blood, parasite load, and mean number of clinical episodes of malaria, with hemoglobin levels showing the highest heritability of the three phenotypes in this cohort (Table 1). The DUP4 structural variant has previously been associated with both severe cerebral malaria and severe malarial anemia,5, 39 and both are diagnoses related to our quantitative traits. For example, although the causes of hemoglobin level variation between individuals from a malaria-endemic region will be multifactorial, they will be strongly affected by malaria infection status of the individual, with infected individuals showing lower levels of hemoglobin.40 At the extreme low end of the distribution of hemoglobin levels is anemia, a sign of malaria that is one important feature in the pathology of the disease.41\nTable 1 Association of DUP4 Allele with Malarial Phenotypes in the Nyamisiti Cohort\nPhenotype Heritability of Phenotype (95% CI)a Individuals Association p Value\nHemoglobin 0.302 (0.136–0.469) 800 0.0054\nParasite load 0.104 (0.002–0.206) 864 0.39\nClinical episodes 0.221 (0.131–0.311) 939 0.72\na Calculated on this cohort using SOLAR30, 31, 46\nWe analyzed data from a longitudinal study of a population from the village of Nyamisati, in the Rufiji river delta, 150 km south of Dar-es-Salaam, Tanzania, described previously.29, 30, 31 This region was holoendemic for malaria, predominantly P. falciparum, which causes 99.5% of all recorded clinical episodes of malaria. Parasite prevalence was recorded as 75% at the start of the study in 1993, falling to 48% in 1998, as measured by microscopy in the 2- to 9-year-old children. A total of 962 individuals with pedigree information were genotyped; of these 278 were DUP4 heterozygotes and 4 were DUP4 homozygotes. Previous work has suggested that the DUP4 variant is at a frequency of about 3% in the Wasambaa of north-eastern Tanzania,5 and our analysis found an allele frequency of 13.4% (95% confidence intervals 11.0%–16.1%) in the 348 unrelated individuals from Nyamisati village. For these unrelated individuals, 87 were DUP4 heterozygotes and 3 were DUP4 homozygotes, with genotype frequencies in Hardy-Weinberg equilibrium. We used the pedigree and genotype information from our full cohort to test for association of three malaria-related phenotypes with the DUP4 variant. Using a family-based association method modeled in QTDT,36 we found a statistically significant association of the DUP4 variant with hemoglobin levels (p = 0.0054, Table 1). We estimated the direction of effect by comparing the mean corrected hemoglobin levels of unrelated individuals with and without the DUP4 variant. Individuals with the DUP4 allele showed a higher hemoglobin level compared to those without a DUP4 variant, showing that DUP4 variant is associated with higher hemoglobin levels."}