RESUMO
Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR(A allele) = 9.87, P = 2.13 × 10(-217); non-Japanese: OR(A allele) = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.
Assuntos
Canais de Cálcio/genética , Síndrome de Exfoliação/genética , Polimorfismo de Nucleotídeo Único , Animais , Povo Asiático/genética , Povo Asiático/estatística & dados numéricos , Estudos de Casos e Controles , Mapeamento Cromossômico , Síndrome de Exfoliação/epidemiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Glaucoma de Ângulo Aberto/epidemiologia , Glaucoma de Ângulo Aberto/genética , Células HEK293 , Células HeLa , Humanos , Japão/epidemiologia , Células MCF-7 , Camundongos , Camundongos Endogâmicos C57BL , Células Tumorais CultivadasRESUMO
PURPOSE: Pseudoexfoliation (PEX) syndrome, an age-related, systemic, elastic microfibrillopathy, is characterized by fibrillar-granular deposits in the anterior segment of the eye. Although not representing a true amyloidosis, PEX syndrome shares some features with amyloid disorders, such as Alzheimer disease. It has been shown that amyloid-associated proteins also occur in association with PEX fibrils. Apolipoprotein E (Apo-E) is directly involved in these amyloid deposition and fibrils formation. The ε4 allele of APOE gene was shown to be associated both with an increased risk for coronary heart disease and late-onset Alzheimer disease. In this study, we therefore investigated whether APOE alleles are associated with PEX syndrome and/or PEX glaucoma (PEXG) in 2 large cohorts of German and Italian origin. METHODS: The 3 common APOE alleles ε2, ε3, and ε4 were genotyped in 661 unrelated patients (459 PEXG and 202 PEX patients) and 342 healthy individuals of German origin and furthermore in 209 unrelated patients (133 PEXG and 76 PEX patients) and 190 healthy individuals of Italian origin using TaqMan assays for allelic discrimination. A genetic association study was then performed. RESULTS: The ε3 allele was found to be the most common in both populations (80% to 83%), whereas the ε2 allele was the rarest (6% to 9%). No significant differences in allele and genotype frequencies between both groups were observed in either population. CONCLUSION: Our data show that APOE genotypes are not associated with PEX and PEXG in either Germans or Italians.