The ABCA4 Gene and Age-Related Macular Degeneration

Gorin, Michael B.

doi:10.1001/archopht.119.5.752

Cited by 10 publications

(3 citation statements)

References 19 publications

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“…A number of genes implicated in other morphologically distinct forms of macular degeneration (Allikmets 1997b;De La Paz et al 1997;Rivera et al 2000;Gorin 2001;Guymer et al 2001Guymer et al , 2002Bernstein et al 2002) have been investigated in ARMD, but no consistent associations have emerged. More recently, several genomewide scans (Klein et al 1998a;Weeks et al 2000;Weeks et al 2001;Majewski et al 2003;Schick et al 2003) for ARMD have been conducted and analyzed using both model-free and model-based linkage methods.…”

Section: Introductionmentioning

confidence: 99%

Dissection of Genomewide-Scan Data in Extended Families Reveals a Major Locus and Oligogenic Susceptibility for Age-Related Macular Degeneration

Iyengar

Song

Klein

et al. 2004

The American Journal of Human Genetics

155

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To examine the genetic basis of age-related macular degeneration (ARMD), a degenerative disease of the retinal pigment epithelium and neurosensory retina, we conducted a genomewide scan in 34 extended families (297 individuals, 349 sib pairs) ascertained through index cases with neovascular disease or geographic atrophy. Family and medical history was obtained from index cases and family members. Fundus photographs were taken of all participating family members, and these were graded for severity by use of a quantitative scale. Model-free linkage analysis was performed, and tests of heterogeneity and epistasis were conducted. We have evidence of a major locus on chromosome 15q (GATA50C03 multipoint P=1.98x10-7; empirical P< or =1.0x10-5; single-point P=3.6x10-7). This locus was present as a weak linkage signal in our previous genome scan for ARMD, in the Beaver Dam Eye Study sample (D15S659, multipoint P=.047), but is otherwise novel. In this genome scan, we observed a total of 13 regions on 11 chromosomes (1q31, 2p21, 4p16, 5q34, 9p24, 9q31, 10q26, 12q13, 12q23, 15q21, 16p12, 18p11, and 20q13), with a nominal multipoint significance level of P< or =.01 or LOD > or =1.18. Family-by-family analysis of the data, performed using model-free linkage methods, suggests that there is evidence of heterogeneity in these families. For example, a single family (family 460) individually shows linkage evidence at 8 loci, at the level of P<.0001. We conducted tests for heterogeneity, which suggest that ARMD susceptibility loci on chromosomes 9p24, 10q26, and 15q21 are not present in all families. We tested for mutations in linked families and examined SNPs in two candidate genes, hemicentin-1 and EFEMP1, in subsamples (145 and 189 sib pairs, respectively) of the data. Mutations were not observed in any of the 11 exons of EFEMP1 nor in exon 104 of hemicentin-1. The SNP analysis for hemicentin-1 on 1q31 suggests that variants within or in very close proximity to this gene cause ARMD pathogenesis. In summary, we have evidence for a major ARMD locus on 15q21, which, coupled with numerous other loci segregating in these families, suggests complex oligogenic patterns of inheritance for ARMD.

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Section: Introductionmentioning

confidence: 99%

Dissection of Genomewide-Scan Data in Extended Families Reveals a Major Locus and Oligogenic Susceptibility for Age-Related Macular Degeneration

Iyengar

Song

Klein

et al. 2004

The American Journal of Human Genetics

155

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“…Accumulation of bisretinoids such as A2E is associated with AMD as well as STGD, and administration of exogenous A2E induces ocular changes similar to AMD and STGD in animal models ( 206 – 208 ). However, defining a causal link between ABCA4 mutations and AMD has proven more challenging, as some researchers find no association ( 209 , 210 ), perhaps due to genetic heterogeneity in the AMD phenotype, or incomplete penetrance of disease-causing alleles ( 211 ). An added complication lies in the comparable presentations of Stargardt’s and AMD, albeit usually in younger and older patients, respectively, with consensus favouring the role of ABCA4 as limited to Stargardt’s and related retinal dystrophies and mimicking, rather than causing AMD ( 211 , 212 ).…”

Section: Parainflammatory Degenerative Retinal Diseasementioning

confidence: 99%

“…However, defining a causal link between ABCA4 mutations and AMD has proven more challenging, as some researchers find no association ( 209 , 210 ), perhaps due to genetic heterogeneity in the AMD phenotype, or incomplete penetrance of disease-causing alleles ( 211 ). An added complication lies in the comparable presentations of Stargardt’s and AMD, albeit usually in younger and older patients, respectively, with consensus favouring the role of ABCA4 as limited to Stargardt’s and related retinal dystrophies and mimicking, rather than causing AMD ( 211 , 212 ). ABCA4 is nevertheless included in the EYE-RISK genotype assay for AMD, as retinal dystrophies are an important differential diagnosis in patients presenting with macular pathology ( 212 ).…”

Section: Parainflammatory Degenerative Retinal Diseasementioning

confidence: 99%

Vitamin A, systemic T-cells, and the eye: Focus on degenerative retinal disease

2022

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The first discovered vitamin, vitamin A, exists in a range of forms, primarily retinoids and provitamin carotenoids. The bioactive forms of vitamin A, retinol and retinoic acid, have many critical functions in body systems including the eye and immune system. Vitamin A deficiency is associated with dysfunctional immunity, and presents clinically as a characteristic ocular syndrome, xerophthalmia. The immune functions of vitamin A extend to the gut, where microbiome interactions and nutritional retinoids and carotenoids contribute to the balance of T cell differentiation, thereby determining immune status and contributing to inflammatory disease around the whole body. In the eye, degenerative conditions affecting the retina and uvea are influenced by vitamin A. Stargardt’s disease (STGD1; MIM 248200) is characterised by bisretinoid deposits such as lipofuscin, produced by retinal photoreceptors as they use and recycle a vitamin A-derived chromophore. Age-related macular degeneration features comparable retinal deposits, such as drusen featuring lipofuscin accumulation; and is characterised by parainflammatory processes. We hypothesise that local parainflammatory processes secondary to lipofuscin deposition in the retina are mediated by T cells interacting with dietary vitamin A derivatives and the gut microbiome, and outline the current evidence for this. No cures exist for Stargardt’s or age-related macular degeneration, but many vitamin A-based therapeutic approaches have been or are being trialled. The relationship between vitamin A’s functions in systemic immunology and the eye could be further exploited, and further research may seek to leverage the interactions of the gut-eye immunological axis.

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