Comprehensive analysis of the candidate genes CCL2, CCR2, and TLR4 in age-related macular degeneration.

PURPOSE To determine whether variants in the candidate genes TLR4, CCL2, and CCR2 are associated with age-related macular degeneration (AMD). METHODS This study was performed in two independent Caucasian populations that included 357 cases and 173 controls from the Netherlands and 368 cases and 368 controls from the United States. Exon 4 of the TLR4 gene and the promoter, all exons, and flanking intronic regions of the CCL2 and CCR2 genes were analyzed in the Dutch study and common variants were validated in the U.S. study. Quantitative (q)PCR reactions were performed to evaluate expression of these genes in laser-dissected retinal pigment epithelium from 13 donor AMD and 13 control eyes. RESULTS Analysis of single nucleotide polymorphisms (SNPs) in the TLR4 gene did not show a significant association between D299G or T399I and AMD, nor did haplotypes containing these variants. Univariate analyses of the SNPs in CCL2 and CCR2 did not demonstrate an association with AMD. For CCR2, haplotype frequencies were not significantly different between cases and controls. For CCL2, one haplotype containing the minor allele of C35C was significantly associated with AMD (P = 0.03), but this did not sustain after adjustment for multiple testing (q = 0.30). Expression analysis did not demonstrate altered RNA expression of CCL2 and CCR2 in the retinal pigment epithelium from AMD eyes (for CCL2 P = 0.62; for CCR2 P = 0.97). CONCLUSIONS No evidence was found of an association between TLR4, CCR2, and CCL2 and AMD, which implies that the common genetic variation in these genes does not play a significant role in the etiology of AMD.

[1]  P. D. de Jong,et al.  Comparison of human retinal pigment epithelium gene expression in macula and periphery highlights potential topographic differences in Bruch's membrane. , 2007, Molecular vision.

[2]  T. Das,et al.  Analysis of CFH, TLR4, and APOE polymorphism in India suggests the Tyr402His variant of CFH to be a global marker for age-related macular degeneration. , 2006, Investigative ophthalmology & visual science.

[3]  Johanna M Seddon,et al.  Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration , 2006, Nature Genetics.

[4]  A. Hofman,et al.  Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. , 2006, JAMA.

[5]  R. T. Smith,et al.  Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration , 2006, Nature Genetics.

[6]  C. Sabatti,et al.  Guidelines for association studies in Human Molecular Genetics. , 2005, Human molecular genetics.

[7]  G. Abecasis,et al.  Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration. , 2005, Human molecular genetics.

[8]  R. T. Smith,et al.  A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[9]  J. Gilbert,et al.  Complement Factor H Variant Increases the Risk of Age-Related Macular Degeneration , 2005, Science.

[10]  J. Ott,et al.  Complement Factor H Polymorphism in Age-Related Macular Degeneration , 2005, Science.

[11]  A. Edwards,et al.  Complement Factor H Polymorphism and Age-Related Macular Degeneration , 2005, Science.

[12]  I. Charo,et al.  Chemokines in the pathogenesis of vascular disease. , 2004, Circulation research.

[13]  D. Schwartz,et al.  Toll-like receptors in the pathogenesis of human disease , 2004, Nature Immunology.

[14]  Mardge H. Cohen,et al.  CCR2 genotype and disease progression in a treated population of HIV type 1-infected women. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[15]  Howard R. Petty,et al.  Toll-Like Receptor 4 (TLR4) of Retinal Pigment Epithelial Cells Participates in Transmembrane Signaling in Response to Photoreceptor Outer Segments , 2004, The Journal of general physiology.

[16]  S. Akira,et al.  Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Eiji Sakurai,et al.  An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice , 2003, Nature Medicine.

[18]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  A. Hofman,et al.  The risk and natural course of age-related maculopathy: follow-up at 6 1/2 years in the Rotterdam study. , 2003, Archives of ophthalmology.

[20]  D. Rader,et al.  Val64Ile Polymorphism in the C-C Chemokine Receptor 2 Is Associated With Reduced Coronary Artery Calcification , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[21]  B. Rovin,et al.  HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levels , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  F. Speleman,et al.  Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes , 2002, Genome Biology.

[23]  H. Ullum,et al.  Effects of CCR5- 32, CCR2-64I, and SDF-1 3A Alleles on HIV-1 Disease Progression: An International Meta-Analysis of Individual-Patient Data , 2001, Annals of Internal Medicine.

[24]  Robert F. Mullins,et al.  An Integrated Hypothesis That Considers Drusen as Biomarkers of Immune-Mediated Processes at the RPE-Bruch's Membrane Interface in Aging and Age-Related Macular Degeneration , 2001, Progress in Retinal and Eye Research.

[25]  Z. Prohászka,et al.  Involvement of polymorphisms in the chemokine system in the susceptibility for coronary artery disease (CAD). Coincidence of elevated Lp(a) and MCP-1 -2518 G/G genotype in CAD patients. , 2001, Atherosclerosis.

[26]  D. Schwartz,et al.  TLR4 mutations are associated with endotoxin hyporesponsiveness in humans , 2000, Nature Genetics.

[27]  P T de Jong,et al.  An international classification and grading system for age-related maculopathy and age-related macular degeneration , 1995 .

[28]  R. Medzhitov,et al.  Toll-like receptors: linking innate and adaptive immunity. , 2004, Microbes and infection.

[29]  H. Ullum,et al.  Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on HIV-1 disease progression: An international meta-analysis of individual-patient data. , 2001, Annals of internal medicine.