Association between chromosome 2p16.3 variants and glaucoma in populations of African descent

Abstract

Jiao et al. (1) recently reported significant association of three SNPs on chromosome 2p16.3 (rs12994401, rs10202118, and rs1533428) with an increased risk of primary open-angle glaucoma (POAG) in the Barbados population. In an effort to replicate these findings, we genotyped these three SNPs in our African-American and Ghanaian (West African) datasets. The research was reviewed and approved by the Institutional Review Board of Duke University Medical Center and for Ghanaian subjects, by the Noguchi Memorial Institute of Medical Research of the College of Health Sciences at the University of Ghana.The African-American dataset included 382 cases and 275 controls, and the Ghanaian dataset contained 170 cases and 132 controls as previously described (2).Genotyping of blood DNA was performed with TaqMan allelic discrimination assays according to the standard protocols (Applied Biosystems). We required 95% genotyping efficiency and matching genotypes of quality-control samples within and across all plates to include samples in the statistical analysis. Within each population, genotype frequencies of cases and controls were compared by logistic regression with adjustment for gender using SAS software (SAS Institute).All markers were in Hardy-Weinberg equilibrium (P > 0.05) in cases and controls from both populations. Only rs12994401 was significantly associated with an increased risk of POAG in the African-American population (P = 0.003) ( Table 1). We observed no linkage disequilibrium (LD) between the three SNPs in either population based on r 2 (r 2 < 0.35 for all SNP pairs in the respective cases and controls). Although we identified a modest association with POAG risk in the African-American population, risk was conferred by the C allele at rs12994401 rather than the T allele as reported by Jiao et al. (1). T allele frequencies in our African-American controls and the Barbados controls were nearly identical. Thus, this discrepancy may be attributed to population differences in the POAG cases. The Barbados population is believed to be fairly homogenous with only 10% European admixture (3), whereas African Americans have ∼21% European admixture (4). Lack of LD between rs12994401 and rs1533428 in our datasets strongly contrasts with a D′ value of 0.72 between these SNPs in the Barbados population. The lack of an observed association in the Ghanaian population may be because of population differences or reduced statistical power, because this smaller dataset had only 42% power (at 5% significance level) to detect an odds ratio of 0.5 for a minor allele frequency of 6%. In summary, we identified a significant association between SNP rs12994401 and POAG in the North Carolina African-American population with a different risk allele than reported for Barbados. As previously discussed (5), this suggests that the as yet unidentified causal variant in this region of chromosome 2 has different levels of LD with the genotyped SNP in these distinct populations of African descent. More studies will be necessary to identify the ...

Evaluation of SNPs on Chromosome 2p with Primary Open Angle Glaucoma in the South Indian Cohort

“…Thus, analysis of the association in the South Indian population may narrow the associated region more closely than those in other studied populations could. This is the first report to show the association of SNPs rs10202118 and rs11125375 with POAG in an Indian population and confirms the findings of Jiao et al, 13 Liu et al, 19 and Chen et al 20 The results suggest that these two SNP markers either might influence risk for POAG, or more likely, might be in linkage disequilibrium with markers that do. As POAG is a multifactorial disease, the specific genes responsible for its pathogenic mechanism remain to be identified.…”

“…Genetic associations are biologically meaningful if they are replicated in different ethnic populations. Association at the chromosome 2p locus was confirmed in an African-American population by Liu et al 19 who also saw suggestive results in a Ghanaian population. Association was also seen in a Chinese population by Chen et al (personal communication, 2010, see Chen et al, ASHG 2010, abstract 979).…”

Primary Open-Angle Glaucoma Genetics in African Americans

“…Liu et al . genotyped these three SNPs in African-American and Ghanaian (West African) samples and also detected an association at rs12994401 in the African-American population(44). Interestingly the risk alleles reported between these two studies were for opposite alleles with the ‘T’ allele associated with risk in Jiao et al .…”

“…and the ‘C’ allele similarly associated with risk in Liu et al . This reverse correlation may be due to the effects of differing levels of European ancestry admixture between African Americans (~21%) and Barbadians (~10%) or a result of a genotyping call error (44). …”

Involvement of Genetic Variants Associated With Primary Open-Angle Glaucoma in Pathogenic Mechanisms and Family History of Glaucoma

“…In fact, although non-IOP-related genetic variants near the ELOVL5 gene have been identified in the Japanese population, 16 no replicated associations for these genetic variants have been observed in other ethnic populations. 31 IOP-related genetic variants on chromosome 2p have been found in Afro-Caribbean, 32 African-American, 33 and Indian 34 populations. However, no significant associations between these genetic variants and POAG (NTG and HTG) have been observed in the Japanese population.…”