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.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/14594 |
| Date | 25 April 2014 |
| Creators | Williams, Susan Eileen Isabella |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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