Infection is Implicated in Macular Degeneration

Smokers are more likely to have been infected by cytomegalovirus and Chlamydia pneumonia, for socioeconomic reasons. The Surgeon General report of 2014 makes no mention at all of the role of these pathogens in macular degeneration, therefore it is a deliberate act of scientific fraud.

Inflammation has been implicated in macular degeneration since at least 1992 (Drusen in Bruch's membrane. Their significance for the pathogenesis and therapy of age-related macular degeneration. D Pauleikhoff. Ophthalmologe 1992 Oct;89(5):363-386). Among the viruses that can infect human retinal pigment cells are cytomegalovirus and herpes simplex virus. (Cytomegalovirus has been implicated in cardiovascular disease as well, particularly in restenois after coronary bypass surgery.)

Pauleikhoff - Ophthalmologe 1992 abstract / PubMed

A potential role for immune complex pathogenesis in drusen formation. LV Johnson, S Ozaki, MK Staples, PA Erickson, DH Anderson. Exp Eye Res 2000 Apr;70(4):441-449. "Drusen are abnormal extracellular deposits that accumulate between the retinal pigmented epithelium and Bruch's membrane and are commonly associated with age-related macular degeneration. Our recent work has identified a number of plasma proteins as molecular components of drusen. Of interest is the fact that many of these drusen-associated molecules are acute-phase reactant proteins and some have established roles in mediating immune responsiveness. As immune and inflammatory responses appear to play a role in the formation of other pathologic age-related deposits, we examined the distribution of immunoglobulin molecules and terminal complement complexes at sites of drusen deposition. Here, we report that concentrations of immunoglobulin G and terminal C5b-9 complement complexes are present in drusen. In addition, we observe that retinal pigmented epithelial cells overlying or directly adjacent to drusen, as well as some within apparently normal epithelia, exhibit cytoplasmic immunoreactivity for immunoglobulin and the C5 component of complement. Taken together, these results suggest that drusen biogenesis may be a byproduct of immune responsiveness, and they implicate immune complex-mediated pathogenesis involving retinal pigmented epithelial cells as an initiating event in drusen formation."

Johnson - Exp Eye Res 2000 abstract / PubMed

Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. RF Mullins, SR Russell, DH Anderson, GS Hageman. FASEB J 2000 May;14(7):835-846.) "Age-related macular degeneration (AMD), a blinding disorder that compromises central vision, is characterized by the accumulation of extracellular deposits, termed drusen, between the retinal pigmented epithelium and the choroid. Recent studies in this laboratory revealed that vitronectin is a major component of drusen. Because vitronectin is also a constituent of abnormal deposits associated with a variety of diseases, drusen from human donor eyes were examined for compositional similarities with other extracellular disease deposits. Thirty-four antibodies to 29 different proteins or protein complexes were tested for immunoreactivity with hard and soft drusen phenotypes. These analyses provide a partial profile of the molecular composition of drusen. Serum amyloid P component, apolipoprotein E, immunoglobulin light chains, Factor X, and complement proteins (C5 and C5b-9 complex) were identified in all drusen phenotypes. Transcripts encoding some of these molecules were also found to be synthesized by the retina, retinal pigmented epithelium, and/or choroid. The compositional similarity between drusen and other disease deposits may be significant in view of the recently established correlation between AMD and atherosclerosis. This study suggests that similar pathways may be involved in the etiologies of AMD and other age-related diseases."

Mullins - FASEB J 2000 abstract / PubMed
Mullins - FASEB J 2000 Full Article

Chlamydia pneumoniae and/or cytomegalovirus and macular degeneration

Serological association between Chlamydia pneumoniae infection and age-related macular degeneration. MV Kalayoglu, C Galvan, OS Mahdi, GI Byrne, S Mansour. Arch Ophthalmol 2003 Apr;121(4):478-482. In 25 patients and 18 controls, a serological association was found between ARMD and anti-C pneumoniae antibodies (P =.047) but not between ARMD and the anti-C trachomatis or anti-E coli heat shock protein antibodies. The association remained statistically significant after adjusting for age and smoking, both established risk factors for ARMD." [This claim that smoking is an "established risk factor" for ARMD is a lie, because it is based on wilfull disregard of confounding by infection.]

Kalayoglu - Arch Ophthalmol 2003 abstract / PubMed

The association of prior cytomegalovirus infection with neovascular age-related macular degeneration. DM Miller, DG Espinosa-Heidmann, J Legra, SR Dubovy, IJ Suner, DD Sedmak, RD Dix, SW Cousins. Am J Ophthalmol 2004 Sep;138(3):323-328. In 150 patients, "The average cytomegalovirus IgG titer was higher in patients with wet AMD versus controls (p = 0.02, Student t-test, two-tailed) and patients with dry AMD (p = 0.06). Twenty-six (55%) of 47 subjects with wet AMD had high cytomegalovirus IgG titers compared with 14 (39%) of 36 patients with dry AMD (odds ratio [OR] = 2.23, 95% confidence interval [CI] = 0.77 to 6.44) and 23 (34%) of 67 control patients (OR = 2.49, 95% CI = 0.98 to 6.33). There was no major difference in the distribution of titers for Chlamydia pneumoniae IgG and Helicobacter pylori IgG in wet and dry AMD patients."

Miller - Am J Ophthalmol 2004 abstract / PubMed

Is Chlamydia pneumoniae infection a risk factor for age related macular degeneration? O Ishida, H Oku, T Ikeda, M Nishimura, K Kawagoe, K Nakamura. British Journal of Ophthalmology 2003;87(5):523-524. Commentary.

Ishida / Brit J Ophthalmology 2005 extract

Exposure to Chlamydia pneumoniae infection and progression of age-related macular degeneration. L Robman, O Mahdi, C McCarty, P Dimitrov, G Tikellis, J McNeil, G Byrne, H Taylor, R Guymer. Am J Epidemiol. 2005 Jun 1;161(11):1013-1019. In 246 subjects, "AMD progression was associated with a higher antibody titer. After adjustment for age, smoking, family history of AMD, history of cardiovascular diseases, and source study, the subjects in the upper tertiles of antibody titers were 2.1 (95% confidence interval: 0.92, 4.69), 2.6 (95% confidence interval: 1.24, 5.41), and 3.0 (95% confidence interval: 1.46, 6.37) times more at risk of progression than those in the lowest tertile, using three definitions of progression, respectively." Unfortunately, unadjusted odds ratios were not given.

Robman - Am J Epidemiol 2005 abstract / PubMed
Robman / Am J Epidemiol 2005 full article

Identification of Chlamydia pneumoniae within human choroidal neovascular membranes secondary to age-related macular degeneration. MV Kalayoglu, D Bula, J Arroyo, ES Gragoudas, D D'Amico, JW Miller. Graefes Arch Clin Exp Ophthalmol 2005 Nov;243(11):1080-1090; and: Bacterium Present In Eyes With 'Wet' Age-Related Macular Degeneration. DGNews Nov. 7, 2005. "Researchers at the Massachusetts Eye and Ear Infirmary (MEEI) have found that Chlamydia pneumoniae, a bacterium linked to heart disease and capable of causing chronic inflammation, was present in the diseased eye tissue of five out of nine people with neovascular, or "wet," age-related macular degeneration (AMD). However, it was not found in the eyes of more than 20 individuals without AMD, providing more evidence that this disease may be caused by inflammation." Also, people with wet macular degeneration have higher levels of vascular endothelial growth factor (VEGF), and C. pneumoniae infection of human eye cell types increased production of VEGF.

Kalayoglu - Graefes Arch Clin Exp Ophthalmol. 2005 abstract / PubMed
Bacterium Present / DGNews 2005 full article

Chlamydia pneumoniae is not detectable in subretinal neovascular membranes in the exudative stage of age-related macular degeneration. W Kessler, CA Jantos, J Dreier, S Pavlovic. Acta Ophthalmol Scand 2006 Jun;84(3):333-337. 13 consecutive subretinal neovascular (SRNV) membranes surgically excised from patients with exudative AMD, age 68 to 85. "[N]o DNA of either C. pneumoniae or other pathogens was found by PCR."

Kessler - Acta Ophthalmol Scand 2006 abstract / PubMed

Inflammation in dry age-related macular degeneration. EB Rodrigues. Ophthalmologica 2007;221(3):143-152. Review. "Some important evidence for inflammation in early ARMD consists in the isolation of immunoglobulins, complement proteins, cytokines and activated microglia, in retinal pigment epithelium (RPE) cells and drusen. Pivotal mechanisms in early ARMD include the accumulation of debris and proteins along the RPE surface, followed by immune-complex deposition and complement activation."

Rodrigues - Ophthalmologica 2007 abstract / PubMed

Chlamydia pneumoniae and age-related macular degeneration: a role in pathogenesis or merely a chance association? R Guymer, L Robman. Clin Experiment Ophthalmol 2007 Jan-Feb;35(1):89-93. Review. The role of inflammation in the aetiology of age-related macular degeneration (AMD) has become very topical as the discovery that genetic variation in complement pathway genes influences the risk of developing AMD. Complement factor H gene, an inhibitor of the alternative complement activation pathway along with other complement pathway genes factor F (BF) and C2 show significant contribution to the risk of AMD. The alternative complement pathway is activated by a trigger, which is often microbial in nature. One current model of AMD aetiology implicates aberrant regulation of the alternative pathway of complement, in combination with some unknown infectious agents. Chlamydia pneumoniae could be one such potential trigger of the alternative complement pathway and several investigations have linked C. pneumoniae to AMD. However, there are only a few studies to date and numbers in most studies are small. Also there are many difficulties in verifying laboratory techniques for the detection of C. pneumoniae chronic infection. As such we need to be cautious not to over interpret the current results. However, the findings certainly give impetus for further work on C. pneumoniae and AMD. This paper provides an overview of work in this area."

Guymer - Clin Experiment Ophthalmol 2007 abstract / PubMed

Exposure to Chlamydia pneumoniae infection and age-related macular degeneration: the Blue Mountains Eye Study. L Robman, OS Mahdi, JJ Wang, G Burlutsky, P Mitchell, G Byrne, R Guymer, H Taylor. Invest Ophthalmol Vis Sci 2007 Sep;48(9):4007-4011. 197 AMD cases and 433 control subjects matched for age, sex and smoking status, from the Blue Mountains Eye Study (BMES) cohort. "After adjustment for age, gender, and smoking, no significant association was evident between C. pneumoniae antibody titer and any prevalent early or late AMD (OR 1.02, 95% CI 0.66-1.56 comparing upper with lower tertile of antibody titer). Findings were similar when early or late AMD was analyzed separately. Analysis confined to incident AMD also showed no significant association with the incidence of either early (OR 0.92, 95% CI 0.52-1.64) or late (OR 1.85, 95% CI 0.57-6.05) AMD. The results did not change after adjustment for family history of AMD and cardiovascular disease. CONCLUSIONS: In this nested case-control sample of an older Australian population we found no association between C. pneumoniae antibody titers and early AMD. The study has insufficient power to assess an association with late AMD." [However, adjustment for non-causal associations can weaken associations with causal factors.]

Robman - Invest Ophthalmol Vis Sci 2007 abstract / PubMed

Gene-environment interaction in progression of AMD: the CFH gene, smoking and exposure to chronic infection. PN Baird, LD Robman, AJ Richardson, PN Dimitrov, G Tikellis, CA McCarty, RH Guymer. Hum Mol Genet 2008 May 1;17(9):1299-1305. In 233 AMD patients followed for progression, "The CC risk genotype of Y402H was significantly associated with increased AMD progression [odds ratio (OR) 2.43, 95% confidence interval (95% CI) 1.07-5.49] as was smoking (OR 2.28, 95% CI 1.26-4.12). However, the risk of progression was greatly increased to almost 12-fold (OR 11.8, 95% CI 2.1-65.8) when, in addition to having the C risk allele, subjects also presented with the upper tertile of antibodies to the bacterial pathogen C. pneumoniae compared with those with the T allele of Y402H and the lowest antibody tertile."

Baird - Hum Mol Genet 2008 abstract / PubMed

Complement factor H gene polymorphisms and Chlamydia pneumoniae infection in age-related macular degeneration. P Haas, K Steindl, KE Schmid-Kubista, T Aggermann, W Krugluger, GS Hageman, S Binder. Eye (Lond) 2009 Dec;23(12):2228-32. 75 unrelated AMD patients and 75 controls. Results CFH Y402H genotype frequencies differed significantly between AMD patients and healthy controls (1277 TT, 22.7%; 1277 TC, 53.3%; and 1277 CC, 22.7% in the AMD group; 1277 TT, 48.0%; 1277 TC, 38.7%; and 1277 CC, 13.3% in the control group) showing a P-value <0.005 (OR:2.920/3.811).No association was found between a positive C. pneumoniae titre and AMD (P=0.192), nor was any association found between C. pneumoniae and the CFH Y402H polymorphism."

Haas - Eye (Lond) 2009 abstract / PubMed

Chlamydia pneumoniae infection, complement factor H variants and age-related macular degeneration. D Shen, J Tuo, M Patel, AA Herzlich, X Ding, EY Chew, CC Chan. Br J Ophthalmol 2009 Mar;93(3):405-408. DNA from peripheral blood of 148 advanced AMD patients and 162 controls. "C pneumoniae infection was associated with increased risk of AMD (OR = 2.17, p<0.017). A CFH variant was also linked to increased risk of AMD (OR = 1.98, p<0.0001). However, no relationship was found between risk-conferring CFH variant and C pneumoniae (OR = 1.81, p = 0.08."

Shen - Br J Ophthalmol 2009 abstract / PubMed

Choroidal neovascularization enhanced by Chlamydia pneumoniae via Toll-like receptor 2 in the retinal pigment epithelium. T Fujimoto, KH Sonoda, K Hijioka, K Sato, A Takeda, E Hasegawa, Y Oshima, T Ishibashi. Invest Ophthalmol Vis Sci 2010 Sep;51(9):4694-4702. "[C]ultured mouse RPE cells from C57BL/6 mice expressed IL-6 and VEGF, but not TNF-alpha mRNA, in response to C. pneumoniae antigen. RPE cells from either MyD88 KO mice or TLR2 KO mice did not respond to the C. pneumoniae antigen."

Fujimoto - Invest Ophthalmol Vis Sci 2010 abstract / PubMed

Macrophage Activation Associated with Chronic Murine Cytomegalovirus Infection Results in More Severe Experimental Choroidal Neovascularization. SW Cousins, DG Espinosa-Heidmann, DM Miller, S Pereira-Simon, EP Hernandez, H Chien, C Meier-Jewett, RD Dix. PLoS Pathog 2012 Apr;8(4): e1002671. "Although all MCMV-infected mice exhibited more severe CNV when compared with control mice, the most severe CNV developed in mice with chronic infection, a time when MCMV-specific gene sequences could not be detected within choroidal tissues. Splenic macrophages collected from mice with chronic MCMV infection, however, expressed significantly greater levels of TNF-α, COX-2, MMP-9, and, most significantly, VEGF transcripts by quantitative RT-PCR assay when compared to splenic macrophages from control mice. Direct MCMV infection of monolayers of IC-21 mouse macrophages confirmed significant stimulation of VEGF mRNA and VEGF protein as determined by quantitative RT-PCR assay, ELISA, and immunostaining."

Cousins / PLoS Pathog 2012 full article

Detection of Chlamydia and Complement Factors in Neovascular Membranes of Patients with Age-related Macular Degeneration. UE Wolf-Schnurrbusch, R Hess, F Jordi, AK Stuck, GM Sarra, S Wolf, V Enzmann. Ocul Immunol Inflamm 2013 Feb;21(1):36-43. 26 patients. "C. pneumoniae was found in 68% of the investigated membranes, and 88% of these membranes were also positive for CD68. Staining for CFH and C5 gave a positive reaction in 68 and 41% of the membranes, respectively. Patients with C5-positive membranes had significantly larger CNV mean area and were younger than patients with CFH-positive membranes at the operation time point."

Wolf-Schnurrbusch - Ocul Immunol Inflamm 2013 abstract / PubMed

Interferon γ-dependent migration of microglial cells in the retina after systemic cytomegalovirus infection. MS Zinkernagel, HR Chinnery, ML Ong, C Petitjean, V Voigt, S McLenachan, PG McMenamin, GR Hill, JV Forrester, ME Wikstrom, MA Degli-Esposti. Am J Pathol 2013 Mar;182(3):875-885. "Systemic infection with murine cytomegalovirus elicited a significant increase in the number of microglia in the subretinal space and an accumulation of iris macrophages, along with morphological signs of activation. Interferon γ (IFN-γ)-deficient mice failed to induce changes in microglia distribution. Bone marrow chimera experiments confirmed that microglial cells in the subretinal space were not recruited from the circulating monocyte pool, but rather represented an accumulation of resident microglial cells from within the retina."

Zinkernagel - Am J Pathol 2013 abstract / PubMed

Serological Association of Chlamydia pneumoniae Infection with Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis. X Chen, V Jhanji, C Chen, H Chen. PLoS One 2014 Jul 25;9(7):e103466. In 9 studies evaluated, "The overall OR of Chlamydia pneumoniae infection with AMD was 1.11 (95% confidence interval: 0.78-1.57, P = 0.56). The overall SMD of antibody titer between AMD and control was 0.43 (95% confidence interval: -0.12 to 0.99, P = 0.13)."

Chen - PLoS One 2014 full article / PubMed Central
Chen / PLoS One 2014 full article

Calcium, ARMS2 Genotype, and Chlamydia Pneumoniae Infection in Early Age-Related Macular Degeneration: a Multivariate Analysis from the Nagahama Study. I Nakata, K Yamashiro, T Kawaguchi, H Nakanishi, Y Akagi-Kurashige, M Miyake, A Tsujikawa, R Yamada, F Matsuda, N Yoshimura; Nagahama Study Group. Sci Rep 2015 Mar 20;5:9345. 971 large drusen cases and 3,209 controls. "Multivariate analyses identified a significant association in serum calcium level (odds ratio [OR] = 0.932, P = 1.05 × 10(-3)), ARMS2 A69S (rs10490924) genotype (OR = 1.046, P < 0.001), Chlamydia pneumoniae IgG (OR = 1.020, P = 0.0440), and age (OR = 1.013, P < 0.001) for large drusen... C. pneumoniae infections was more frequent in large drusen cases (56.4%) than in conrols (51.7%, P = 0.00956)."

Nakata - Sci Rep 2015 abstract / PubMed

Factor H and Macular Degeneration

A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. GS Hageman, DH Anderson, LV Johnson, LS Hancox, AJ Taiber, LI Hardisty, JL Hageman, HA Stockman, JD Borchardt, KM Gehrs, RJ Smith, G Silvestri, SR Russell, CC Klaver, I Barbazetto, S Chang, LA Yannuzzi, GR Barile, JC Merriam, RT Smith, AK Olsh, J Bergeron, J Zernant, JE Merriam, B Gold, M Dean, R Allikmets. Proc Natl Acad Sci USA 2005 May 17;102(20):7227-7232. Among ~900 AMD patients and 400 matched controls, "One common at-risk haplotype is present at a frequency of 50% in AMD cases and 29% in controls [odds ratio (OR) = 2.46, 95% confidence interval (1.95-3.11)]. Homozygotes for this haplotype account for 24% of cases and 8% of controls [OR = 3.51, 95% confidence interval (2.13-5.78)]... We propose that genetic variation in a regulator of the alternative complement pathway, when combined with a triggering event, such as infection, underlie a major proportion of AMD in the human population." "Drusen are the hallmark deposits associated with early AMD (eAMD), and recent studies have implicated local inflammation and activation of the complement cascade in their formation."

Hageman / PNAS 2005 full article

A renewed appreciation for ocular immune privilege / Una nueva apreciación del privilegio ocular inmune. JY Niederkorn. Arch Soc Esp Oftalmol 2005 Aug;80(8):437-8; 439-440. Editorial. "The role of complement activation and inflammation in the pathogenesis of AMD was proposed over three years ago by Anderson et al (4) and fits neatly with the aforementioned reports indicating a strong association between polymorphism in the factor H gene and AMD. One of the hallmarks of AMD is the formation of drusen, which are insoluble deposits of proteinaceous molecules and cell debris that accumulate at the interface between Bruch’s membrane and the retinal pigment epithelium (RPE). Drusen contain a variety of inflammation-related proteins, including c-reactive protein, complement components (including the C5b-9 complex), and even immunoglobulin. The presence of c-reactive protein in drusen is particularly interesting, as it is an acute phase proinflammatory molecule that can directly activate the complement cascade. However, the deposition of the C5b-9 complement complex is inhibited by complement factor H. Thus, malfunction of complement factor H, due to a single nucleotide substitution, could affect the buffering effect of factor H on the complement cascade and culminate in chronic inflammation and AMD."

Niederkorn / Arch Soc Esp Oftalmol 2005 full article

Association of the Y402H polymorphism in complement factor H gene and neovascular age-related macular degeneration in Chinese patients. LI Lau, SJ Chen, CY Cheng, MY Yen, FL Lee, MW Lin, WM Hsu, YH Wei. Invest Ophthalmol Vis Sci 2006 Aug;47(8):3242-3246. One hundred sixty-three Chinese patients with neovascular AMD and 232 age-matched healthy controls. "The frequency of the risk allele, 1277C, was 11.3% in AMD patients compared with 2.8% in controls (P < 0.00001). Genotype frequency differed significantly between the two groups (1277TT 81.0%, 1277TC 15.3%, and 1277CC 3.7% in the AMD group; 1277TT 94.4%, 1277TC 5.6%, and 1277CC 0% in the control group; P < 0.0001). The 1277C allele significantly increased the risk for neovascular AMD and had an odds ratio of 4.4 (95% confidence interval [95% CI], 2.3-8.5; P < 0.00001). CONCLUSIONS: The allele frequency of Y402H polymorphism in CFH has an ethnic variation, with much lower 1277C frequency in Chinese than in white patients. Despite this, the polymorphism is significantly associated with neovascular AMD in the Chinese population."

Lau - Invest Ophthalmol Vis Sci 2006 abstract / PubMed

Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. J Maller, S George, S Purcell, J Fagerness, D Altshuler, MJ Daly, JM Seddon. Nat Genet 2006 Sep;38(9):1055-1059. "In a case-control study drawn from a US-based population of European descent, we have identified a previously unrecognized common, noncoding variant in CFH, the gene encoding complement factor H, that substantially increases the influence of this locus on AMD, and we have strongly replicated the associations of four other previously reported common alleles in three genes (P values ranging from 10(-6) to 10(-70)). Despite excellent power to detect epistasis, we observed purely additive accumulation of risk from alleles at these genes. We found no differences in association of these loci with major phenotypic categories of advanced AMD. Genotypes at these five common SNPs define a broad spectrum of interindividual disease risk and explain about half of the classical sibling risk of AMD in our study population."

Maller - Nat Genet 2006 abstract / PubMed

HTRA1 promoter polymorphism predisposes Japanese to age-related macular degeneration. T Yoshida, A DeWan, H Zhang, R Sakamoto, H Okamoto, M Minami, M Obazawa, A Mizota, M Tanaka, Y Saito, I Takagi, J Hoh, T Iwata. Mol Vis 2007 Apr 4;13:545-548. "SNP rs11200638 conferred disease risk in an autosomal recessive fashion: Odds ratio was 10.1 (95% CI 4.36, 23.06), adjusted for SNP CFH 402, for those carrying two copies of the risk allele, whereas indistinguishable from unity if carrying only one risk allele."

Yoshida / Mol Vis 2007 full article

Fine-scale linkage disequilibrium mapping of age-related macular degeneration in the complement factor H gene region. S Ennis, S Goverdhan, A Cree, J Hoh, A Collins, A Lotery. Br J Ophthalmol 2007 Jul;91(7):966-970. "Data were consistent with other studies in that strong association between the Y402H variant and AMD is observed. However, composite likelihood analysis, which combines association data from all SNPs in the region, and uses genetic locations on a high-resolution LD map, gave a point location for a causal variant between exons 1 and 2 of the CFH gene. CONCLUSION: The findings are consistent with evidence that, in addition to the widely described Y402H variant, there is at least one and, most probably, several other mutations in the CFH gene which determine disease manifestation in AMD. A genetic model in which multiple mutations contribute to a varying degree to disease aetiology has been previously well described in ophthalmic genetics, and is typified by the COL2A1 and ABCA4 genes."

Ennis - Br J Ophthalmol 2007 abstract / PubMed

Association of the HTRA1 -625G>A promoter gene polymorphism with exudative age-related macular degeneration in a Central European population. M Weger, W Renner, I Steinbrugger, K Köfer, A Wedrich, A Groselj-Strele, Y El-Shabrawi, O Schmut, A Haas. Mol Vis 2007 Jul 24;13:1274-1279. 242 patients with exudative AMD and 157 controls. "Carriers of the HTRA1 -625AA genotype were found significantly more often in AMD patients than among control subjects (27.7% versus 5.1%; p<0.001). Binary logistic regression analysis binary logistic regression analysis revealed an odds ratio (OR) of 2.7 (95% confidence interval (CI): 1.1-6.8) for AMD among subjects heterozygous for the HTRA1 -625A allele compared to those with the wildtype genotype, when adjusted for CFH Y402H genotypes (p=0.034). The OR increased to 10.2 (95% CI: 3.0-34.5) among subjects homozygous for the HTRA1 -625A allele (p<0.001). The OR for AMD among heterozygous carriers of the CFH 402H variant was 3.6 (95% CI: 1.6-7.8) compared to those with the wildtype genotype, when adjusted for HTRA1 -625G>A genotypes (p=0.001). The OR increased to 9.8 (95% CI: 3.7-25.9) among subjects homozygous for the CFH 402HH genotype (p<0.001)."

Weger - Mol Vis 2007 abstract / PubMed

Complement factor H polymorphism in age-related macular degeneration. R Narayanan, V Butani, DS Boyer, SR Atilano, GP Resende, DS Kim, S Chakrabarti, BD Kuppermann, N Khatibi, M Chwa, AB Nesburn, MC Kenney. Ophthalmology 2007 Jul;114(7):1327-1331. 66 AMD subjects and 58 age-matched controls. "There was a strong association between homozygous C and AMD compared with the control population (odds ratio [OR] = 3.4; 95% confidence interval [CI], 1.32-8.74; P = 0.0053). Furthermore, dry AMD had a stronger association (OR, 8.32; 95% CI, 2.30-30.11; P = 0.001) than wet AMD (OR, 2.49; 95% CI, 0.90-6.84; P = 0.039) compared with the control population. Homozygous T was more prevalent in the control subjects compared with AMD patients (OR, 5; 95% CI, 2.18-11.43; P = 0.00005). CONCLUSIONS: Complement factor H polymorphism T1277C (tyrosine-402 --> histidine-402) is strongly associated with both dry and wet AMD and points to a possible role for inflammation in the pathogenesis of AMD."

Narayanan - Ophthalmology 2007 abstract / PubMed

Complement factor H and hemicentin-1 in age-related macular degeneration and renal phenotypes. CL Thompson, BE Klein, R Klein, Z Xu, J Capriotti, T Joshi, D Leontiev, KE Lee, RC Elston, SK Iyengar. Hum Mol Genet 2007 Sep 1;16(17):2135-2148. Family Age-Related Macular degeneration Study (FARMS) and Beaver Dam Eye Study (BDES). "Strong evidence of the association of rs1061170 (Y402H) variation with AMD was confirmed (P = 9.15 x 10(-5) in BDES, P = 0.016 in FARMS). This association was observed in multiple AMD scales, suggesting that its role is not phenotype-specific. Polymorphisms in both CFH and HMCN1 appeared to influence the longitudinal rate of change of AMD. The rs1061170 polymorphism was also associated with a reduction in estimated glomerular filtration rate (eGFR) (P = 0.046). Another CFH polymorphism, rs800292, was similarly associated with eGFR [beta = -0.90 (P = 0.022)]. Associations between rs743137 (P = 0.05) and rs680638 (P = 0.022) in HMCN1 with calculated creatinine clearance progression were also observed. Both genes appear to play a role in both AMD and renal pathophysiology. These findings support evidence for common pathways influencing ocular and renal function and suggest that further work is required on their common determinants."

Thompson - Hum Mol Genet 2007 abstract / PubMed
Thompson / Hum Mol Genet 2007 full article (pdf, 14 pp)

LOC387715/HTRA1 variants in polypoidal choroidal vasculopathy and age-related macular degeneration in a Japanese population. N Kondo, S Honda, K Ishibashi, Y Tsukahara, A Negi. Am J Ophthalmol 2007 Oct;144(4):608-612. 76 PCV cases, 73 wet AMD cases, and 94 controls. "Two SNPs generated highly significant allelic associations with PCV (rs10490924, P = 5.7 x 10(-6); rs11200638, P = 5.2 x 10(-6)) and AMD (rs10490924, P = 1.4 x 10(-6); rs11200638, P = 3.4 x 10(-7)). The odds ratios and population attributable risks were higher for the AMD cases than for the PCV cases. Homozygotes for the risk allele at rs11200638 had a 6.33-fold increased risk of PCV and a 13.77-fold increased risk of wet AMD when compared with homozygotes for the wild-type allele. There were no significant differences in either allelic or genotypic frequencies between PCV and AMD cases."

Kondo - Am J Ophthalmol 2007 abstract / PubMed

LOC387715/HTRA1 and Complement Factor H Variants in Patients with Age-Related Macular Degeneration Seen at the Mayo Clinic. JS Pulido, LM Peterson, L Mutapcic, S Bryant, WE Highsmith. Ophthalmic Genet 2007 Oct;28(4):203-207. 89 Caucasian patients with neovascular (exudative) AMD and 232 Caucasian controls. "For CFH, the odds ratio for the homozygous variant was 4.97 (CI 2.52 to 9.79). For LOC387715/HTRA1 the odds ratio for the homozygous risk variant was 7.75 (CI 3.46 to 17.35). The odds ratio for heterozygous carriers was 3.35 (CI 1.91 to 5.90)."

Pulido - Ophthalmic Genet 2007 abstract / PubMed

Complement Factor H polymorphism Y402H associates with inflammation, visual acuity, and cardiovascular mortality in the elderly population at large. SP Mooijaart, KM Koeijvoets, EJ Sijbrands, MR Daha, RG Westendorp. Exp Gerontol 2007 Nov;42(11):1116-1122. "Within the Leiden 85-plus Study, a prospective population-based study of participants aged 85 years and older, we found that carriers of the CFH 402HH variant had a higher production of IL-6 in whole blood samples compared to those carrying the 402YY variant (P=0.029). Carriers of the 402HH genotype also had a steeper increase in circulating C-reactive protein levels during follow-up (P=0.009), lower visual acuity (P=0.020), and an increased risk of cardiovascular mortality (P=0.004). Subjects in the lowest tertile of visual acuity had a twofold increased risk of cardiovascular mortality compared to those in the highest tertile (P=0.001)."

Koeijvoets - Exp Gerontol 2007 abstract / PubMed

Coding and noncoding variants in the CFH gene and cigarette smoking influence the risk of age-related macular degeneration in a Japanese population. K Mori, PL Gehlbach, S Kabasawa, I Kawasaki, M Oosaki, H Iizuka, S Katayama, T Awata, S Yoneya. Invest Ophthalmol Vis Sci 2007 Nov;48(11):5315-5319. 188 patients with AMD and 139 control subjects. "The intronic SNP (rs1410996) and the synonymous SNP (rs2274700) were associated with a significant risk of AMD (P = 2.37 x 10(-5) and 3.52 x 10(-5), respectively). A significant association was also noted between a coding variant (rs800292, I62V) and AMD (P = 8.63 x 10(-6)). In contrast, the Y402H variant showed no significant association with AMD (P = 0.101). Two common haplotypes also demonstrated significant association with AMD (P = 1.08 x 10(-3) and 2.00 x 10(-5)). Among the environmental factors, smoking alone had a significant association with AMD (P = 1.17 x 10(-4))."

Mori - Invest Ophthalmol Vis Sci 2007 abstract / PubMed

PLEKHA1-LOC387715-HTRA1 polymorphisms and exudative age-related macular degeneration in the French population. N Leveziel, EH Souied, F Richard, V Barbu, A Zourdani, G Morineau, J Zerbib, G Coscas, G Soubrane, P Benlian. Mol Vis 2007 Nov 26;13:2153-2159. "The A allele frequency was 0.67 in cases versus 0.41 in controls, (p=0.0001). After age and sex adjustment, the odds ratio for risk of AMD was 9.1 (4.0-20.9, 95% CI, p=0.0001) for the AA genotype and 2.6 (1.3-5.5, 95% CI, p=0.04) for the AG genotype, conditional on HTRA1. Association was even stronger and independent with HTRA1. The A allele frequency was 0.51 in cases versus 0.22 in controls, (p=0.0001). The odds ratio was 15.5 (5.5-43.9, 95% CI, p=0.0001) for the AA genotype and 3.4 (1.9-6.1, 95% CI, p=0.0001) for the AG genotype."

Leveziel - Mol Vis 2007 abstract / PubMed

HTRA1 variant increases risk to neovascular age-related macular degeneration in Chinese population. F Lu, J Hu, P Zhao, Y Lin, Y Yang, X Liu, Y Fan, B Chen, S Liao, Q Du, C Lei, DJ Cameron, K Zhang, Z Yang. Vision Res 2007 Nov;47(24):3120-3123. 164 Chinese patients (90 wet AMD and 74 drusen) and 106 normal controls. "rs11200638 was significantly associated with wet AMD (p=5.00x10(-12)). Unlike in the Caucasian population, the risk allele of rs11200638 was not associated with drusen in our Chinese population."

Lu - Vision Res 2007 abstract / PubMed

Haplotypes in the Complement Factor H (CFH) Gene: Associations with Drusen and Advanced Age-Related Macular Degeneration. PJ Francis, DW Schultz, S Hamon, J Ott, RG Weleber, ML Klein. PLoS ONE. 2007 Nov 28;2(11):e1197. Age-Related Eye Disease Study (AREDS). (1) a cohort of families with AMD (1253 Caucasian affected and unaffected individuals from 124 extended families (average age 68.2 years; 492 males, 761 females); (2) a sporadic case/control cohort: 211 sporadic cases (age 79 years, range 57–100; 70 male, 141 female; 210 Caucasian, 1 Other racial origin) of advanced AMD and 183 unrelated ophthalmologically evaluated controls (age 74, range 63–92; 81 male, 102 female; 183 Caucasian; 2201 cases and controls from the Age-related Eye Disease Study (AREDS). "A subtractive approach utilized 27 haplotypes to determine the combination of SNPs with the lowest p-value of association with AMD using FBAT. This best combination comprised the following 3 SNPs: rs1061147, rs1061170, rs2274700 (p<0.0002, Table 2). Two nucleotide combinations of this 3-SNP haplotype were significantly associated with AMD status: rs1061147 ‘A’, rs1061170 ‘C’, rs2274700 ‘C’ and rs1061147 ‘C’, rs1061170 ‘T’, rs2274700 ‘T’. The other rs1061147, rs1061170, rs2274700 haplotype ‘C T C’ was not associated with AMD. We then investigated whether these haplotypes were associated with AMD development in the AREDS and case-control populations and found similar results (Table 3). Since the ‘CTC’ haplotype conferred no additional odds of developing AMD, it was also possible in the populations to assess the direction of the effects, finding that the ACC haplotype conferred higher disease odds and the CTT haplotype conferred lower disease odds of advanced AMD."

Francis / PLoS ONE. 2007 full article
Francis - PLoS ONE. 2007 full article / PubMed

Neovascular Age-Related Macular Degeneration Risk Based on CFH, LOC387715/HTRA1, and Smoking. AE Hughes, N Orr, C Patterson, H Esfandiary, R Hogg, V McConnell, G Silvestri, U Chakravarthy. PLoS Med 2007 Dec;4(12):e355. 401 cases from ophthalmology clinics in the Royal Victoria Hospital, Belfast, UK. "Five common haplotypes of CFH conferred a range of odds ratios (ORs) per copy from 1 to 4.17. Most of the effect of LOC387715/HTRA1 was mediated through one detrimental haplotype (carriage of one copy: OR 2.83; 95% confidence interval [CI] 1.91–4.20), with homozygotes being at particularly high risk (OR 32.83; 95% CI 12.53–86.07)." [Contrary to their anti-smoking hype, their data in Fig. 2 show no association between smoking and development of AMD among those with the low-risk genes, and the supposed smoking risk is probably merely a marker for exposure to infection among those with high-risk genes -cast]

Hughes / PLoS Med 2007 full article

Translational mini-review series on complement factor H: genetics and disease associations of human complement factor H. SR de Córdoba, EG de Jorge. Clin Exp Immunol 2008 Jan;151(1):1-13. "Several recent studies have described the association of genetic variations of the complement factor H gene (CFH) with atypical haemolytic uraemic syndrome (aHUS), age-related macular degeneration (AMD) and membranoproliferative glomerulonephritis (MPGN)."

de Córdoba - Clin Exp Immunol 2008 abstract / PubMed
de Córdoba - Clin Exp Immunol 2008 full article / PubMed Central

Age-Related Macular Degeneration Is Associated with Increased Proportion of CD56+ T Cells in Peripheral Blood. C Faber, A Singh, M Krüger Falk, HB Juel, TL Sørensen, MH Nissen. Ophthalmology 2013 Nov;120(11):2310-2316. 117 AMD cases and 106 controls. "[P]atients with AMD had an increased frequency of CD28- T cells that expressed the CD56 surface marker (patients, 34.9% vs. aged controls, 25.8%; P = 0.002). Participants in the highest tertile of CD56+ CD28- T cells had an odds ratio (OR) for the presence of AMD of 3.2 (95% confidence interval [CI], 1.2-8.8) after adjustment for CFH genotype, anti-CMV IgG positivity, age, sex, and smoking history. The adjusted OR of the presence of AMD for persons having at least 1 CFH H402 risk allele increased from 3.5 (95% CI, 1.5-8.1) to 13.3 (95% CI, 3.3-53.6) for persons with at least 1 CFH H402 risk allele and above the median level of CD56+ CD28- T cells."

Faber - Ophthalmology 2013 abstract / PubMed

Identification of Factor H-like Protein 1 as the Predominant Complement Regulator in Bruch's Membrane: Implications for Age-Related Macular Degeneration. SJ Clark, CQ Schmidt, AM White, S Hakobyan, BP Morgan, PN Bishop. J Immunol 2014 Nov 15;193(10):4962-4970. "We show that FHL-1 can passively diffuse through Bruch's membrane, whereas the full sized, glycosylated, FH cannot. FHL-1 is largely bound to Bruch's membrane through interactions with heparan sulfate, and we show that the common Y402H polymorphism in the CFH gene, associated with an increased risk of AMD, reduces the binding of FHL-1 to this heparan sulfate. We also show that FHL-1 is retained in drusen whereas FH coats the periphery of the lesions, perhaps inhibiting their clearance."

Clark - J Immunol 2014 abstract / PubMed

Estimating cumulative pathway effects on risk for age-related macular degeneration using mixed linear models. JB Hall, JN Cooke Bailey, JD Hoffman, MA Pericak-Vance, WK Scott, JL Kovach, SG Schwartz, A Agarwal, MA Brantley Jr, JL Haines, WS Bush. BMC Bioinformatics 2015 Oct 14;16:329. 1813 subjects. "The goal of our study was to estimate the cumulative genetic contribution of common variants on AMD risk for multiple pathways related to the etiology of AMD, including angiogenesis, antioxidant activity, apoptotic signaling, complement activation, inflammatory response, response to nicotine, oxidative phosphorylation, and the tricarboxylic acid cycle. While these mechanisms have been associated with AMD in literature, the overall extent of the contribution to AMD risk for each is unknown... We found that 19 previously associated AMD risk SNPs contributed to 13.3 % of the risk for AMD in our dataset, while the remaining genotyped SNPs contributed to 36.7 % of AMD risk. Adjusting for the 19 risk SNPs, the complement activation and inflammatory response pathways still explained a statistically significant proportion of additional risk for AMD (9.8 % and 17.9 %, respectively), with other pathways showing no significant effects (0.3 % - 4.4 %)." Nicotine metabolism pathways "explained approximately 2% of the risk or less (non-significant)." "After adjusting for smoking, the proportion of risk explained by each pathway did not change considerably... All pathways exhibited little change and we conclude that adjusting for smoking status does not modulate the cumulative effect of SNPs within any of the targeted pathways."

Hall - BMC Bioinformatics 2015 full article / PubMed Central
Hall / BMC Bioinformatics 2015 full article

Age-related macular degeneration: Complement in action. M van Lookeren Campagne, EC Strauss, BL Yaspan. Immunobiology 2015 Dec 19 [Epub ahead of print]. Review.

van Lookeren Campagne - Immunobiology 2015 full article / Science Direct

Increased serum IgA concentration and plasmablast frequency in patients with age-related macular degeneration. H Yu, L Yuan, Y Yang, S Ma, L Peng, Y Wang, C Zhang, T Li. Immunobiology 2016 Jan 16 [Epub ahead of print]. Number of subjects not in abstract. "Despite the close associations between AMD development and inhibitory complement factor H mutations, the first step of complement activation, which is the antibody response in AMD patients, has not been studied... We found that compared to Non-AMD controls, AMD subjects had increased IgA titers in serum and tear, and had elevated levels of circulating antibody-secreting plasmablasts. The increase in antibody titer was limited to the IgA isotype, since no significant differences were observed in IgM and IgG isotypes between AMD patients and Non-AMD controls. Interestingly, this increased antibody response in AMD patients was correlated with disease severity, as late AMD patients had increased IgA titers in serum and tear, as well as elevated plasmablast frequency after staphylococcal enterotoxin B stimulation, compared to early AMD patients. Together, our results implicated a role of overreactive IgA responses in AMD pathogenesis."

Yu - Immunobiology 2016 abstract / PubMed

Streptococci and Factor H

The M protein of group A streptococci, the beta protein of group B streptococci, and Hic proteins of pneumococci (Streptococcus pneumoniae) bind to factor H.

Pathogenesis of Group A Streptococcal Infections. MW Cunningham. Clinical Microbiology Reviews 2000 Jul;13(3):470-511. "Group A streptococci are extracellular bacterial pathogens which produce a variety of pyogenic infections involving the mucous membranes, tonsils, skin, and deeper tissues, including pharyngitis, impetigo/pyoderma, erysipelas, cellulitis, necrotizing fasciitis, toxic streptococcal syndrome, scarlet fever, septicemia, pneumonia, and meningitis. Infections may be mild to extremely severe. Complications such as sepsis, pneumonia, and meningitis can occur, which may lead to a fatal outcome. Several specific clinical syndromes, such as toxic streptococcal syndrome and necrotizing fasciitis, have reemerged and perhaps become more prevalent in the past 10 years due to infections with S. pyogenes." Different strains of the bacteria cause the different illnesses: "The strong resistance of the group A streptococcus to phagocytosis is related to factor H and fibrinogen binding by M protein and to disarming complement component C5a by the C5a peptidase. Molecular mimicry appears to play a role in autoimmune mechanisms involved in rheumatic fever, while nephritis strain-associated proteins may lead to immune-mediated acute glomerulonephritis." "[A]n unexplained resurgence of group A streptococcal infections has been observed since the mid-1980s." "[G]roup A streptococci have the potential to invade human epithelial cells at frequencies equal to or greater than classical intracellular bacterial pathogens, such as Listeria and Salmonella spp."

Cunningham / Clin Microbiol Rev 2000 full article

The group B streptococcal beta and pneumococcal Hic proteins are structurally related immune evasion molecules that bind the complement inhibitor factor H in an analogous fashion. H Jarva, J Hellwage, TS Jokiranta, MJ Lehtinen, PF Zipfel, S Meri. J Immunol 2004 Mar 1;172(5):3111-3118. "Complement evasion by different mechanisms is important for microbial virulence and survival in the host. One strategy used by pathogenic bacteria is to bind the soluble complement inhibitor factor H (fH) to their surfaces. In group B streptococci and pneumococci, fH binding has been shown to be mediated by the surface proteins and Hic, respectively... Group B β-hemolytic streptococci (GBS; Streptococcus agalactiae) cause life-threatening infections especially during the neonatal period...GBS express several surface proteins, some of which are involved in the immune evasion. One of these proteins is the β protein (also called Bac). The protein binds to the Fc part of human IgA. Recently it was found to bind C inhibitor factor H (fH)... Binding of fH has been observed also by other types of streptococci, such as group A streptococci (GAS; Streptococcus pyogenes) and pneumococci (Streptococcus pneumoniae). Most GAS strains express one to three different types of fibrillar M family proteins that are antiphagocytic and important for the virulence of the bacteria. Some types of M proteins bind fH and/or the classical pathway complement regulator C4b-binding protein... The purpose of the present study was to take a comparative approach and analyze the fH binding properties of the GBS β protein and pneumococcal Hic by locating the binding site of β on fH and the fH binding sites on both β and Hic. We found that β and Hic, although expressed by different bacterial species, show remarkable homology and similarities in their fH binding properties."

Jarva / J Immunol 2004 full article

Biochemical analysis of a common human polymorphism associated with age-related macular degeneration. J Yu, P Wiita, R Kawaguchi, J Honda, A Jorgensen, K Zhang, VA Fischetti, H Sun. Biochemistry 2007 Jul 17;46(28):8451-8461. "A large number of human genetic studies have associated a common variant (Y402H) of complement factor H (CFH) with a highly significant increase in AMD risk... The Y402H variant is located in SCR7 of both CFH and factor H-like protein 1 (FHL-1), a splice variant of CFH (containing SCR1-7) with unique biochemical properties. Because SCR7 is known to bind to heparin, C-reactive protein (CRP), and M protein from Streptococcus pyogenes, it has been hypothesized that the AMD-associated polymorphism may affect interactions with these CFH ligands. In this study, we tested this hypothesis in the context of full-length CFH (SCR1-20) and FHL-1. We systematically analyzed the interactions of the Y402 and H402 variants of CFH and FHL-1 with heparin, CRP, and several bacterial ligands: M6 protein of Streptococcus pyogenes, PspC of Streptococcus pneumoniea, and BbCRASP-1 of Borrelia burgdorferi. In comparing the Y and H variants of CFH and FHL-1, we found no significant difference in their protein secretion, cofactor activity, or interactions with heparin, BbCRASP-1, or PspC, but a significant difference in binding to CRP and M6 protein. This study reveals the fundamental properties of a common polymorphism of CFH and lays the groundwork for elucidating the role of CFH in AMD pathogenesis."

Yu - Biochemistry 2007 abstract / PubMed

Molecular Basis of Factor H R1210C Association with Ocular and Renal Diseases. S Recalde, A Tortajada, M Subias, J Anter, M Blasco, R Maranta, R Coco, S Pinto, M Noris, A García-Layana, S Rodríguez de Córdoba. J Am Soc Nephrol 2015 Sep 16 [Epub ahead of print]. "The complement factor H (FH) mutation R1210C, which was described in association with atypical hemolytic uremic syndrome (aHUS), also confers high risk of age-related macular degeneration (AMD) and associates with C3 glomerulopathy (C3G)... Disease status, determined in patients and relatives, revealed an absence of AMD phenotypes in the aHUS cohort and, vice versa, a lack of renal disease in the AMD cohort." Factor H complexes with HSA "impairs accessibility to all FH functional domains. These data suggest that R1210C is a unique C-terminal FH mutation that behaves as a partial FH deficiency, predisposing individuals to diverse pathologies with distinct underlying pathogenic mechanisms; the final disease outcome is then determined by R1210C-independent genetic risk factors."

Recalde - J Am Soc Nephrol 2015 abstract / PubMed

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