Common variants on chromosome 2 and risk of primary open-angle glaucoma in the Afro-Caribbean population of Barbados

Abstract

Primary open-angle glaucoma (POAG) is the second leading cause of blindness worldwide. Although a number of genetic loci have shown association or genetic linkage to monogenic forms of POAG, the identified genes and loci do not appear to have a major role in the common POAG phenotype. We seek to identify genetic loci that appear to be major risk factors for POAG in the Afro-Caribbean population of Barbados, West Indies. We performed linkage analyses in 146 multiplex families ascertained through the Barbados Family Study of Glaucoma (BFSG) and identified a strong linkage signal on chromosome 2p (logarithm of odds score ‫؍‬ 6.64 at ‫؍‬ 0 with marker D2S2156). We subsequently performed case-control analyses using unrelated affected individuals and unaffected controls. A set of SNPs on chromosome 2p was evaluated in two independent groups of BFSG participants, a discovery group (130 POAG cases, 65 controls) and a replication group (122 POAG cases, 65 controls), and a strong association was identified with POAG and rs12994401 in both groups (P < 3.34 E؊09 and P < 1.21E؊12, respectively). The associated SNPs form a common disease haplotype. In summary, we have identified a locus with a major impact on susceptibility to the common POAG phenotype in an AfroCaribbean population in Barbados. Our approach illustrates the merit of using an isolated population enriched with common disease variants as an efficient method to identify genetic underpinning of POAG.association study ͉ linkage analysis ͉ SNP ͉ eye ͉ intraocular pressure

Lack of association of common variants on chromosome 2p with primary open-angle glaucoma in the Japanese population

“…There was no significant association of either of these two SNPs with HTG and NTG in the present cohort (Tables 1 and 2), and this locus was not associated with POAG in the Japanese population. These two SNPs are common variants in the Japanese population as well as in the Afro-Caribbean population, and the present results indicate that these two SNPs are markers of a neighboring susceptible gene polymorphism responsible for POAG in the Afro-Caribbean population, although Jiao et al (1) reported that they may perform a regulatory role influencing the neighboring gene expression and that, alternatively, one cannot exclude the possibility that they are located within a yet-to-beannotated gene. A variety of genetic factors would contribute to optic neuropathy in POAG.…”

“…Primary open-angle glaucoma (POAG) is the most common form of glaucoma, and it is clinically classified into high-tension glaucoma (HTG), in which an elevated intraocular pressure (IOP) is a major feature, and normal-tension glaucoma (NTG), in which the IOPs are consistently within the statistically normal population range. Jiao et al (1) performed linkage analyses in 146 multiplex families and identified a locus with a major impact on the susceptibility to POAG in the Afro-Caribbean population in Barbados, West Indies. They demonstrated a strong association of rs12994401 and rs1533428 on chromosomes 2p with POAG, according to the findings of subsequent case-control analyses.…”

“…It is presumed that non-IOP-related genetic factors would predominate in patients with NTG and that, conversely, high IOP-related genetic factors would predominate in patients with HTG. Although it is not yet clear how this locus might act in the Afro-Caribbean population, it is thought that it contributes to optic neuropathy as a high IOPrelated genetic factor, because the mean IOP (26.7 mm Hg) of affected individuals is higher than that (17.0 mm Hg) of unaffected individuals ascertained from the family study (1). A direct comparison of the epidemiologic data between different ethnic populations may be difficult, because the diagnostic criteria are not always the same among the epidemiologic studies of glaucoma.…”

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

“…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.…”

Mechanism of Aqueous Humor Secretion, Its Regulation and Relevance to Glaucoma

“…There is a correlation between IOP and the likelihood of development of glaucoma and its progression (Boland and Quigley, 2007). Other risk factors are age (Tschumper and Johnson, 1990); family history, ethnicity or genetic variation (Jiao et al, 2009;Rao et al, 2011); other ocular or systemic disease, such as myopia, uveitis, decreased corneal or choroidal thickness, thyroid abnormality, sleep apnea, migraine (Boland and Quigley, 2007;Foster et al, 2002); vacular factors (Yanagi et al, 2011) and others. Age plays an important role in the development of glaucoma.…”