A missense variant in CST3 exerts a recessive effect on susceptibility to age-related macular degeneration resembling its association with Alzheimer’s disease

Abstract

Age-related macular degeneration (AMD) and Alzheimer’s disease (AD) are degenerative, multifactorial diseases involving age-related accumulation of extracellular deposits linked to dysregulation of protein homeostasis. Here, we strengthen the evidence that an nsSNP (p.Ala25Thr) in the cysteine proteinase inhibitor cystatin C gene CST3, previously confirmed by meta-analysis to be associated with AD, is associated with exudative AMD. To our knowledge, this is the first report highlighting a genetic variant that increases the risk of developing both AD and AMD. Furthermore, we demonstrate that the risk associated with the mutant allele follows a recessive model for both diseases. We perform an AMD-CST3 case–control study genotyping 350 exudative AMD Caucasian individuals. Bringing together our data with the previously reported AMD-CST3 association study, the evidence of a recessive effect on AMD risk is strengthened (OR = 1.89, P = 0.005). This effect closely resembles the AD-CST3 recessive effect (OR = 1.73, P = 0.005) previously established by meta-analysis. This resemblance is substantiated by the high correlation between CST3 genotype and effect size across the two diseases (R2 = 0.978). A recessive effect is in line with the known function of cystatin C, a potent enzyme inhibitor. Its potency means that, in heterozygous individuals, a single functional allele is sufficient to maintain its inhibitory function; only homozygous individuals will lack this form of proteolytic regulation. Our findings support the hypothesis that recessively acting variants account for some of the missing heritability of multifactorial diseases. Replacement therapy represents a translational opportunity for individuals homozygous for the mutant allele.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-015-1552-7) contains supplementary material, which is available to authorized users.

Investigating APOE, APP-Aβ metabolism genes and Alzheimer’s disease GWAS hits in brain small vessel ischemic disease

“…In addition, we report a common polymorphism in CST3 (p.A25T), whose homozygous carrier frequency was significantly higher compared to HEX controls (4.16% and 1.63%, respectively). Interestingly, this polymorphism has been already associated to macular degeneration and LOAD 40 . The presence of one or two minor alleles increases LOAD risk and lowered the age at onset, in a fashion described both independent and dependent from APOE ε4 allele 39,53 .…”

“…Importantly, homozygosity for CST3 p.A25T has been significantly associated with AD 39 and other neurodegenerative conditions such as macular degeneration 40 . In our cohort, we report 4/96 [4.16%] patients homozygous for the minor allele A, a carrier frequency which was 2.55 times higher when compared with HEX controls (6/368 [1.63%]).…”

Unraveling the genes implicated in Alzheimer's disease

“…In addition, the authors revealed that reduced levels of CST3 may impair the neuronal ability to prevent neurodegeneration in AD (105). Recently, Butler et al (106) found that a missense variant in CST3 rs1064039 was associated with age-associated macular degeneration and AD.…”

Associations of Alzheimer rsquo s disease with macular degeneration

“…year later, CST3, previously confirmed by meta-analysis to be associated with AD, has been found to be associated also with exudative AMD (40). Finally, a study by Hoffman and colleagues tried to search for a possible correlation with AMD progression, defined by using drusen number and total area, and a set of selected genetic loci, but they failed to find any significant correlation (41).…”