DNA variants and organophosphate neurotoxicity among emerging farmers in the Western Cape of South Africa.

BACKGROUND: Previous epidemiological studies investigating modification of organophosphate (OP) neurotoxicity by xenobiotic metabolizing enzymes (XMEs) polymorphisms have produced inconsistent results. METHODS: A cross-sectional study of 301 emerging farmers was conducted. Neurotoxicity testing included forward and backward recall, digit span, and vibration sensitivity testing. Questionnaire data included demography, potential confounders, and work history of pesticide exposures. Genomic DNA was analyzed from study participants for DNA variants of two glutathione S-transferases (GSTM1 and GSTT1), N-acetyltransferase 2 (NAT2), and Paraoxonase 1 (PON1). RESULTS: There was evidence of OP pesticide neurotoxicity modification by rs1799931 (NAT2), rs662 (PON1), and the null allele of GSTM1 in multivariate analysis. The strongest evidence of modification was observed for rs1799931 (NAT2) on the relationship between pesticide poisoning and impaired vibration sense. CONCLUSIONS: DNA variants of NAT2, PON1, and GSTM1 may modify OP neurotoxicity, and this requires further exploration.

Association of variants at BCL11A and HBS1L-MYB with hemoglobin F and hospitalization rates among sickle cell patients in Cameroon.

BACKGROUND: Genetic variation at loci influencing adult levels of HbF have been shown to modify the clinical course of sickle cell disease (SCD). Data on this important aspect of SCD have not yet been reported from West Africa. We investigated the relationship between HbF levels and the relevant genetic loci in 610 patients with SCD (98% HbSS homozygotes) from Cameroon, and compared the results to a well-characterized African-American cohort. METHODS AND FINDINGS: Socio-demographic and clinical features were collected and medical records reviewed. Only patients >5 years old, who had not received a blood transfusion or treatment with hydroxyurea were included. Hemoglobin electrophoresis and a full blood count were conducted upon arrival at the hospital. RFLP-PCR was used to describe the HBB gene haplotypes. SNaPshot PCR, Capillary electrophoresis and cycle sequencing were used for the genotyping of 10 selected SNPs. Genetic analysis was performed with PLINK software and statistical models in the statistical package R. Allele frequencies of relevant variants at BCL11A were similar to those detected in African Americans; although the relationships with Hb F were significant (p <.001), they explained substantially less of the variance in HbF than was observed among African Americans (∼ 2% vs 10%). SNPs in HBS1L-MYB region (HMIP) likewise had a significant impact on HbF, however, we did not find an association between HbF and the variations in HBB cluster and OR51B5/6 locus on chromosome 11p, due in part to the virtual absence of the Senegal and Indian Arab haplotypes. We also found evidence that selected SNPs in HBS1L-MYB region (HMIP) and BCL11A affect both other hematological indices and rates of hospitalization. CONCLUSIONS: This study has confirmed the associations of SNPs in BCL11A and HBS1L-MYB and fetal haemoglobin in Cameroonian SCA patients; hematological indices and hospitalization rates were also associated with specific allelic variants.

Mutation spectrum and founder chromosomes for the ABCA4 gene in South African patients with Stargardt disease.

PURPOSE: To assess the mutation spectrum of ABCA4 underlying Stargardt disease (STGD) in South Africa (SA) and to determine whether there is a single or a few founder chromosomes in SA STGD families. METHODS: Sixty-four probands exhibiting the STGD phenotype were screened for mutations in the 50 exons of ABCA4 by single-strand conformational polymorphism-heteroduplex analysis sequencing and restriction fragment length polymorphism analysis. Microsatellite marker haplotyping was used to determine the ancestry in 10 families. RESULTS: Fifty-seven ABCA4 disease-associated alleles were identified that comprised 16 different sequence variants, of which two were novel, in 40 individuals of the cohort of 64 subjects. The most common variants identified included the C1490Y, L2027F, R602W, V256splice, R152X, and 2588G-->C mutations. The C1490Y variant was the most common disease-associated variant identified (19/64 subjects) and was absent in 392 control chromosomes. At least 10 ABCA4 disease-associated haplotypes were identified. Two of these haplotypes, which carried the C1490Y mutation, were identified in three unrelated families. CONCLUSIONS: Results suggest that ABCA4 is the major gene underlying STGD in the cohort investigated. Five of the six common sequence variants identified were at a higher frequency in the SA cohort than reported in published data on individuals of similar ancestry. The mutation and haplotype data suggests that there are several ancestral haplotypes underlying STGD in SA. There seems to be at least two different origins for the common C1490Y mutation, as well as two for the R602W mutation, thereby suggesting several founder effects for STGD in SA.