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G. Jun, B. E. K. Klein, R. Klein, T. Joshi, J. Capriotti, K. E. Lee, S. K. Iyengar; Lengsin Is Associated With Age-Related Cortical and Posterior Subcapsular Cataracts. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5450.
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Lengsin (GLULD1) is one of the most abundant RNA transcripts with almost exclusive expression in the lens. It shows a 52-fold under expression in age-related cataract compared with the normal lens, but has not been examined for association or linkage. Lengsin is under our most significant linkage region (6q12) in both cortical (CC) and posterior subcapsular cataract (PSC) genome scans. We investigated association with both cataracts using the Beaver Dam Eye Study (BDES).
We selected four SNPs in GLULD1 and six SNPs in genes flanking GLULD1 for genotyping in a subset of the BDES (325 individuals from 102 pedigrees). Only SNPs in GLULD1 showed significant association and led to a reduction in the linkage signal on 6q12 using the associated SNPs as covariates. These SNPs were followed up in all related individuals from BDES (2268 individuals in 626 pedigrees). The cataracts were graded from photographs taken with dilated pupils, and the percent of the lens surface as well as a central circle area affected was reported. We used three quantitative traits after adjusting for covariates: % of lens surface with cortical cataract (CC), % of center circle with PSC (CPSC), and % of lens surface with PSC (LPSC). We performed family-based association analyses using ASSOC (S.A.G.E.). Pairwise linkage disequilibrium (D’) was estimated from the full BDES data using HAPFREQ in FBAT.
Pairwise D’ among the genotyped SNPs in GLULD1 is > 0.90 in our data similar to HapMap. The most significant association using the dominant model was identified with SNP rs9343928 (CC: p=7.7x10-4; CPSC: p=3.8x10-10; LPSC: p=2.5x10-6). Other SNPs in GLULD1 showed the similar results.
GLULD1 accounts for the linkage on 6q12, and SNPs in this gene are significantly associated with both CC and PSC. Previous expression results and our evidence for association support it as being an important lens protein mediating age-related cataractogenesis.
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