ABSTRACT: Age-related macular degeneration (AMD) is a retinal degenerative disease that is the leading cause of blindness worldwide for individuals over the age of 60. Although the etiology of AMD remains largely unknown, numerous studies have suggested that both genes and environmental risk factors significantly influence the risk of developing AMD. Identification of the underlying genes has been difficult, with both genomic screen (locational) and candidate gene (functional) approaches being used. The present study tested candidate genes for association with AMD.
Eight genes (alpha-2-macroglobulin [A2M], creatine kinase [CKB], angiotensin-converting enzyme [DCP1], interleukin-1alpha [IL1A], low-density lipoprotein receptor-related protein 6 [LRP6], microsomal glutathione-S-transferase 1 [MGST1], vascular entothelial growth factor [VEGF], and very low density lipoprotein receptor [VLDLR]) were tested for genetic linkage and allelic association, using two independent datasets: a family-based association dataset including 162 families and an independent case-control dataset with 399 cases and 159 fully evaluated controls.
Test results suggested that genetic variation in five of these genes (IL1A, CKB, A2M, MGST1, and DCP1) is unlikely to explain a significant fraction of the risk of developing AMD in this population. LRP6 showed evidence both for linkage (heterogeneity lod [HLOD] = 1.14) in the family-based dataset and for association (P = 0.004) in the case-control dataset. VEGF showed evidence of linkage (HLOD = 1.32) and demonstrated significant independent allelic association in both the family-based (P = 0.001) and case-control (P = 0.02) datasets. VLDLR showed evidence of association in both the family based (P = 0.03) and case-control (P = 0.01) datasets.
These data suggest that LRP6, VEGF, and VLDLR may play a role in the risk of developing AMD.
Investigative Ophthalmology & Visual Science 02/2006; 47(1):329-35. · 3.60 Impact Factor
ABSTRACT: We and others have previously detected association of the Tau H1 haplotype on chromosome 17 with risk of idiopathic Parkinson disease (PD). The H1 haplotype appears to have a fundamental importance in neurodegeneration, as multiple studies have shown it is also associated with an increased risk for progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration syndromes, and primary progressive aphasia. Therefore, to divide the H1 haplotype into sub-haplotypes that could be more significantly associated with the risk of developing PD, and to delimit the genes lying in the H1 haplotype, we analyzed 34 single nucleotide polymorphisms (SNPs) spanning over 3.15 megabases in the region containing Tau. These SNPs are located in or flank the corticotropin-releasing hormone receptor 1, presenilin homolog 2, Tau, Saitohin, and KIAA1267 genes. Analysis of linkage disequilibrium (LD) using these 34 SNPs suggests that the H1 haplotype extends over about 1.3 megabases, making it the largest region of LD reported to date. Of the 29 SNPs lying in this region of LD, 5 were identified as "haplotype tagging" SNPs (htSNPs), capturing 96% of the sample's haplotype diversity. Association analysis with these htSNPs revealed a new H1 sub-haplotype that is significantly associated with PD ( P<0.02). These results define the genes and regulatory regions included in this region of LD, containing an important susceptibility allele contributing to increased risk of neurodegeneration.
Neurogenetics 10/2004; 5(3):147-55. · 3.35 Impact Factor
ABSTRACT: To determine whether mutations in the optineurin gene contribute to susceptibility to adult-onset primary open-angle glaucoma.
The optineurin gene was screened in 86 probands with adult-onset primary open-angle glaucoma and in 80 age-matched control subjects. Exons 4 and 5, containing the recurrent mutations identified in patients with normal-tension glaucoma, were sequenced in all individuals studied, while the remaining exons were screened for DNA sequence variants with denaturing high-performance liquid chromatography.
The recurrent mutation, Met98Lys, previously found to be associated with an increased risk of disease was found in 8 (9%) of 86 probands. We also found the Met98Lys mutation in 10% of individuals from a control population of similar age, sex, and ethnicity. Consistent segregation of the mutation with the disease was not demonstrated in any of the 8 families. No other DNA changes altering the amino acid structure of the protein were found.
The mutations in the optineurin gene associated with normal-tension glaucoma are not associated with adult-onset primary open-angle glaucoma in this patient population. Clinical Relevance Genetic abnormalities that render the optic nerve susceptible to degeneration are excellent candidates for genetic factors that could contribute to adult-onset primary open-angle glaucoma. Mutations in optineurin have been associated with normal-tension glaucoma, but are not associated with disease in patients with adult-onset primary open-angle glaucoma. This result may indicate that normal-tension glaucoma is not necessarily part of the phenotypic spectrum of adult open-angle glaucoma.
Archives of Ophthalmology 09/2003; 121(8):1181-3. · 3.71 Impact Factor