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Human Molecular Genetics Advance Access originally published online on April 13, 2005
Human Molecular Genetics 2005 14(11):1449-1455; doi:10.1093/hmg/ddi154
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

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

Sepideh Zareparsi1,{dagger}, Monika Buraczynska1,{dagger}, Kari E.H. Branham1, Sapna Shah1, Donna Eng1, Mingyao Li2, Hemant Pawar1, Beverly M. Yashar1,3, Sayoko E. Moroi1, Paul R. Lichter1, Howard R. Petty1, Julia E. Richards1,4, Gonçalo R. Abecasis2, Victor M. Elner1,5 and Anand Swaroop1,3,*

1Department of Ophthalmology and Visual Sciences, 2Department of Biostatistics, 3Department of Human Genetics, 4Department of Epidemiology and 5Department of Pathology, University of Michigan, Ann Arbor, MI 48105, USA

* To whom correspondence should be addressed. Tel: +1 7346152246; Fax: +1 7346470228; Email: swaroop{at}umich.edu

Received February 7, 2005; Accepted April 6, 2005

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.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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