Dataset Information

Matrix metalloproteinases and educational attainment in refractive error: evidence of gene-environment interactions in the Age-Related Eye Disease Study.

ABSTRACT:

Purpose

A previous study of Old Order Amish families showed an association of ocular refraction with markers proximal to matrix metalloproteinase (MMP) genes MMP1 and MMP10 and intragenic to MMP2. A candidate gene replication study of association between refraction and single nucleotide polymorphisms (SNPs) within these genomic regions was conducted.

Design

Candidate gene genetic association study.

Participants

Two thousand participants drawn from the Age-Related Eye Disease Study (AREDS) were chosen for genotyping. After quality-control filtering, 1912 individuals were available for analysis.

Methods

Microarray genotyping was performed using the HumanOmni 2.5 bead array (Illumina, Inc., San Diego, CA). Single nucleotide polymorphisms originally typed in the previous Amish association study were extracted for analysis. In addition, haplotype tagging SNPs were genotyped using TaqMan assays. Quantitative trait association analyses of mean spherical equivalent refraction were performed on 30 markers using linear regression models and an additive genetic risk model while adjusting for age, sex, education, and population substructure. Post hoc analyses were performed after stratifying on a dichotomous education variable. Pointwise (P(emp)) and multiple-test study-wise (P(multi)) significance levels were calculated empirically through permutation.

Main outcome measures

Mean spherical equivalent refraction was used as a quantitative measure of ocular refraction.

Results

The mean age and ocular refraction were 68 years (standard deviation [SD], 4.7 years) and +0.55 diopters (D; SD, 2.14 D), respectively. Pointwise statistical significance was obtained for rs1939008 (P(emp) = 0.0326). No SNP attained statistical significance after correcting for multiple testing. In stratified analyses, multiple SNPs reached pointwise significance in the lower-education group: 2 of these were statistically significant after multiple testing correction. The 2 highest-ranking SNPs in Amish families (rs1939008 and rs9928731) showed pointwise P(emp)<0.01 in the lower-education stratum of AREDS participants.

Conclusions

This study showed suggestive evidence of replication of an association signal for ocular refraction to a marker between MMP1 and MMP10. Evidence of a gene-environment interaction between previously reported markers and education on refractive error also was shown. Variants in MMP1 through MMP10 and MMP2 regions seem to affect population variation in ocular refraction in environmental conditions less favorable for myopia development.

SUBMITTER: Wojciechowski R

PROVIDER: S-EPMC3563738 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Publications

Matrix metalloproteinases and educational attainment in refractive error: evidence of gene-environment interactions in the Age-Related Eye Disease Study.

Wojciechowski Robert R Yee Stephanie S SS Simpson Claire L CL Bailey-Wilson Joan E JE Stambolian Dwight D

Ophthalmology 20121023 2

<h4>Purpose</h4>A previous study of Old Order Amish families showed an association of ocular refraction with markers proximal to matrix metalloproteinase (MMP) genes MMP1 and MMP10 and intragenic to MMP2. A candidate gene replication study of association between refraction and single nucleotide polymorphisms (SNPs) within these genomic regions was conducted.<h4>Design</h4>Candidate gene genetic association study.<h4>Participants</h4>Two thousand participants drawn from the Age-Related Eye Diseas ...[more]

PMID: 23098370

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Project description:Importance:Uncorrected refractive error (RE) is a leading cause of visual impairment, and variations in ocular anatomy determine RE. The unique ocular determinants of RE in Chinese American individuals have not been studied previously. Objective:To report ocular determinants of RE in a Chinese American population 50 years and older in Monterey Park, California. Design, Setting, and Participants:The Chinese American Eye Study, a population-based, cross-sectional study, was conducted from February 1, 2010, through October 31, 2013, in Monterey Park, with this particular data analysis performed from January 1 through December 31, 2016. This study included data from 4582 participants who underwent an eye examination to obtain axial length (AL), central corneal thickness, vitreous chamber depth (VCD), anterior chamber depth (ACD), lens thickness (LT), corneal power (CP), noncycloplegic subjective refraction, and lens nuclear opalescence (NOP) grading. Data from the right phakic eye of each participant were used. Multiple regression models (standardized regression coefficients [SRCs] and semipartial correlation coefficients squared [SPCCs2]) identified key determinants of RE. Main Outcomes and Measures:Ocular determinants of RE. Results:Among the 4071 participants eligible for analysis (1496 men [36.7%] and 2575 women [63.3%]; mean [SD] age, 60.5 [8.1] years), mean (SD) RE was -0.52 (2.95) diopters (D), with no sex-related difference. A hyperopic shift occurred in women from -0.62 (2.95) D at 50 to 59 years to 0.60 (1.62) D at 80 years or older and in men from -0.69 (3.00) D at 50 to 59 years to 0.40 (2.29) D at 80 years or older (P < .001 for both). Compared with men, women had shorter AL (mean [SD], 23.62 [1.34] vs 24.14 [1.27] mm; P = .006), shorter ACD (mean [SD], 3.33 [0.34] vs 3.44 [0.34] mm; P < .001), and steeper CP (mean [SD], 43.50 [1.52] vs 42.88 [1.45] D; P = .02), after adjusting for age and height. No sex differences were found in VCD, LT, and NOP after height adjustment. Compared with younger individuals, older individuals had shallower ACD, thicker LT, and more NOP compared with younger individuals (P < .001 for both), even after adjustment for height. Axial length was the strongest determinant of RE (SRC = -0.92; SPCC2 = 0.55), followed by CP (SRC = -0.43; SPCC2 = 0.15). When individual components of AL were evaluated, VCD had the greatest contributing effect (SRC = -0.99; SPCC2 = 0.52), followed by CP (SRC = -0.47; SPCC2 = 0.15) and LT (SRC = -0.29; SPCC2 = 0.06). Conclusions and Relevance:These data suggest that Chinese American individuals have longer AL and greater contribution of AL to RE than do Latino and other Chinese populations. Future studies should explore risk factors for increased AL in Chinese Americans and potential interventions that may ultimately prevent myopia-related disease.

Project description:Refractive error is a complex trait with multiple genetic and environmental risk factors, and is the most common cause of preventable blindness worldwide. The common nature of the trait suggests the presence of many genetic factors that individually may have modest effects. To achieve an adequate sample size to detect these common variants, large, international collaborations have formed. These consortia typically use meta-analysis to combine multiple studies from many different populations. This approach is robust to differences between populations; however, it does not compensate for the different haplotypes in each genetic background evidenced by different alleles in linkage disequilibrium with the causative variant. We used the Age-Related Eye Disease Study (AREDS) cohort to replicate published significant associations at two loci on chromosome 15 from two genome-wide association studies (GWASs). The single nucleotide polymorphisms (SNPs) that exhibited association on chromosome 15 in the original studies did not show evidence of association with refractive error in the AREDS cohort. This paper seeks to determine whether the non-replication in this AREDS sample may be due to the limited number of SNPs chosen for replication.We selected all SNPs genotyped on the Illumina Omni2.5v1_B array or custom TaqMan assays or imputed from the GWAS data, in the region surrounding the SNPs from the Consortium for Refractive Error and Myopia study. We analyzed the SNPs for association with refractive error using standard regression methods in PLINK. The effective number of tests was calculated using the Genetic Type I Error Calculator.Although use of the same SNPs used in the Consortium for Refractive Error and Myopia study did not show any evidence of association with refractive error in this AREDS sample, other SNPs within the candidate regions demonstrated an association with refractive error. Significant evidence of association was found using the hyperopia categorical trait, with the most significant SNPs rs1357179 on 15q14 (p=1.69×10?³) and rs7164400 on 15q25 (p=8.39×10??), which passed the replication thresholds.This study adds to the growing body of evidence that attempting to replicate the most significant SNPs found in one population may not be significant in another population due to differences in the linkage disequilibrium structure and/or allele frequency. This suggests that replication studies should include less significant SNPs in an associated region rather than only a few selected SNPs chosen by a significance threshold.

Dataset Information

Matrix metalloproteinases and educational attainment in refractive error: evidence of gene-environment interactions in the Age-Related Eye Disease Study.

Purpose

Design

Participants

Methods

Main outcome measures

Results

Conclusions

Publications

Matrix metalloproteinases and educational attainment in refractive error: evidence of gene-environment interactions in the Age-Related Eye Disease Study.

Similar Datasets

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