Exclusion of TIMP3 as a Candidate Locus in Age-related Macular Degeneration

Paz, Monica A. De La; Pericak‐Vance, Margaret A.; Lennon, Felicia; Haines, J. L.; Seddon, J.M.

doi:10.1097/00006982-199818020-00025

Cited by 32 publications

(32 citation statements)

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“…Our study of the TIMP3 locus and AMD in 1997, inspired by the association of this gene to Sorsby fundus dystrophy that has similar phenotypic features to advanced AMD, did not find evidence of association or linkage between AMD and TIMP3 among 38 AMD families. However, as we stated, "the possibility that a subset of cases could be caused by the TIMP3 locus could not be ruled out" by this relatively small study (28).…”

Section: −9mentioning

confidence: 79%

Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene ( LIPC )

Neale

Fagerness

Reynolds

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

422

381

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Advanced age-related macular degeneration (AMD) is the leading cause of late onset blindness. We present results of a genome-wide association study of 979 advanced AMD cases and 1,709 controls using the Affymetrix 6.0 platform with replication in seven additional cohorts (totaling 5,789 unrelated cases and 4,234 unrelated controls). We also present a comprehensive analysis of copy-number variations and polymorphisms for AMD. Our discovery data implicated the association between AMD and a variant in the hepatic lipase gene (LIPC) in the high-density lipoprotein cholesterol (HDL) pathway (discovery P = 4.53e-05 for rs493258). Our LIPC association was strongest for a functional promoter variant, rs10468017, (P = 1.34e-08), that influences LIPC expression and serum HDL levels with a protective effect of the minor T allele (HDL increasing) for advanced wet and dry AMD. The association we found with LIPC was corroborated by the Michigan/ Penn/Mayo genome-wide association study; the locus near the tissue inhibitor of metalloproteinase 3 was corroborated by our replication cohort for rs9621532 with P = 3.71e-09. We observed weaker associations with other HDL loci (ABCA1, P = 9.73e-04; cholesterylester transfer protein, P = 1.41e-03; FADS1-3, P = 2.69e-02). Based on a lack of consistent association between HDL increasing alleles and AMD risk, the LIPC association may not be the result of an effect on HDL levels, but it could represent a pleiotropic effect of the same functional component. Results implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD.A ge-related macular degeneration (AMD) is a common, lateonset neurodegenerative disorder that is modified by covariates including smoking and body mass index, and it has a 3-to 6-fold higher recurrence ratio in siblings than in the general population (1). The burden of AMD is increasing among the growing elderly population. The advanced form of AMD is clinically significant, and it causes visual loss and reduces quality of life.

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Section: −9mentioning

confidence: 79%

Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene ( LIPC )

Neale

Fagerness

Reynolds

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

422

381

View full text Add to dashboard Cite

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“…Despite the similarities between Sorsby fundus dystrophy and AMD, there are differences (eg, younger age of CNV development in the former), and TIMP-3 mutations do not seem to cause AMD. 247,248 Although lysosomal storage diseases due to single gene defects in metabolism are characterized by accumulations of intracellular material in the RPE, their resemblance to AMD is modest. 249 Cai and coworkers 79 noted that Cockayne syndrome may be a more relevant disease model.…”

Section: Role Of Geneticsmentioning

confidence: 99%

Current Concepts in the Pathogenesis of Age-Related Macular Degeneration

Zarbin¹

2004

Arch Ophthalmol

916

697

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To review and synthesize information concerning the pathogenesis of age-related macular degeneration (AMD).Methods: Review of the English-language literature.Results: Five concepts relevant to the cell biology of AMD are as follows: (1) AMD involves aging changes plus additional pathological changes (ie, AMD is not just an aging change); (2) in aging and AMD, oxidative stress causes retinal pigment epithelial (RPE) and, possibly, choriocapillaris injury; (3) in AMD (and perhaps in aging), RPE and, possibly, choriocapillaris injury results in a chronic inflammatory response within the Bruch membrane and the choroid; (4) in AMD, RPE and, possibly, choriocapillaris injury and inflammation lead to formation of an abnormal extracellular matrix (ECM), which causes altered diffusion of nutrients to the retina and RPE, possibly precipitating further RPE and retinal damage; and(5) the abnormal ECM results in altered RPE-choriocapillaris behavior leading ultimately to atrophy of the retina, RPE, and choriocapillaris and/or choroidal new vessel growth. In this sequence of events, both the environment and multiple genes can alter a patient's susceptibility to AMD. Implicit in this characterization of AMD pathogenesis is the concept that there is linear progression from one stage of the disease to the next. This assumption may be incorrect, and different biochemical pathways leading to geographic atrophy and/or choroidal new vessels may operate simultaneously.Conclusions: Better knowledge of AMD cell biology will lead to better treatments for AMD at all stages of the disease. Many unanswered questions regarding AMD pathogenesis remain. Multiple animal models and in vitro models of specific aspects of AMD are needed to make rapid progress in developing effective therapies for different stages of the disease.

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“…Besides one sequence variation found in one patient with AMD, no other disease-causing mutations have been detected in this gene (Felbor et al, 1997). Familial linkage studies have also failed to implicate TIMP3 in AMD (De La Paz et al, 1997). Although no association has been established between AMD and the TIMP3 gene variations, it may be possible that a variation within the genes that regulate TIMP3 translation causes the observed protein-level elevation.…”

Section: Amd-related Snps In Genes Associated With Monogenic Macular mentioning

confidence: 99%

Genetic factors of age-related macular degeneration

Tuo

Bojanowski

Chan

2004

Progress in Retinal and Eye Research

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Age-related macular degeneration (AMD) is a leading cause of blindness in the United States and developed countries. Although the etiology and pathogenesis of AMD remain unknown, a complex interaction of genetic and environmental factors is thought to exist. The incidence and progression of all of the features of AMD are known to increase significantly with age. The tendency for familial aggregation and the findings of gene variation association studies implicate a significant genetic component in the development of AMD. This review summarizes in detail the AMD-related genes identified by studies on genetically engineered and spontaneously gene-mutated (naturally mutated) animals, AMD chromosomal loci identified by linkage studies, AMD-related genes identified through studies of monogenic degenerative retinal diseases, and AMD-related gene variation identified by association studies.

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Exclusion of TIMP3 as a Candidate Locus in Age-related Macular Degeneration

Cited by 32 publications

References 0 publications

Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene ( LIPC )

Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene ( LIPC )

Current Concepts in the Pathogenesis of Age-Related Macular Degeneration

Genetic factors of age-related macular degeneration

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