The genetics of primary open-angle glaucoma in black South Africans

Williams, Susan Eileen Isabella
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Purpose Primary Open Angle Glaucoma (POAG) is an important cause of irreversible visual loss in South Africa. POAG is asymptomatic, yet early detection and treatment can prevent visual loss. POAG has a genetic component, and identifying genetic risk factors could facilitate early detection as well as elucidate pathogenic mechanisms of the disease. POAG is more common in populations of African descent, but has been understudied in the context of POAG genetic risk factors in these populations. The purpose of this research was to identify genetic risk factors for POAG in black South Africans. Methods Self-identified black South African POAG patients and unaffected control participants were enrolled at St John Eye Hospital in Soweto. The study population was evaluated in case-control association studies for genetic risk factors in the following genomic regions: CDKN2B/CDKN2BAS-1, MYOC, TMCO1, CAV1/CAV2, CYP1B1, WDR36, COL1A1, COL1A2, COL5A1, COL8A2, ZNF469, SIX1/SIX6, ATOH7 and the chromosome 2p16 locus. The study was powered to detect moderate-sized genetic effects. Family members of participants identified with potentially pathogenic mutations in MYOC were counselled, screened for the mutations and clinically screened for glaucoma. Genotyping data from SNPs in TMCO1, CAV1/CAV2, CDKN2BAS-1 and SIX1/SIX6 that had also been genotyped in a West African and an African American population were compared with the South African data and the three datasets were combined to create a larger sample of individuals of African descent for association analyses. Results There were 247 POAG patients and 255 control participants enrolled in the study that were representative of the black population of South Africa. The POAG participants had advanced disease with more than half having severe visual impairment from the disease. Potentially pathogenic mutations in MYOC were identified in 4.2% of the POAG patients (Lys500Arg in 1.2%, Gly374Val in 0.9% and Tyr453del in 2.3%) and in 20% of the family members screened. The screening successfully identified individuals at high risk for future visual loss and enabled them to receive counselling and follow-up. Lys500Arg is a benign variant, whereas Gly374Val and Tyr453del are pathogenic. Tyr453del is incompletely penetrant. In the association studies, single SNPs in the COL1A1, ZNF469 and MYOC regions showed marginal associations with POAG, but the identified associations did not withstand correction for multiple testing. Ocular quantitative trait association analyses also yielded no significant associations after correction but a significant association was identified with type 2 diabetes mellitus and rs12522383 in WDR36. There was also a significant association identified with SNP rs10120688 in CDKN2BAS-1 and visual impairment in the African American dataset. Combining the three datasets of individuals of African descent increased the power to detect small genetic effects and identified suggestive associations with SNPs in TMCO1 and CAV1/CAV2. Conclusions Black South Africans with POAG may have a MYOC mutation that either causes or contributes to their risk for developing POAG in approximately 3.3%. MYOC mutation screening in affected families successfully demonstrated the value of genetic information in identifying and protecting individuals at risk for visual loss from glaucoma. The genetic risk associated with the candidate genes evaluated in this study and POAG in black South Africans, if such a risk exists, is a small risk. There is therefore a critical need for further genetic association studies in POAG in this significantly affected population to identify other genetic risk factors. This study has important implications for the management and counselling of black South African patients with POAG and their families.