Association of Clusterin Variants and Exfoliation Syndrome: An Analysis in Two Caucasian Datasets and A Summary Meta-analysis

Abstract

Purpose: Exfoliation syndrome (XFS) is an important risk factor for glaucoma 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. To help clarify its relation to XFS, we evaluated common CLU variants for association with XFS in two independent Caucasian datasets from the United States (US) and Israel. Additionally, we performed a meta-analysis that included these two datasets as well as published results from Australia, Germany, Italy and India.

Methods: Seven tag SNPs that captured >95% of alleles at r² >0.8 across the CLU genomic region, including all exons, introns, 5’UTR, 3’UTR and the 7 kb proximal promoter region were genotyped by TaqMan assays in two datasets from the US (222 cases and 344 controls) and Israel (92 cases and 102 controls). Genotypes of an eighth SNP, rs2279590 were imputed using phased haplotypes of HapMap reference samples and MACH 1.0 software. The association analysis was performed using PLINK 1.07.

Results: None of the 8 CLU SNPs 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). Haplotype analysis using all 8 SNPs or only the promoter region SNPs did not show significant associations of CLU with XFS in either dataset (P > 0.05). Meta-analysis of the data from this study and previous studies in Caucasian populations also did not find significant associations of rs3087554 and rs2279590 with XFS (rs3087554: OR = 0.90, 95% CI: 0.77-1.05, P = 0.17; rs2279590: OR = 1.15, 95% CI: 0.98-1.35, P = 0.09); however, including an Indian dataset (1,406 cases and 3,489 controls in total) resulted in nominal association for rs3087554 (OR = 0.87, 95% CI: 0.76-1.00; P = 0.049), despite limited power to detect such a small genetic effect.

Conclusions: Our results suggest that a common CLU variant contributes to modest XFS risk but even larger datasets are required to confirm these findings.