Epigenetics and the burden of noncommunicable disease: a paucity of research in Africa.

Epidemiological evidence suggests that an adverse in utero environment is associated with an increased risk for developing adult onset diseases. The molecular mechanisms for susceptibility to chronic noncommunicable diseases are not fully understood, although recent research has proposed that epigenetic modifications play an important role in fetal programming. Genetic and environmental factors contribute to interindividual and spatiotemporal tissue-specific methylation patterns. Although the diverse environments and high genetic diversity of African populations provide unparalleled potential to investigate the effects of environmental change on the epigenetic profile in humans, only a small percentage of genomic and epigenetic studies have focused on populations from this continent. This emphasizes the need to build capacity in Africa for research that leads to an understanding of the association between genetic, epigenetic and environmental risk factors for noncommunicable diseases on the continent.

MYOC mutations in black south african patients with primary open-angle glaucoma: genetic testing and cascade screening.

BACKGROUND: Primary Open Angle Glaucoma (POAG) is an important cause of irreversible blindness in South Africa. Mutations in the MYOC gene are important in monogenic POAG. This study aimed to characterize potentially pathogenic MYOC mutations in this population. MATERIALS AND METHODS: Self-identified black South African POAG patients (215) and unaffected control participants (214) had ophthalmological examinations and DNA extraction. Potentially pathogenic MYOC variants were genotyped in the study population. Family members of participants with the mutations were screened for glaucoma clinically and for the mutations using Sanger sequencing. RESULTS: The following mutations were genotyped: Gly374Val (2 POAG patients), Lys500Arg (3 POAG patients) and Tyr453del (5 POAG patients). None of the relatives screened for Gly374Val had the mutation or POAG. The Lys500Arg mutation did not co-segregate with the disease in an affected family. The Tyr453del mutation co-segregated with the disease, but demonstrated incomplete penetrance. POAG patients with the Tyr453del mutation had adult-onset POAG with high intraocular pressures and advanced cupping. CONCLUSIONS: Overall, 3.3% of black South Africans with POAG have a Gly374Val or Tyr453del MYOC mutation. The Tyr453del mutation is incompletely penetrant. That the mutation is necessary but insufficient introduces a counseling dilemma. Mutation screening can, however, identify high-risk individuals who can be monitored to detect early signs of the disease. The Gly374Val mutation is predicted to be damaging to MYOC. The Lys500Arg mutation is predicted to be benign and tolerated. This study has important implications for the management and counseling of black South African patients with POAG and their families.

The elusive gene for keratolytic winter erythema.

Keratolytic winter erythema (KWE), also known as Oudtshoorn skin disease, is characterised by a cyclical disruption of normal epidermal keratinisation affecting primarily the palmoplantar skin with peeling of the palms and soles, which is worse in the winter. It is a rare monogenic, autosomal dominant condition of unknown cause. However, due to a founder effect, it occurs at a prevalence of 1/7 200 among South African Afrikaans-speakers. In the mid-1980s, samples were collected from affected families for a linkage study to pinpoint the location of the KWE gene. A genome-wide linkage analysis, using microsatellite markers, identified the KWE critical region on chromosome 8p23.1-p22. Subsequent genetic studies focused on screening candidate genes in this critical region; however, no pathogenic mutations that segregated exclusively with KWE were identified. The cathepsin B (CTSB) and farnesyl-diphosphate farnesyltransferase 1 (FDFT1) genes revealed no potentially pathogenic variants, nor did they show differential gene expression in affected skin. Mutation detection in additional candidate genes also failed to identify the KWE-associated variant, suggesting that the causal variant may be in an uncharacterised functional region. Bioinformatic analysis revealed highly conserved regions within the KWE critical region and a custom tiling array was designed to cover this region and to search for copy number variation. Although the study did not identify a variant that segregates exclusively with KWE, it provided valuable insight into the complex KWE-linked region. Next-generation sequencing approaches are being used to comb the region, but the causal variant for this interesting hyperkeratotic palmoplantar phenotype still remains elusive. 

Chitotriosidase deficiency: a mutation update in an african population.

Human plasma chitotriosidase activity is a commonly used diagnostic and therapeutic biomarker for non-neuronopathic Gaucher disease. Chitotriosidase deficiency is common in non-African populations and is primarily caused by a 24 bp duplication in the encoding gene (CHIT1). Allele frequencies for the 24 bp duplication range from 20-50 % outside Africa. The present study found chitotriosidase deficiency to be rare in the South African Black population (1.6 %) and the otherwise common 24 bp duplication is absent in this African population. Instead, chitotriosidase deficiency is caused by a 4 bp deletion across the exon/intron 10 boundary (E/I-10_delGAgt) of the CHIT1 gene. The exact position of this mutation was found to differ from the previously reported location. Allele frequencies for six coding variants of CHIT1 (p.G102S, p.G354R, 24 bp duplication, E/I-10_delGAgt, p.A442V/G) were determined and the 4 bp deletion was found to be in complete linkage disequilibrium (LD) with two of the coding variants (p.G354R and p.A442V). The in silico assessments of the two missense mutations in LD predict a protein-damaging nature and functional studies are needed to clarify if one or both abolish the enzyme's activity. Overall, the low frequency of chitotriosidase deficiency in South African Blacks makes chitotriosidase activity an excellent biomarker of choice in this population.

Exclusion of CTSB and FDFT1 as positional and functional candidate genes for keratolytic winter erythema (KWE).

BACKGROUND: Keratolytic winter erythema (KWE) or Oudtshoorn skin disease is a rare autosomal dominant monogenic disorder of epidermal keratinisation characterized clinically by cyclical peeling of the palms and soles. Due to a founder effect many KWE families have been identified in South Africa and the gene has been localized to 8p23.1-22, but the causal gene has yet to be identified. OBJECTIVE: To examine two compelling positional and functional candidate genes within the critical region on 8p: cathepsin B (CTSB), a lysosomal cysteine protease localized to pericellular spaces between keratinocytes, possibly playing a role in cell-cell adhesion; and farnesyl-diphosphate farnesyltransferase (FDFT1), a membrane-associated enzyme in cholesterol biosynthesis which, among its many functions, plays a role in barrier permeability and integrity. METHOD: Mutation screening of the coding regions, 5'UTRs and intron/exon boundaries of CTSB and FDFT1 in genomic DNA and cDNA of patients affected with KWE. Relative gene expression profiles of CTSB and FDFT1 in palmoplantar skin biopsies were assessed by real-time RT-PCR. RESULTS: No DNA variants that segregate exclusively with KWE were identified. There was no significant difference in the CTSB expression profiles but a trend towards increased expression of FDFT1 was observed in the skin of affected individuals (p=0.063). This observation prompted analysis of the FDFT1 promoter region; however, no genetic variants segregating with the KWE phenotype were observed and it is likely that the increased expression was triggered in response to skin inflammation and peeling. CONCLUSION: CTSB and FDFT1 are excluded as candidates for KWE.