Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is a genetically heterogeneous disease that leads to progressive and irreversible vision loss among the elderly. Inflammation, oxidative damage, cholesterol metabolism and/or impaired function of retinal pigment epithelium (RPE) have been implicated in AMD pathogenesis. We examined toll-like receptor 4 (TLR4) as a candidate gene for AMD susceptibility because: (i) the TLR4 gene is located on chromosome 9q32-33, a region exhibiting evidence of linkage to AMD in three independent reports; (ii) the TLR4-D299G variant is associated with reduced risk of atherosclerosis, a chronic inflammatory disease with subendothelial accumulation; (iii) the TLR4 is not only a key mediator of proinflammatory signaling pathways but also linked to regulation of cholesterol efflux and (iv) the TLR4 participates in phagocytosis of photoreceptor outer segments by the RPE. We examined D299G and T399I variants of TLR4 in a sample of 667 unrelated AMD patients and 439 unrelated controls, all of Caucasian ancestry. Multiple logistic regression demonstrated an increased risk of AMD in carriers of the G allele at TLR4 residue 299 (odds ratio=2.65, P=0.025), but lack of an independent effect by T399I variant. TLR4-D299G showed an additive effect on AMD risk (odds ratio=4.13, P=0.002) with allelic variants of apolipoprotein E (APOE) and ATP-binding cassette transporter-1 (ABCA1), two genes involved in cholesterol efflux. Interestingly, the effect of TLR4, APOE and ABCA1 variants on AMD susceptibility was opposite to that of association with atherosclerosis risk. Our data provide evidence of a link between multiple diverse mechanisms underlying AMD pathogenesis.

The lipofuscin fluorophore A2E perturbs cholesterol metabolism in retinal pigment epithelial cells

“…The presence of cholesterol and CE deposits in the Bruch's membrane of AMD eyes (9,10) and the correlation of genetic variations in cholesterol transporters with AMD susceptibility (12,13) point to an age-related alteration in cholesterol homeostasis in the RPE that may contribute to AMD progression. In this context, it is noteworthy that cholesterol and CE deposits in the Bruch's membrane are thought to originate from the RPE, including incompletely processed OS and additional sources such as the RPE itself (9).…”

“…Apolipoproteins, cholesterol and cholesteryl esters (CE) are abundant in both drusen (lipid-protein aggregates in the Bruch's membrane) and other subRPE deposits in AMD eyes (9)(10)(11), suggesting compromised cholesterol homeostasis in the RPE. Moreover, cardiovascular disease and allelic variants in apolipoprotein E and ATP-binding cassette protein A1 (ABCA1) have been linked to AMD susceptibility in humans (12,13).…”

Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe

“…Chronic retinal inflammation in humans is expected to cause iron overload within the retina, but whether such effects have any relevance to the pathogenesis of age-related macular degeneration remains to be seen. It is interesting to note that genetic variations in genes involved in inflammation and oxidative stress, including the Toll-like receptor-4 [43], have been implicated in the pathogenesis of age-related macular degeneration [44][45][46].…”

Toll-like Receptor 3 Is Required for Development of Retinopathy Caused by Impaired All-trans-retinal Clearance in Mice

“…Although single nucleotide polymorphisms of TLR3 and TLR4 have been reported to regulate AMD susceptibility (20,36), several conflicting reports indicating a weak relationship between AMD and these TLRs accentuate the need for studies other than single nucleotide polymorphism analyses (37)(38)(39)(40)(41)(42). To examine the biological role of TLRs in retinal degeneration, we performed gene expression analyses of TLR-signaling molecules in the eyes of Rdh8…”

“…Genes encoding complement factor H (7-14), HtrA serine peptidase 1 (HTRA1) (60 -63), and complement components 2 and 3 (C2 and C3) (15,16) were reported to predispose to AMD, and both human and mouse studies have demonstrated complement deposition at AMD lesions (64 -66). In addition, the F412L polymorphism of TLR3 (20) and the D299G of TLR4 (36) have been reported, but these findings were refuted by multiple groups (37)(38)(39)(40)(41)(42). Thus, there is an emerging consensus that innate immunity plays an important role in the pathogenesis of AMD.…”