Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration.
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.
Zareparsi
Sepideh
S
Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA.
Buraczynska
Monika
M
Branham
Kari E H
KE
Shah
Sapna
S
Eng
Donna
D
Li
Mingyao
M
Pawar
Hemant
H
Yashar
Beverly M
BM
Moroi
Sayoko E
SE
Lichter
Paul R
PR
Petty
Howard R
HR
Richards
Julia E
JE
Abecasis
Gonçalo R
GR
Elner
Victor M
VM
Swaroop
Anand
A
D000368:Aged; D000375:Aging / Q000473:pathology*; D001483:Base Sequence; D015331:Cohort Studies; D017931:DNA Primers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics*
D017931:DNA Primers