Lack of association of common variants on chromosome 2p with primary open-angle glaucoma in the Japanese population.
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ABSTRACT:
SUBMITTER: Mabuchi F
PROVIDER: S-EPMC2906897 | biostudies-literature | 2010 May
REPOSITORIES: biostudies-literature
Publications
Lack of association of common variants on chromosome 2p with primary open-angle glaucoma in the Japanese population.
Mabuchi Fumihiko F Sakurada Yoichi Y Kashiwagi Kenji K Yamagata Zentaro Z Iijima Hiroyuki H Tsukahara Shigeo S
Proceedings of the National Academy of Sciences of the United States of America 20100427 21
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Project description: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 Afro-Caribbean 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.
| S-EPMC2761374 | biostudies-literature
Project description:We conducted a genome-wide association study for primary open-angle glaucoma (POAG) in 1,263 affected individuals (cases) and 34,877 controls from Iceland. We identified a common sequence variant at 7q31 (rs4236601[A], odds ratio (OR) = 1.36, P = 5.0 × 10?¹?). We then replicated the association in sample sets of 2,175 POAG cases and 2,064 controls from Sweden, the UK and Australia (combined OR = 1.18, P = 0.0015) and in 299 POAG cases and 580 unaffected controls from Hong Kong and Shantou, China (combined OR = 5.42, P = 0.0021). The risk variant identified here is located close to CAV1 and CAV2, both of which are expressed in the trabecular meshwork and retinal ganglion cells that are involved in the pathogenesis of POAG.
| S-EPMC3222888 | biostudies-literature
Project description:PURPOSE: To assess whether tumor protein p53 gene (p53) polymorphisms are associated with primary open angle glaucoma (POAG) in the Japanese population. METHODS: Four hundred and twenty-five Japanese patients with POAG, including normal tension glaucoma (NTG, n=213) and high tension glaucoma (HTG, n=212) and 189 control subjects without glaucoma were analyzed for two p53 polymorphisms (rs1042522; a G-->C substitution at codon 72 in exon 4 and rs59758982; a 16 base pair insertion in intron 3) using allele specific primer PCR and a pyrosequencing technique respectively. The genotypic and allelic frequencies were compared between NTG or HTG patients and control subjects. RESULTS: No significant difference (NTG versus control, p=0.99, and HTG versus control, p=0.69, chi(2) test) was observed regarding the p53 genotype frequencies at codon 72 between the NTG (GG: 43.2%, GC: 44.6%, CC: 12.2%) or HTG (GG: 40.1%, GC: 48.1%, CC: 11.8%) patients and the control subjects (GG: 43.9%, GC: 43.9%, CC: 12.2%). In addition, there was no significant difference (NTG versus control, p=0.94; and HTG versus control, p=0.66, Fisher's exact test) in the p53 allele frequencies at codon 72 between the NTG (G allele: 65.5%, C allele: 34.5%) or HTG (G allele: 64.2%, C allele: 35.8%) patients and the control subjects (G allele: 65.9%, C allele: 34.1%). No 16 base pair insertion in intron 3 was found in this study. CONCLUSION: p53 polymorphisms were not associated with POAG in the Japanese population. Further studies in the other ethnic populations should therefore be performed to elucidate whether the p53 intron 3 insertion polymorphism is a genetic risk factor for POAG, because the intron 3 insertion polymorphism occurs very rarely in the Japanese population.
| S-EPMC2684750 | biostudies-literature
Project description:Significant association has recently been reported between pseudoexfoliation glaucoma (XFG) and two single-nucleotide polymorphisms (SNPs), rs3825942, and rs1048661, in the lysyl oxidase-like 1 gene (LOXL1). The purpose of this study was to investigate whether XFG-associated variants of LOXL1 play a significant role in primary open-angle glaucoma in the Caucasian, African-American, and Ghanaian (West-African) populations.POAG was defined as the presence of glaucomatous optic nerve damage, associated visual field loss, and elevated intraocular pressure (>22 mm Hg in both eyes). Thirteen tagging SNPs were genotyped by allelic discrimination assays in the Caucasian (279 cases and 227 controls), African-American (193 cases and 97 controls), and Ghanaian (170 cases and 138 controls) populations. Allele and genotype frequencies were compared between the cases and controls from each population.None of the SNPs associated with XFG in LOXL1 were significantly associated with POAG in these populations. The risk allele frequencies for rs2165241 and rs3825942 were significantly lower in the African-American and Ghanaian populations, compared with Caucasian individuals.There was no association between SNPs in the LOXL1 gene and POAG. This is the first analysis of the LOXL1 gene in African-American and West-African populations. LOXL1 gene variants do not appear to play a significant role in the pathogenesis of POAG in populations of either Caucasian or West-African ancestry.
| S-EPMC2671060 | biostudies-literature
Project description:PurposeTo evaluate the association of lysyl oxidase like 1 (LOXL1) gene variants in Japanese patients with open-angle glaucoma.MethodsWe evaluated the association of three LOXL1 variants (rs1048661, rs3825942, and rs2165241) in 142 Japanese patients with exfoliation syndrome (EX; n=59) and exfoliation glaucoma (EG; n=83) as well as in 251 control patients aged 70 years or older with primary open-angle glaucoma (PG; n=40), normal tension glaucoma (NG; n=54), and cataract (CT; n=157).ResultsIn comparison with the CT group, the single nucleotide polymorphisms (SNPs) showed significant association with EX, EG, and EX+EG. The odds ratio (OR)=19.71-28.23 and p=1.69 x 10(-23) - 3.00 x 10(-45) for allele T of rs1048661; OR=28.21-39.78 and p=1.77 x 10(-8) - 2.42 x 10(-22) for allele G of rs3825942; and OR=16.59-23.40 and p=4.79 x 10(-5) - 1.08 x 10(-9) for allele C of rs2165241. In comparison with the controls (CT+PG+NG), the haplotype rs1048661/rs3825942 (T/G) was significantly associated with EX+EG (p=8.27 x 10(-44)), and haplotype G/A had a significant protective effect (p=2.25 x 10(-14)). None of the three SNPs showed significant differences between the EX and EG groups or between the PG and NG groups.ConclusionsThese SNPs are associated with exfoliation syndrome/glaucoma in the Japanese population. The risk alleles in rs1048661 and rs2165241 are different from other populations. Additional genetic or environmental risk factors other than these LOXL1 SNPs could be associated with the development of exfoliation syndrome as well as exfoliation glaucoma among exfoliation syndrome patients.
| S-EPMC2573732 | biostudies-literature
Project description:PurposeDespite the different etiology of primary open angle glaucoma (POAG), primary angle closure glaucoma (PACG), and pseudoexfoliative glaucoma (PEXG), several studies have suggested that these forms of glaucoma have overlapping genetic risk factors. Therefore, the aim of this study was to evaluate the role of genetic variants recently associated with POAG in different types of glaucoma in Pakistani POAG, PACG, and PEXG patient cohorts.MethodsSix variants in CDKN2B-AS1 (rs4977756), CDKN2B (rs1063192), ATOH7 (rs1900004), CAV1 (rs4236601), TMCO1 (rs4656461), and SIX1 (rs10483727) were genotyped using TaqMan assays. A total of 513 unrelated patients with glaucoma (268 with POAG, 125 with PACG, and 120 with PEXG) and 233 healthy controls were included in the study. Genotypic and allelic associations were analyzed with a chi-square test.ResultsThe frequency of the G allele of TMCO1 rs4656461 was significantly lower in the patients with POAG (p=0.003; OR [odds ratio]=0.57), PACG (p=0.009; OR=0.52), and PEXG (p=0.01; OR=0.54) compared to the control individuals. The T allele of ATOH7 rs1900004 was observed less frequently in the patients with PACG (p=0.03; OR=0.69) compared to the control individuals. The A allele of CAV1 rs4236601 was found more frequently in the patients with POAG (p=0.008; OR=1.49) compared to the control individuals. This study demonstrates that the TMCO1 rs4656461 variant is associated with POAG, PACG and PEXG in the Pakistani population. Our study was unable to confirm previous associations reported for variants in CDKN2B-AS1, CDKN2B, and SIX1 with any type of glaucoma.ConclusionsIn conclusion, we found consistent evidence of the significant association of three common variants in TMCO1, ATOH7, and CAV1.
| S-EPMC4225136 | biostudies-literature
Project description:PurposePrimary open-angle glaucoma (POAG) is a common but complex disease with a strong genetic component. Notably, few genes have been robustly associated with POAG. An obvious group of genes to test as susceptibility factors for POAG are the developmental genes forkhead box C1 (FOXC1), transforming growth factor-beta 2 (TGFβ2), and bone morphogenic protein 4 (BMP4). These genes are known to play important roles in the normal morphogenesis of the anterior segment and/or have been implicated in intra-ocular pressure (IOP) regulation and trabecular meshwork function. This study investigates the role of FOXC1, TGFβ2, and BMP4 in POAG.MethodsThe contribution of common genetic variation at the FOXC1, TGFβ2, and BMP4 loci to risk of POAG was investigated in a case-control association study in 330 British Caucasian individuals comprised of 272 high-tension glaucoma (HTG) and 58 ocular hypertension (OHT), and 276 matched controls.ResultsAll the single nucleotide polymorphisms (SNPs) were in Hardy-Weinberg equilibrium and genotyping success rate was >92% for all SNPs. With the exception of a weak association between the BMP4 tagging SNP rs2761884 and the combined patient group HTG+OHT that did not withstand permutation testing (uncorrected p=0.0400, corrected p=0.1320), no associations (p<0.05) were identified between the patient groups (HTG and OHT) and FOXC1, TGFβ2, and BMP4 alleles and haplotypes compared to the control group.ConclusionsThis is the first association analysis of FOXC1, TGFβ2, and BMP4 and POAG. These genes were selected as candidate genes for POAG because of their biologic roles. No significant associations were identified between FOXC1, TGFβ2, and BMP4 alleles and haplotypes and POAG. The lack of association suggests that common variation in these genes do not have a significant role in the pathogenesis of POAG among British Caucasian subjects.
| S-EPMC3380945 | biostudies-literature
Project description:Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 × 10(-19)), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 × 10(-10)) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 × 10(-10)). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.
| S-EPMC4177327 | biostudies-literature
Project description:Purpose. To clarify the association of endothelial nitric oxide synthase (eNOS) polymorphisms and primary open angle glaucoma (POAG). Methods. After a systematic literature search in the MEDLINE, EMBASE, and ISI Web of Science databases, all relevant studies evaluating the association between the polymorphisms (rs2070744 and rs1799983) of eNOS gene and POAG were screened and included. The pooled odds ratios (ORs) and the 95% confidence interval (CI) of each single-nucleotide polymorphism (SNP) in five genetic models were estimated using fixed-effect model if I (2) < 50% in the test for heterogeneity; otherwise the random-effects model was used. Results. Thirty-one records were obtained, with five being suitable for meta-analysis. The overall results showed that both TT genotype in rs2070744 and GG genotype in rs1799983 are associated with decreased risk of POAG susceptibility. Stratified analysis based on ethnicity showed that the association of rs2070744 with POAG remained only in Caucasians. Results of subgroup analysis by sex indicated association between both polymorphisms and POAG in female group, but not in male group. Conclusions. TT genotype and/or T-allele in rs2070744, as well as GG genotype and/or G-allele in rs1799983, was associated with decreased risk for POAG overall and in female group.
| S-EPMC4875980 | biostudies-literature
Project description:PurposeTo estimate the population frequencies of all common mitochondrial variants and ancestral haplogroups among 1,999 subjects recruited for the Primary Open-Angle African American Glaucoma Genetics (POAAGG) Study, including 1,217 primary open-angle glaucoma (POAG) cases and 782 controls, and to identify ancestral subpopulations and mitochondrial mutations as potential risk factors for POAG susceptibility.MethodsSubject classification by characteristic glaucomatous optic nerve findings and corresponding visual field defects, as defined by enrolling glaucoma specialists, stereo disc photography, phlebotomy, extraction of total DNA from peripheral blood or saliva, DNA quantification and normalization, PCR amplification of whole mitochondrial genomes, Ion Torrent deep semiconductor DNA sequencing on DNA pools ("Pool-seq"), Sanger sequencing of 3,479 individual mitochondrial DNAs, and bioinformatic analysis.ResultsThe distribution of common African haplogroups within the POAAGG study population was broadly similar to prior surveys of African Americans. However, the POAG case population was found to be enriched in L1c2 haplogroups, which are defined in part by missense mutations m.6150G>A (Val83Ile, odds ratio [OR] 1.8, p=0.01), m.6253C>T (Met117Thr, rs200165736, OR 1.6, p=0.04), and m.6480G>A (Val193Ile, rs199476128, OR 4.6, p=0.04) in the cytochrome c oxidase subunit 1 (MT-CO1) gene and by a variant, m.2220A>G (OR 2.0, p=0.01), in MT-RNR2, which encodes the mitochondrial ribosomal 16s RNA gene. L2 haplogroups were predicted to be overrepresented in the POAG case population by Pool-seq, and the difference was confirmed to be significant with Sanger sequencing, that targeted the L2-associated variants m.2416T>C (rs28358580, OR 1.2, p=0.02) and m.2332C>T (OR 1.2, p=.02) in MT-RNR2. Another variant within MT-RNR2, m.3010G>A (rs3928306), previously implicated in sensitivity to the optic neuropathy-associated antibiotic linezolid, and arising on D4 and J1 lineages, associated with Leber hereditary optic neuropathy (LHON) severity, was confirmed to be common (>5%) but was not significantly enriched in the POAG cases. Two variants linked to the composition of the gut microbiome, m.15784T>C (rs527236194, haplogroup L2a1) and m.16390G>A (rs41378955, L2 haplogroups), were also enriched in the case DNA pools.ConclusionsThese results implicate African mtDNA haplogroups L1c2, L1c2b, and L2 as risk factors for POAG. Approximately one in four African Americans have these mitochondrial ancestries, which may contribute to their elevated glaucoma risk. These haplogroups are defined in part by ancestral variants in the MT-RNR2 and/or MT-CO1 genes, several of which have prior disease associations, such as MT-CO1 missense variants that have been implicated in prostate cancer.
| S-EPMC4872278 | biostudies-literature