Aims: To determine whether allelic variants of the cystatin C gene CST3 are genetically associated with exudative age related macular degeneration (ARMD). Cystatin C is a cysteine protease inhibitor that regulates the activity of cathepsin S, a protease with central regulatory functions in retinal pigment epithelial cells.
Methods: CST3 of 167 patients with exudative ARMD was genotyped by using polymerase chain reaction of genomic DNA and restriction enzyme digestion with KspI and compared with those of 517 control subjects. Patients and controls were white.
Results: There was a significant difference in genotype counts between patients and controls (chi(2) = 7.158, df = 2; Fisher's exact test: p = 0.037). There was no significant difference in allele frequencies between patients and controls and between controls from Germany, Switzerland, Italy, and United States. The significant difference in genotype counts between patients and controls could be explained completely by an excess of the homozygous CST3 genotype B/B in patients with exudative ARMD (6.6%) over controls (2.3%), suggesting an odds ratio for ARMD in association with CST3 B/B of 2.97 (95% CI: 1.28-6.86). The results also suggest a stronger association of B/B with ARMD in males than in females. However, in both males and females there was a similar and significant effect of CST3 B/B on disease free survival assessed by Kaplan-Meier analysis. The mean disease free survival time in pooled males and females with genotypes A/A or A/B was 85 years (SE 1; 95% CI: 83-86) and 76 years (SE 2; 95% CI: 72-79) respectively in B/B homozygotes (log rank p = 0.0006).
Conclusion: Genotyping data, the absence of a significant difference in allele frequencies between patients and controls, and survival analyses suggest an increased susceptibility for ARMD in CST3 B/B homozygotes. Therefore, CST3 B may be a recessive risk allele, significantly contributing to disease risk in up to 6.6% of German ARMD patients. Functional correlates of the allelic CST3 variants A and B remain to be investigated.