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Genetic association of COL5A1 variants in keratoconus patients suggests a complex connection between corneal thinning and keratoconus.

ABSTRACT: Single nucleotide polymorphisms (SNPs) located near or within the COL5A1 gene, at 9q34.2-q34.3 chromosomal region have been reported in association with central corneal thickness (CCT). Using family linkage analysis, we identified a keratoconus susceptibility locus at 9q34. These findings led us to perform an association study between COL5A1 variation and keratoconus susceptibility.A Caucasian case-control cohort of 222 keratoconus patients and 3324 controls was selected as the discovery panel. An independent case-control panel of 304 cases and 518 controls and a family panel of 186 subjects were replicated for genotyping and association. Forty-four SNPs (21 for discovery and 23 for fine-mapping) spanning 300 kilobases in and around COL5A1 were genotyped and tested for genetic association. Logistic regression models implemented in PLINK were used to test for association in case controls. Generalized estimating equation models accounting for familial correlations implemented in genome-wide interaction analyses with family data were used for association testing in families.Two CCT associated SNPs (rs1536482 and rs7044529 near and within COL5A1) were identified in the keratoconus discovery cohort (P values of 6.5 × 10(-3) and 7.4 × 10(-3)). SNP rs1536482 was replicated in the second case-control sample (P = 0.02), and SNP rs7044529 was replicated in a keratoconus family panel (P = 0.03). Meta P values of rs1536482 and rs7044529 in the keratoconus cohorts were 1.5 × 10(-4) (odds ratio [OR] = 1.30) and 2.9 × 10(-3) (OR = 1.39). After Bonferroni correction, the association of SNP rs1536482 remained significant (P = 6.5 × 10(-3)).SNPs in the COL5A1 region, which regulate normal variation in CCT, may play a role in the thinning associated with keratoconus.

SUBMITTER: Li X

PROVIDER: S-EPMC3630822 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Genetic association of COL5A1 variants in keratoconus patients suggests a complex connection between corneal thinning and keratoconus.

Li Xiaohui X Bykhovskaya Yelena Y Canedo Ana Laura Caiado AL Haritunians Talin T Siscovick David D Aldave Anthony J AJ Szczotka-Flynn Loretta L Iyengar Sudha K SK Rotter Jerome I JI Taylor Kent D KD Rabinowitz Yaron S YS

Investigative ophthalmology & visual science 20130412 4

<h4>Purpose</h4>Single nucleotide polymorphisms (SNPs) located near or within the COL5A1 gene, at 9q34.2-q34.3 chromosomal region have been reported in association with central corneal thickness (CCT). Using family linkage analysis, we identified a keratoconus susceptibility locus at 9q34. These findings led us to perform an association study between COL5A1 variation and keratoconus susceptibility.<h4>Methods</h4>A Caucasian case-control cohort of 222 keratoconus patients and 3324 controls was s ...[more]

PMID: 23513063

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Project description:ImportanceKeratoconus is an important cause of visual loss in young adults, but little is known about its genetic causes. Understanding the genetic determinants of corneal biomechanical factors may in turn teach us about keratoconus etiology.ObjectivesTo identify genetic associations with corneal biomechanical properties and to examine whether these genetic variants are associated with keratoconus.Design, setting, and participantsA stage 1 discovery and replication genome-wide association study (GWAS) of corneal biomechanical properties was performed in 2 cross-sectional populations (6645 participants from the European Prospective Investigation into Cancer and Nutrition [EPIC]-Norfolk Eye Study and 2384 participants from the TwinsUK study). In stage 2, the association of genetic determinants identified in stage 1 with keratoconus was examined in a case-control study. A total of 752 patients with keratoconus were compared with 974 TwinsUK participants (undergoing direct sequencing) or 13 828 EPIC-Norfolk participants (undergoing genotyping and imputation) who were not part of the stage 1 analysis. Data were collected from March 1, 1993, through March 13, 2017, and analyzed from November 1, 2015, through February 1, 2018.ExposuresIn stage 1, allele dosage at genome-wide single-nucleotide polymorphisms (SNPs); in stage 2, allele dosage at SNPs with genome-wide significance (P < 5 × 10-8) in stage 1 and not previously reported as associated with corneal disease.Main outcomes and measuresIn stage 1, corneal hysteresis (CH) and corneal resistance factor (CRF), measured with the Ocular Response Analyzer (ORA); in stage 2, association with keratoconus compared with controls.ResultsAmong 6645 participants in the discovery cohort (3635 women (54.7%); mean age, 69 years [range, 48-92 years]), 7 genome-wide significant loci associated with CH or CRF were identified that were independently replicated. Two further suggestive loci were identified after meta-analysis. To date, 5 of the identified loci, at ANAPC1, ADAMTS8, ADAMTS17, ABCA6, and COL6A1, have not previously been reported as associated with corneal disease. The ABCA6 locus (rs77542162) was associated with keratoconus using the TwinsUK (odds ratio [OR], 0.50; 95% CI, 0.27-0.92; P = .03) and EPIC-Norfolk controls (OR, 0.39; 95% CI, 0.22-0.70; P = .002). The other loci were associated with keratoconus using TwinsUK (OR per effect allele for ADAMTS8, 0.51 [95% CI, 0.37-0.71; P = 7.9 × 10-5]; for COL6A1, 1.65 [95% CI, 1.05-2.59; P = .03]) or EPIC-Norfolk (OR per effect allele for ANAPC1, 0.78 [95% CI, 0.68-0.89; P = 3.7 × 10-4]; for ADAMTS17, 0.82 [95% CI, 0.68-0.99; P = .04]) controls.Conclusions and relevanceFive loci that are associated with corneal biomechanical properties and that have suggestive associations with keratoconus were reported. These findings suggest the role of type VI collagen, extracellular matrix, and connective-tissue development for corneal biomechanics and keratoconus and the role of CH and CRF as biomarkers for keratoconus.

Project description:ImportanceKeratoconus is a condition in which the cornea progressively thins and protrudes in a conical shape, severely affecting refraction and vision. It is a major indication for corneal transplant. To discover new genetic loci associated with keratoconus and better understand the causative mechanism of this disease, we performed a genome-wide association study on patients with keratoconus.ObjectiveTo identify genetic susceptibility regions for keratoconus in the human genome.Design, setting, and participantsThis study was conducted with data from eye clinics in Australia, the United States, and Northern Ireland. The discovery cohort of individuals with keratoconus and control participants from Australia was genotyped using the Illumina HumanCoreExome single-nucleotide polymorphism array. After quality control and data cleaning, genotypes were imputed against the 1000 Genomes Project reference panel (phase III; version 5), and association analyses were completed using PLINK version 1.90. Single-nucleotide polymorphisms with P?<?1.00?×?10-6 were assessed for replication in 3 additional cohorts. Control participants were drawn from the cohorts of the Blue Mountains Eye Study and a previous study of glaucoma. Replication cohorts were from a previous keratoconus genome-wide association study data set from the United States, a cohort of affected and control participants from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. Data were collected from January 2006 to March 2019.Main outcomes and measuresAssociations between keratoconus and 6?252?612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components.ResultsThe discovery cohort included 522 affected individuals and 655 control participants, while the replication cohorts included 818 affected individuals (222 from the United States, 331 from Australia and Northern Ireland, and 265 from Victoria, Australia) and 3858 control participants (2927 from the United States, 229 from Australia and Northern Ireland, and 702 from Victoria, Australia). Two novel loci reached genome-wide significance (defined as P?<?5.00?×?10-8), with a P value of 7.46?×?10-9 at rs61876744 in patatin-like phospholipase domain-containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35?×?10-12 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (CSNK1E) on chromosome 22. One additional locus was identified with a P value less than 1.00?×?10-6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P?=?3.91?×?10-7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P?=?2.45?×?10-8).Conclusions and relevanceIn this relatively large keratoconus genome-wide association study, we identified a genome-wide significant locus for keratoconus in the region of PNPLA2 on chromosome 11.

Project description:ObjectiveThe study aimed to evaluate the character of corneal stiffness parameter at the first applanation (SP-A1) in normal and keratoconus eyes and explore the association between SP-A1 and keratoconus severity indicators.MethodsA total of 351 normal and 351 keratoconus eyes were included in the current study. Keratoconus was diagnosed according to the corneal topography map and slit-lamp examination. The severity of keratoconus was classified to mild (steep keratometry (Ks) < 48D), moderate (48 ≤ Ks < 55D), and severe (Ks ≥ 55D). The SP-A1 was measured using the Corvis ST software. The correlation analyses and receiver operating characteristic (ROC) curve were performed in the current analysis.ResultsThe SP-A1 values of keratoconus were lower than that of normal eyes (72.11 (57.02, 83.08) mmHg/mm vs 110.89 (100.45, 122.47) mmHg/mm, P < 0.001). With the severity of keratoconus increasing, the SP-A1 decreased and the value of SP-A1 was 79.54 (70.30, 90.93) mmHg/mm, 65.11 (53.14, 77.46) mmHg/mm, and 47.59 (37.50, 62.14) mmHg/mm in mild, moderate, and severe keratoconus eyes, respectively (P < 0.001). The negative association between SP-A1 and Ks was found in mild, moderate, and severe keratoconus eyes (r mild = -0.171, r moderate = -0.317, r severe = -0.288, all P < 0.05). A positive association between SP-A1 and the thinnest corneal thickness (TCT) was found in all eyes (rnormal = 0.687, r mild = 0.519, r moderate = 0.488, r severe = 0.382, all P < 0.05). SP-A1 was found to be statistically positively associated with intraocular pressure (IOP), biomechanical corrected IOP (bIOP), time from the initiation of air puff until the first applanation (A1T), corneal velocity at the second applanation (A2V), and negatively associated with deformation amplitude (DA), peak distance (PD), corneal velocity at the first applanation (A1V), time from the initiation of air puff until the second applanation (A2T), and DA Ratio Max [2 mm] both in normal and keratoconus eyes (all P < 0.05). The ROC analysis indicated that the AUC (95% CI) of SP-A1 was 0.952 (0.934-0.967) and 0.930 (0.904-0.951) in detecting keratoconus eyes and mild keratoconus eyes from normal eyes, respectively.ConclusionsThe SP-A1 value decreased while the keratoconus severity increased. It was lower in keratoconus than that in normal eyes and could be helpful in identifying keratoconus eyes from normal eyes. Further researches would be warranted to expand the clinical utility of SP-A1.

Project description:To report the in vivo laser confocal microscopy findings of corneas with keratoconus, with special attention to abnormality of Bowman's layer and sub-Bowman's fibrous structures (Kobayashi-structures [K-structures]).Sixteen keratoconic eyes in 8 consecutive patients with keratoconus (4 males, 4 females, mean age, 41.1 years) were included in this study. Slit-lamp biomicroscopic photos were taken with or without fluorescein staining. The existence of anterior corneal mosaic (ACM) after eyelid rubbing under fluorescein staining was documented. In vivo laser confocal microscopic examinations were performed for all patients in both the central cone and the peripheral cornea to examine the existence of K-structures.According to the Amsler-Krumeich scale, the eyes were graded as follows: stage 1 (n=3), stage 2 (n=1), stage 3 (n=1), and stage 4 (n=11). ACM was observed in 7 eyes (61.1%) in the cone area and 16 eyes (100%) in the peripheral cornea among all keratoconic eyes enrolled in this study. In addition, K-structures were observed in the 7 eyes (61.1%) and 16 eyes (100%) in the peripheral cornea among all keratoconic eyes. The presence of the K-structures was completely matched (100%) with the presence of ACM in both the central cone and the peripheral cornea. In 11 eyes with stage 4 keratoconus, ACM and K-structure was absent in 9 eyes (81.8%) in the cone area. On the contrary, in 5 eyes with mild-to-moderate keratoconus (grade 1 to 3), ACM and K-structure was present in all eyes (100%) in the cone area. The absent ratio of ACM and K-structures in the cone area was significantly higher in stage 4 severe keratoconus compared to mild-to-moderate keratoconus (grade 1 to 3) (Fisher, P=0.005).The existence of ACM and K-structures in both the central cone and the peripheral cornea showed perfect accord in patients with keratoconus, indicating a strong association of ACM and K-structures in patients with keratoconus. With the progress of the keratoconus, it seemed that ACM and K-structure progressively disappeared, suggesting Bowman's layer abnormalities due to keratoconus. Further study in larger groups of patients with keratoconus is required to fully understand the significance of ACM/K-structures in keratoconic eyes and their association with Bowman's layer.

Dataset Information

Genetic association of COL5A1 variants in keratoconus patients suggests a complex connection between corneal thinning and keratoconus.

Publications

Genetic association of COL5A1 variants in keratoconus patients suggests a complex connection between corneal thinning and keratoconus.

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