Association of clusterin (CLU) variants and exfoliation syndrome: An analysis in two Caucasian studies and a meta-analysis

Abstract

Exfoliation syndrome (XFS) is an important risk factor for glaucoma (XFG) worldwide. LOXL1 variants are highly associated with XFS in most populations; however, the high frequency of risk alleles in normal individuals and the reversal of risk alleles in different ethnic populations suggest that other factors contribute to XFS pathogenesis. Clusterin (CLU) is an extracellular matrix chaperone that prevents protein aggregation and is highly expressed in ocular tissues affected by XFS. Studies examining common CLU variants for association with XFS have been inconsistent. The purpose of this study was to evaluate CLU variants for association with XFS in two independent datasets from the United States (222 cases and 344 controls) and Israel (92 cases and 102 controls). Seven tag SNPs that captured >95% of alleles at r2 greater than 0.8 across the CLU genomic region were genotyped using TaqMan assays. Genotypes for an additional SNP, rs2279590, were imputed using phased haplotypes of HapMap reference CEU samples. Of the 8 CLU SNPs selected for the study, none were significantly associated with XFS in either case-control group (age and sex adjusted P > 0.14 and 0.36, respectively, in the US and Israeli datasets), or when they were meta-analyzed together (age and sex adjusted P > 0.13). Haplotype analysis using all 8 SNPs or only the promoter region SNPs also did not show significant associations of CLU with XFS in the combined US and Israeli dataset (P > 0.28). Meta-analysis of the data from this study and previous studies in Caucasian populations (1,184 cases and 978 controls) resulted in statistically significant association of rs2279590 with XFS (summary OR = 1.18, 95% CI: 1.03-1.33, P = 0.01). Significant association between rs2279590 and XFS was also found in Indian populations (summary OR = 0.76, 95% CI: 0.61-0.96; P = 0.02); however, significant heterogeneity between the Caucasian and Indian populations possibly due to reversal of the risk allele precluded an overall meta-analysis for rs2279590 (Q = 0.001, I2 = 91%). No significant association was identified for rs3087554 in either Caucasian populations (summary OR = 0.90, 95% CI: 0.77-1.05, P = 0.17) or Indian populations (summary OR = 0.89, 95% CI: 0.72-1.10, P = 0.28), or in both populations combined (1,705 cases and 3,713 controls; summary OR = 0.90, 95% CI: 0.79-1.01, P = 0.08). Significant heterogeneity precluded the addition of the Japanese data to the meta-analysis for rs3087554 (Q = 0.006, I2 = 87%). Our results suggest that common CLU variants may contribute to modest XFS risk but even larger datasets are required to confirm these findings.

Recent advances in risk factors associated with ocular exfoliation syndrome

“…Although clusterin is over-expressed in various stress and pathological conditions, it is downregulated in the anterior chamber of the exfoliative eyes. This suggests the possible contribution of common CLU variants in exfoliation development (Calero et al 2000;Zenkel et al 2006;Magalhães & Saraiva 2011;Padhy et al 2014;Fan et al 2015;Stafiej et al 2017). A CLU SNP (rs3087554) was observed in an Australian population that was identified to be nominally associated with XFS.…”

Clusterin in the eye: An old dog with new tricks at the ocular surface

“…Two SNPs in LOXL1 confer a higher than 99% population attributable risk for PXG in the Nordic population, however, they carry different risks in other populations. Common CLU variants may contribute to modest PXG risk but larger datasets are required to confirm these findings [104].…”

Genetics, Diagnosis, and Monitoring of Pseudoexfoliation Glaucoma

“…Multiple studies have investigated the association of specific single-nucleotide polymorphisms in the clusterin gene with pseudoexfoliation syndrome and pseudoexfoliation glaucoma, but the results remain mixed, with association of certain SNPs in some populations but not others (7-9). …”