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Local genetic ancestry in CDKN2B-AS1 is associated with primary open-angle glaucoma in an African American cohort extracted from de-identified electronic health records.

ABSTRACT: BACKGROUND:Glaucoma is a leading cause of blindness in developed countries. Primary open-angle glaucoma (POAG), the most prevalent clinical subtype of glaucoma in the United States, affects African Americans at a higher rate compared with European Americans. Risk factors identified for POAG include increased age and family history, which coupled with heritability estimates, suggest this complex condition is associated with genetic and environmental factors. To date, several genome-wide studies have identified loci significantly associated with POAG risk, but most of these studies were performed in populations of European-descent. METHODS:To identify population-specific and trans-population genetic associations for POAG, we genotyped 11,521 African Americans using the Illumina Metabochip as part of the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study accessing BioVU, the Vanderbilt University Medical Center's biorepository linked to de-identified electronic health records. Among this study population, we identified 138 cases of POAG and 1376 controls and performed Metabochip-wide tests of association. We also estimated local genetic ancestry at CDKN2B-AS1, a POAG-associated locus established in European-descent populations. RESULTS:Overall, we did not identify significant single SNP-POAG associations after adjusting for multiple testing. We did, however, detect a significant association between POAG risk and local African genetic ancestry at CDKN2B-AS1, where on average cases were of 90% African descent compared with controls at 58% (p?=?2?×?10-?6). CONCLUSIONS:These data suggest that CDKN2B-AS1 is an important locus for POAG risk among African Americans, warranting further investigation to identify the variants underlying this association.

SUBMITTER: Restrepo NA

PROVIDER: S-EPMC6157155 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Local genetic ancestry in CDKN2B-AS1 is associated with primary open-angle glaucoma in an African American cohort extracted from de-identified electronic health records.

Restrepo Nicole A NA Laper Sarah M SM Farber-Eger Eric E Crawford Dana C DC

BMC medical genomics 20180914 Suppl 3

<h4>Background</h4>Glaucoma is a leading cause of blindness in developed countries. Primary open-angle glaucoma (POAG), the most prevalent clinical subtype of glaucoma in the United States, affects African Americans at a higher rate compared with European Americans. Risk factors identified for POAG include increased age and family history, which coupled with heritability estimates, suggest this complex condition is associated with genetic and environmental factors. To date, several genome-wide s ...[more]

PMID: 30255811

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Project description:PurposeTo test the genetic association between Japanese patients with primary open-angle glaucoma (POAG) and the previously reported POAG susceptibility loci and to perform genotype-phenotype analysis.MethodsGenetic associations for 27 SNPs from 16 loci previously linked to POAG were assessed using genome-wide SNP data of the primary cohort (565 Japanese POAG patients and 1,104 controls). Reproducibility of the assessment was tested in 607 POAG cases and 455 controls (second cohort) with a targeted genotyping approach. For POAG-associated variants, a genotype-phenotype correlation study (additive, dominant, recessive model) was performed using the objective clinical data derived from 598 eyes of 598 POAG patients.ResultsAmong 27 SNPs from 16 loci previously linked to POAG, genotypes for total of 20 SNPs in 13 loci were available for targeted association study. Among 8 SNPs in 3 loci that showed at least nominal association (P < 5.00E-02) in the primary cohort, a representative SNP for each loci (rs2157719 for CDKN2B-AS1, rs33912345 for SIX6, and rs9913911 for GAS7) were selected. For these SNPs the association was found significant in both the second cohort analysis and meta-analysis. The genotype-phenotype analysis revealed significant correlations between CDKN2B-AS1 (rs2157719) and decreased intraocular pressure (β = -6.89 mmHg, P = 1.70E-04; dominant model) after multiple corrections. In addition, nominal correlation was observed between CDKN2B-AS1 (rs2157719) and optic nerve head blood flow (β = -0.54 and -0.67 arbitrary units (AU), P = 2.00E-02 and 1.39E-02), between SIX6 (rs33912345) and decreased total peripapillary retinal nerve fiber layer thickness (β = -2.16 and -2.82 μm, P = 4.68E-02 and 2.40E-02, additive and recessive model, respectively) and increased optic nerve head blood flow (β = 0.44 AU, P = 2.20E-02; additive model) and between GAS7 (rs9913911) and increased cup volume (β = 0.03 mm3, P = 4.60E-02) and mean cup depth (β = 0.03 mm3, P = 4.11E-02; additive model) and decreased pattern standard deviation (β = -0.87 dB, P = 2.44E-02; dominant model).ConclusionThe association between SNPs near GAS7 and POAG was found in Japanese patients for the first time. Clinical characterization of the risk variants is an important step toward understanding the pathology of the disease and optimizing treatment of patients with POAG.

Project description:BackgroundVariants in CDKN2B/CDKN2B-AS1 have been reported to modulate glaucoma risk in several GWAS across different populations. CDKN2B/CDKN2A encodes tumor suppressor proteins p16INK4A/p15INK4B which influences cell proliferation/senescence in RGCs, the degeneration of which is a risk factor for glaucoma. CDKN2B-AS1 codes a long non-coding RNA in antisense direction and is involved in influencing nearby CDKN2A/CDKN2B via regulatory mechanisms.MethodsCurrent study investigated four SNPs (rs2157719, rs3217992, rs4977756, rs1063192) of aforementioned genes in a case-control study in a North Indian cohort. Genotyping was done with Taqman chemistry. In addition, an updated meta-analysis was performed.ResultsTwo SNPs, rs3217992 and rs2157719 were found to be significantly associated with the disease. The frequency of 'T' allele of rs3217992 was significantly lower in cases (POAG/PACG) [p = 0.045; OR = 0.80(CI = 0.65-0.99) and p = 0.024; OR = 0.73(CI = 0.55-0.96)], respectively than in controls. Genetic model analysis revealed that TT + CT genotype confers 0.73-fold protection against POAG [p = 0.047; OR = 0.73(CI = 0.54-0.99)] and trend assumed additive model gives 0.53 times higher protection against PACG progression. However the association of rs3217992 with POAG and PACG did not remain significant after Bonferroni correction. For rs2157719, the 'C' allele was found to be less prevalent among cases (POAG/PACG) with respect to controls. Cochran Armitage trend test assuming additive model revealed 0.77 and 0.64-fold protection against POAG and PACG respectively. Bonferroni correction (pcorr = 0.003) was applied and the association of rs2157719 remained significant in PACG cases but not among POAG cases (p = 0.024). The 'CC' genotype also confers protection against primary glaucoma (POAG/PACG) among males and female subjects. The frequency rs1063192 and rs4977756 did not vary significantly among subjects, however the haplotype 'CATA' was found to be associated with increased glaucoma risk. An updated meta-analysis conducted on pooled studies on POAG cases and controls revealed significant association between rs1063192, rs2157719, rs4977756 and POAG except rs3217992.ConclusionThe study concludes significant association between INK4 variants and primary glaucoma in the targeted North Indian Punjabi cohort. We believe that deep-sequencing of INK4 locus may help in identifying novel variants modifying susceptibility to glaucoma. Functional studies can further delineate the role of CDKN2B and CDKN2B-AS1 in primary glaucoma for therapeutic intervention.

Project description:The long noncoding RNA CDKN2B-AS1 harbors a major coronary artery disease risk haplotype, which is also associated with progressive forms of the oral inflammatory disease periodontitis as well as myocardial infarction (MI). Despite extensive research, there is currently no broad consensus on the function of CDKN2B-AS1 that would explain a common molecular role of this lncRNA in these diseases. Our aim was to investigate the role of CDKN2B-AS1 in gingival cells to better understand the molecular mechanisms underlying the increased risk of progressive periodontitis. We downregulated CDKN2B-AS1 transcript levels in primary gingival fibroblasts with LNA GapmeRs. Following RNA-sequencing, we performed differential expression, gene set enrichment analyses and Western Blotting. Putative causal alleles were searched by analyzing associated DNA sequence variants for changes of predicted transcription factor binding sites. We functionally characterized putative functional alleles using luciferase-reporter and antibody electrophoretic mobility shift assays in gingival fibroblasts and HeLa cells. Of all gene sets analysed, collagen biosynthesis was most significantly upregulated (Padj=9.7x10-5 (AUC>0.65) with the CAD and MI risk gene COL4A1 showing strongest upregulation of the enriched gene sets (Fold change = 12.13, Padj = 4.9 x 10-25). The inflammatory "TNFA signaling via NFKB" gene set was downregulated the most (Padj=1x10-5 (AUC=0.60). On the single gene level, CAPNS2, involved in extracellular matrix organization, was the top upregulated protein coding gene (Fold change=48.5, P<9x10-24). The risk variant rs10757278 altered a binding site of the pathogen responsive transcription factor STAT1 (P=5.8x10-6). rs10757278-G allele reduced STAT1 binding 14.4% and rs10757278-A decreased luciferase activity in gingival fibroblasts 41.2% (P=0.0056), corresponding with GTEx data. CDKN2B-AS1 represses collagen gene expression in gingival fibroblasts. Dysregulated collagen biosynthesis through allele-specific CDKN2B-AS1 expression in response to inflammatory factors may affect collagen synthesis, and in consequence tissue barrier and atherosclerotic plaque stability.

Dataset Information

Local genetic ancestry in CDKN2B-AS1 is associated with primary open-angle glaucoma in an African American cohort extracted from de-identified electronic health records.

Publications

Local genetic ancestry in CDKN2B-AS1 is associated with primary open-angle glaucoma in an African American cohort extracted from de-identified electronic health records.

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