Complement Factor H Y402H Research Articles

Relationship between Systemic Cytokines and Complement Factor H Y402H Polymorphism in Patients With Dry Age-Related Macular Degeneration

To investigate the relationship between systemic cytokines, the complement factor H (CFH) Y402H polymorphism, drusen load, and subfoveal choroidal thickness in patients with dry age-related macular degeneration (AMD). Cross-sectional study. Forty-four dry AMD patients under care of the Retina Service at the University of British Columbia were enrolled. Drusen load was measured with an automated software algorithm in spectral-domain optical coherence tomography; subfoveal choroidal thickness was measured manually using enhanced depth imaging. Bio-Plex suspension assays (Bio-Rad Laboratories) were used to analyze cytokines in plasma and CFH Y402H was genotyped. Statistical analyses included analysis of covariance and Pearson correlation, corrected for multiple comparisons. The levels of 3 of 4 studied cytokines were significantly different among patients with CC, CT, or TT variants of the CFH Y402H polymorphism (P < .01). Patients with the at-risk CC variant had higher systemic levels of interleukin-6, interleukin-18, and tumor necrosis factor α than those with the CT variants, the TT variant, or both (P < .01). Interleukin-1β did not reach significance (P= .02), but did demonstrate a consistent trend. No correlation was found between plasma cytokines and drusen load or choroidal thickness (all P > .15). The elevated systemic levels of selected proinflammatory cytokines, including those representing products of inflammasome activation, were associated with the CC at-risk variant of the Y402H polymorphism and suggest that genetic factors regulate the inflammatory status in dry AMD patients. Our data support the central role of inflammation in the pathogenesis of AMD and provide further evidence of a systemic involvement in AMD etiology.

Association between CFH Y402H Polymorphism and Age Related Macular Degeneration in North Indian Cohort

The purpose of the study was to determine serum complement factor H (CFH) levels in patients of age related macular degeneration (AMD) and examine its association with CFH Y402H polymorphism. 115 AMD patients and 61 normal controls were recruited in this study. The single nucleotide polymorphism was assayed by real time PCR and serum CFH levels were measured by ELISA and standardized to total serum protein. Chi-square test was applied to polymorphism analysis while Mann Whitney U-statistic for CFH-levels. Mendelian randomization approach was used for determining causal relationship. The genotype frequency differed between the AMD patients (TT- 18.3%, TC-41.3% and CC-40.4%) and controls (TT-76.3%, TC-13.6%, and CC-10.1%) (p = 0001). The frequency of alleles was also significantly different when AMD (T-39% and C-61%) was compared to controls (T-83% and C-17%) (p = 0.0001). Level of serum CFH was significantly lower in AMD patients as compared to normal controls (p = 0.001). Our data showed that the CFH Y402H polymorphism is a risk factor for AMD in the North Indian population. Mendelian randomization approach revealed that CFH Y402H polymorphism affects AMD risk through the modification of CFH serum levels.

Age-related Macular Degeneration and Modification of Systemic Complement Factor H Production Through Liver Transplantation

To investigate whether modification of liver complement factor H (CFH) production, by alteration of liver CFH Y402H genotype through liver transplantation (LT), influences the development of age-related macular degeneration (AMD). Multicenter, cross-sectional study. We recruited 223 Western European patients ≥ 55 years old who had undergone LT ≥ 5 years previously. We determined AMD status using a standard grading system. Recipient CFH Y402H genotype was obtained from DNA extracted from recipient blood samples. Donor CFH Y402H genotype was inferred from recipient plasma CFH Y402H protein allotype, measured using enzyme-linked immunosorbent assays. This approach was verified by genotyping donor tissue from a subgroup of patients. Systemic complement activity was ascertained by measuring levels of plasma complement proteins using an enzyme-linked immunosorbent assay, including substrates (C3, C4), activation products (C3a, C4a, and terminal complement complex), and regulators (total CFH, C1 inhibitor). We evaluated AMD status and recipient and donor CFH Y402H genotype. In LT patients, AMD was associated with recipient CFH Y402H genotype (P = 0.036; odds ratio [OR], 1.6; 95% confidence interval [CI], 1.0-2.4) but not with donor CFH Y402H genotype (P = 0.626), after controlling for age, sex, smoking status, and body mass index. Recipient plasma CFH Y402H protein allotype predicted donor CFH Y402H genotype with 100% accuracy (n = 49). Plasma complement protein or activation product levels were similar in LT patients with and without AMD. Compared with previously reported prevalence figures (Rotterdam Study), LT patients demonstrated a high prevalence of both AMD (64.6% vs 37.1%; OR, 3.09; P<0.001) and the CFH Y402H sequence variation (41.9% vs 36.2%; OR, 1.27; P = 0.014). Presence of AMD is not associated with modification of hepatic CFH production. In addition, AMD is not associated with systemic complement activity in LT patients. These findings suggest that local intraocular complement activity is of greater importance in AMD pathogenesis. The high AMD prevalence observed in LT patients may be associated with the increased frequency of the CFH Y402H sequence variation. The authors have no proprietary or commercial interest in any materials discussed in this article.

Association of Complement Factor H Tyrosine 402 Histidine Genotype with Posterior Involvement in Sarcoid-Related Uveitis

To determine whether the complement factor H (CFH) tyrosine 402 histidine (Y402H) variant, recently shown to be associated with age-related macular degeneration (AMD) and multifocal choroiditis, is associated with specific ocular sarcoidosis clinical phenotypes in black and white persons. Case-control study. The CFH Y402H polymorphism (rs1061170) was genotyped in 41 subjects with ocular sarcoidosis and 393 control subjects. Allele frequencies in the ocular sarcoidosis cases were compared with controls using chi-square score tests. Genotypic model-based (dominant, recessive, and additive) associations of the rs1061170 allele were tested using multivariate logistic regression. Bayesian information criteria were used to formalize modelselection. Genotypes were correlated with disease characteristics and severity of ocular inflammation. The C allele (rs1061170) was found in 35% of controls, but occurred with a significantly higher frequency (48.7%) in ocular sarcoidosis cases (odds ratio, 1.72; 95% confidence interval, 1.09 to 2.78; P= .018). Logistic regression demonstrated an association between rs1061170 and ocular sarcoidosis in 2 of 3 genetic models (additive, P= .0078; recessive, P= .0018). Posterior uveitis and panuveitis were overrepresented significantly in cases with the homozygous variant genotype (CC, 91%; P= .047). The population-attributable risk related to this CFH risk variant was 20%. The Y402H polymorphism of CFH seems to be associated with ocular sarcoidosis in black and white persons. Carriage of the CFH Y402H polymorphism in both alleles is associated with an increased risk for posterior uveitis and panuveitis presentation. The prognostic importance of this genotype will require prolonged follow-up studies.

Effect of the Y402H Variant in the Complement Factor H Gene on the Incidence and Progression of Age-Related Macular Degeneration

To investigate the effect of age, sex, and the Y402H variant in the complement factor H (CFH) gene on the incidence, progression, and regression of age-related macular degeneration (AMD) as well as the effect of these factors and AMD on mortality, using multistate models. Analyses included 4379 persons aged 43 to 84 years at the time of the census. The status of AMD on a 5-level severity scale was graded from retinal photographs taken at up to 5 study visits between 1988 and 2010. Multistate models in continuous time were used to model the effects of age, sex, and CFH genotype on the incidence, progression, and regression of AMD and mortality. The CFH Y402H genotype CC was associated, relative to genotype TT (reported as hazard ratio; 95% CI), with increased incidence of AMD (no to minimally severe early AMD, 1.98; 1.57-2.49), progression of AMD (minimally severe early to moderately severe early AMD, 1.73; 1.29-2.33; moderately severe early to severe early AMD, 1.30; 0.86-1.94; and severe early to late AMD, 1.72; 1.01-2.91) but not with regression of AMD or mortality. Late AMD was associated with increased mortality (1.37; 1.15-1.62) relative to no AMD, but earlier stages of AMD were not. Using the multistate models, we show that the Y402H risk variant is associated with lifetime incidence of early AMD and progression of early to late AMD and that late AMD is associated with mortality risk.

Association between complementary factor H Y402H polymorphisms and age-related macular degeneration in Chinese: Systematic review and meta-analysis.

Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world and complement factor H (CFH) polymorphism has been found to associate with the AMD. To investigate whether the Y402H variant in CFH is associated with AMD in Chinese populations, a systematic review and meta-analysis were performed to estimate the magnitude of the gene effect and the possible mode of action. A meta-analysis was performed using data available from ten case-control studies assessing association between the CFH Y402H polymorphism and AMD in Chinese populations involving 1538 AMD. Data extraction and study quality assessment were performed in duplicate. Summary odds ratios (ORs) and 95% confidence intervals (CIs) an allele contrast and genotype contrast were estimated using fixed- effects models. The Q-statistic test was used to assess heterogeneity, and Funnel plot was used to evaluate publication bias. Seven of ten case-control studies were neovascular AMD, and few studies came from west and north of China. There was strong evidence for association between CFH and AMD in Chinese population, with those having risk allele C 2.35 times more likely to have AMD than subjects with T allele. Evidence of publication bias was not observed in our meta-analysis. [corrected] This meta-analysis summarizes the strong evidence for an association between CFH and AMD in Chinese and indicates each C allele increasing the odds of AMD by 2.33-fold.But more evidences about the relation between CFH polymorphism and different type of Chinese AMD from various district were needed.

Contribution of complement factor H Y402H polymorphism to sudden sensorineural hearing loss risk and possible interaction with diabetes

Sudden sensorineural hearing loss (SSNHL) is one of the most common diseases encountered by otolaryngologists; however, the etiology is unclear. The aim of this study was to assess the association between SSNHL and polymorphism of complement factor H (CFH) Y402H, which is implicated in age-related macular degeneration. We conducted a case–control study, in which the cases were 72 SSNHL patients and the controls were 2161 residents selected randomly from the resident register. The odds ratio (OR) for SSNHL risk was determined using the additive-genetic model of CFH Y402H polymorphism. The OR for SSNHL risk was 1.788 (95% confidence interval [CI]: 1.008–3.172) with no adjustments and 1.820 (CI: 1.025–3.232) after adjusting for age and sex. Of the three lifestyle-related diseases hypertension, dyslipidemia, and diabetes, only diabetes was significantly associated with SSNHL risk. We classified both the controls and SSNHL patients into those with or without diabetes, and the OR for SSNHL risk was 6.326 (CI: 1.885–21.225) in diabetic subjects and 1.214 (CI: 0.581–2.538) in nondiabetic subjects. We conclude that CFH Y402H polymorphism and SSNHL risk are significantly related, and that diabetic CFH Y402H minor allele carriers may be susceptible to SSNHL.

Pharmacogenetic Influence of LOC387715/HTRA1 on the Efficacy of Bevacizumab Treatment for Age-Related Macular Degeneration in a Korean Population

PurposeThe purpose of this study was to determine the pharmacogenetic effects of complement factor H (CFH) Y402H, LOC387715 and high-temperature requirement factor A1 (HTRA1) genotypes on the treatment of exudative age-related macular degeneration (AMD) by intravitreal bevacizumab injection in a Korean population.MethodsSeventy-five patients diagnosed with exudative AMD were treated with intravitreal bevacizumab (2.5 mg) monotherapy. All patients received three initial intravitreal bevacizumab injections every four weeks and were then treated "as needed" based on clinical findings, optical coherence tomography and fluorescein angiography during the 12 month follow-up period after the third injection.ResultsThe difference in visual acuity improvement among the three genotypes of LOC387715 were statistically significant at six months post-treatment (logarithm of the minimum angle of resolution; TT, 0.346; GT, 0.264; GG, 0.188; p = 0.037). Among the LOC387715 genotypes, the number of additional injections was lower in patients who had the risk T allele (GG, 2.143; GT, 2.000; TT, 1.575; p = 0.064). There was no significant difference between visual acuity and central macular thickness change in the CFH Y402H polymorphism group during the 12 month follow-up period. However, the TC group of CFH Y402H required more additional bevacizumab injections than the TT group (TT, 1.517; TC, 3.363; p = 0.020).ConclusionsThis study demonstrated that different LOC387715/HTRA1 genotypes resulted in different bevacizumab treatment responses on exudative AMD. Patients with the risk allele had an improved treatment response and less need for additional injections. However, patients with the CFH Y402H risk allele needed more additional injections of bevacizumab in order to improve visual acuity. This study illustrates how pharmacogenetic factors may help determine treatment modality and dosing. This could ultimately provide basic data for 'personalized medicine' in AMD.

Cigarette smoking strongly modifies the association of complement factor H variant and the risk of lung cancer

The complement system is an important immunosurveillance mechanism against tumors, and complement factor H (CFH) is a key regulator for activation of the complement system. Expression of complement factor H has been demonstrated in cell lines from several malignancies. In this study we examined the contribution of the single-nucleotide polymorphism (SNP) Try402His (Y402H) (rs1061170) in the CFH gene to the risk of lung cancer in a case–control study with 1000 cases and 1000 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed by logistic regression. The frequencies for CFH Y402H genotypes among the cases were statistically significantly different from those among controls (χ2=8.66, P=0.003), with 402His/His or 402His/Try genotypes being over-represented among patients compared with controls (13.6% versus 9.4%, P<0.004). A multivariate regression analysis showed that a significantly increased risk of lung cancer for the 402His/His or 402His/Try carriers with OR (95% CI), 1.50 (1.12–2.00). When stratified by smoking status, the elevated risk of the cancer associated with variant CFH genotypes was observed among smokers, but not among non-smokers. When analyzed with cumulative smoking dose (pack-years), a super-multiplicative interaction was observed at different smoking levels. Among carriers with the 402Tyr/His or His/His genotype, the ORs of developing lung cancer for smoking<16, 16–28, or >28 pack-years were 0.98 (0.49–1.94), 2.36 (1.14–4.90), and 6.39 (3.49–11.68), respectively. These findings suggest that CFH Y402H polymorphism may interact with cigarette smoking to effect the development of lung cancer in the Chinese population.

The major risk alleles of age-related macular degeneration (AMD) in CFH do not play a major role in rheumatoid arthritis (RA)

Because activation of the alternative pathway (AP) of the complement system is an important aspect of both age-related macular degeneration (AMD) and rheumatoid arthritis (RA), we wished to address the question whether genetic risk factors of the AP inhibitor complement factor H (CFH) for AMD would also be risk factors for RA. For this purpose we genotyped single nucleotide polymorphisms (SNPs) in a Dutch set of RA patients and controls. Similarly, a meta-analysis using a Spanish cohort of RA as well as six large genome-wide association studies (GWAS) studies was performed. For these SNPs we analysed more than 6000 patients and 20,000 controls. The CFH variants, I62V, Y402H, IVS1 and IVS10, known to associate strongly with AMD, did not show a significant association with the risk of developing RA despite a strong statistical power to detect such differences. In conclusion, the major risk alleles of AMD in CFH do not have a similar effect on developing RA.

Association of Alzheimer's disease and age‐related macular degeneration

AbstractPurpose The pathomechanisms of age‐related macular degeneration (AMD) and Alzheimer dementia (AD) show several similarities. Allelic variations of apolipoprotein E (apoE) are associated with both diseases: apoE4 with increased risk of AD, whereas apoE2 with reduced susceptibility of AD, but increased risk of AMD. The AMD associated complement factor H (CFH) gene has also been shown to influence the risk of AD. We investigated, therefore, the occurrence of AMD in AD patients and compared their lipid profile, apoE and CFH polymorphisms.Methods 96 AMD, 84 AD and 30 control patients were examined (visual acuity, biomicroscopy, fundoscopy). Measurements of triglyceride, total‐ and HDL cholesterol levels, as well as the analysis of apoE and CFH alleles were performed.Results The prevalence of the apoE4 isoform in the AMD, AD and control patients was 6%, 34% and 27%, while that of apoE2 was 14%, 11% and 6%, respectively. The occurrence rate of CFH Y402H CC homozygote mutation was 35%, 19% and 16%, respectively. Triglyceride, total‐ and HDL cholesterol levels were in the reference range. Advanced AMD was found in 13% of the 68 cooperating AD patients, the early and intermediate form was seen in 17%.Conclusion A higher frequency of apoE2 in AMD, and a higher frequency of apoE4 in Alzheimer's patients have been found. The CFH mutation is associated with AMD, but does not differ significantly between Alzheimer's patients and controls. The frequency of early and intermediate AMD in AD patients was lower than expected from the population‐based studies.

Associations of Complement Factor H and Smoking with Early Age-Related Macular Degeneration: The ALIENOR Study

To assess the associations of complement factor H (CFH) Y402H polymorphism and smoking with specific features of early AMD (type, location, and area). The ALIENOR study is a population-based study of age-related eye diseases in 963 residents of Bordeaux (France), aged 73 years or more. AMD features were graded from nonmydriatic color retinal photographs. CFH Y402H was genotyped by using DNA extracted from blood. Statistical analyses included 796 subjects with complete data. CFH CC genotype was strongly associated with late neovascular AMD (OR, 6.0; 95% confidence interval [CI], 1.5-23.5) but not with late atrophic AMD (OR, 0.9; 95% CI, 0.2-4.3). Among early characteristics, it was associated with central soft drusen (within 500 μm of the fovea), whether of intermediate (63-125 μm; OR, 2.7; 95% CI, 1.5-4.8), or large (>125 μm; OR, 5.9; 95% CI, 2.2-15.7) size, but not with pericentral soft drusen (500-3000 μm from the fovea). It was also strongly associated with a large central area of soft drusen (OR, 5.7; 95% CI, 1.7-19.2). Similarly, heavy smoking (>20 pack-years) was strongly associated with central large drusen (OR, 3.9; 95% CI, 1.6-9.6) and a large central area of drusen (OR, 3.5; 95% CI, 1.2-10.0), but not with pericentral soft drusen. By contrast, both CFH CC and smoking tended to be more strongly associated with pericentral pigmentary abnormalities. Location of abnormalities, together with type and area, may prove useful for the identification of subjects at high risk for late AMD.

LOC387715/HTRA1 polymorphisms, smoking and combined effects on exudative age‐related macular degeneration in a Korean population

This study was to investigate the association of two single nucleotide polymorphisms (SNPs) in LOC387715 and HTRA1 with exudative age-related macular degeneration (AMD) in a Korean population and the gene-gene and gene-environment interactions in the development of AMD. We genotyped two SNPs that are located in the LOC387715 locus (rs10490924) and HTRA1 (rs11200638) in 137 cases of exudative AMD and 187 controls. Both two SNPs were significantly associated with AMD (P = 0.0001). Homozygotes for the risk allele at LOC387715 and HTRA1 had a 3.80-fold and a 4.03-fold increased risk of exudative AMD, respectively, compared with homozygotes for the wild-type allele (P = 0.0001). The joint effects for complement factor H (CFH) Y402H and 10q26 variants indicated an increased risk of exudative AMD. The odds ratios (ORs) of AMD for individuals carrying one-, two- and three-copy risk alleles of CFH Y402H and LOC387715 were 1.08, 3.49 and 3.64, respectively. Also, the combination effect of the CFH Y402H risk alleles with HTRA1 risk alleles was dose-dependent. The interaction analysis between gene and environmental factors showed that among several factors, smoking synergistically increased the susceptibility of AMD for variants of LOC387715 and HTRA1, with OR 8.33 (3.05-22.74) and OR 8.50 (3.07-23.51), respectively. This study demonstrated the significant association of the 10q26 SNPs (HTRA1 and LOC387715) in an AMD cohort from Korea and was consistent with previous studies from other populations. Also, a statistically significant interaction between genetic and environmental factors was found.

6116 Epidermal growth factor receptor (EGFR) expression in stage II-III colon carcinoma (CC) – nine years of follow-up

To investigate vascular endothelial growth factor (VEGF) gene polymorphisms in unrelated Taiwan Chinese patients with late age-related macular degeneration (AMD) and controls.Retrospective case-control study.We enrolled 190 late AMD patients and 180 age-matched and gender-matched controls. Late AMD was classified as either dry (atrophic; grade 4) or wet (neovascular; grade 5) according to the International Age-Related Maculopathy Epidemiologic Study. Genomic deoxyribonucleic acid was prepared from peripheral blood obtained from all subjects. Polymerase chain reactions were used to analyze five candidate single-nucleotide polymorphisms (SNPs) in VEGF gene: +405C/G (rs2010963), −460 T/C (rs833061), +674 C/T (rs1413711), +936C/T (rs3025039), and −2578C/A (rs699947).Of the 190 late AMD patients, dry AMD was diagnosed in 104 and wet AMD in 86. Among the five candidate SNPs studied, only the +936 C/T was significantly associated with wet AMD (T allele: 30% in wet AMD vs 14% in controls; P = 1.45 × 10−5; odds ratio, 2.61; 95% confidence interval, 1.68 to 4.07). No single haplotype was significantly associated with either late AMD or controls. Based on genotypes at both VEGF +936 C/T and the complement factor H (CFH) Y402H (rs1061170), the association of VEGF +936 C/T to AMD was significant when analyzed conditional on the presence of the CFH C risk allele and vice versa (P < .0001). The VEGF +936 C/T was in strong linkage disequilibrium with CFH Y402H (D′ = 0.99).Both VEGF +936 C/T and CFH Y402H polymorphisms are dependently associated with wet AMD in the Taiwan Chinese population.

Complement Factor H Y402H and C-Reactive Protein Polymorphism and Photodynamic Therapy Response in Age-Related Macular Degeneration

To investigate the association between complement factor H (CFH) and C-reactive protein (CRP) genotypes and response to photodynamic therapy (PDT) treatment for neovascular age-related macular degeneration (AMD). Retrospective cohort study. The study cohort consisted of 273 neovascular AMD patients treated with PDT. Genotypes were determined for the common T-->C single nucleotide polymorphism (SNP) in exon 9 of the CFH gene (rs1061170; Y402H), as well as 9 selected tagging SNPs across the CRP gene (rs2808635, rs1417938, rs1800947, rs1130864, rs1205, rs3093077, rs876538, rs876537, and rs1572970). Visual acuity outcome after PDT was retrospectively calculated and patients were classified as PDT-positive responders or PDT-negative responders. Logistic regression analysis was used to evaluate the association between individual SNPs and PDT treatment response while adjusting for relevant covariates. Response to PDT treatment defined by visual acuity; genotypes of CFH Y402H and CRP polymorphism. Of the 273 patients, 75 had a positive response after PDT treatment. The frequency of CC genotype of the CFH Y402H polymorphism in the PDT-positive response group was lower than in the negative PDT response group (26.4% vs 31.6%) but this difference failed to reach statistical significance. Two CRP SNPs (rs2808635 and rs876538) were significantly associated with PDT treatment response. Positive treatment response was seen in individuals homozygous for the minor allele of the rs2808635 (GG; odds ratio [OR], 3.92; 95% confidence interval [CI], 1.40-10.97; P = 0.048) and rs876538 (AA; OR, 6.49; 95% CI, 1.65-25.47; P = 0.048) variants after adjusting for relevant covariates. The remaining 7 CRP genetic variants did not reveal any significant association with treatment response. Our data did not show significant association between the CFH Y402H polymorphism and PDT treatment response for neovascular AMD; however, CRP genetic variants were associated with a positive response to PDT treatment for neovascular AMD.

Complement factor H gene polymorphism and risk of cardiovascular disease in end-stage renal disease patients

The main cause of increased mortality in end-stage renal disease (ESRD) is cardiovascular disease (CVD). Complement factor H (CFH) may affect risk of CVD. Our study investigates a role of CFH Y402H polymorphism as a potential risk factor of CVD in a large group of patients. A group of 1200 patients with ESRD and 818 healthy controls were genotyped for the Y402H (T1277C) polymorphism. There was a significant difference in genotype frequencies between patients with CVD and those without CVD and healthy controls (p<0.001). Homozygosity for the C allele in CVD patients was associated with an odds ratio of 7.28 (95 % CI 5.32-9.95). No significant difference was found between patients without CVD and controls. Multivariate logistic regression analysis showed that Y402H genotype was independently associated with cardiovascular comorbidity in ESRD patients. This is the first study suggesting an association between CFH gene polymorphism and susceptibility to CVD in dialyzed patients.

The Y402H variant of complement factor H is associated with age‐related macular degeneration but not with diabetic retinal disease in the Go‐DARTS study

The Y402H variant of complement factor H (CFH) is associated with risk of age-related macular degeneration (ARMD). In common with ARMD, diabetic retinal disease also appears to involve complement activation. The aim was to investigate the impact of Y402H on both retinal pathologies in patients with Type 2 diabetes (T2DM) undergoing systematic eye screening. Patients with T2DM (n = 2350) were genotyped for the CFH Y402H variant. The association of genotype with retinal disease was determined in both retrospective and prospective models. The retrospective study demonstrated that the HH genotype was associated with an age-adjusted odds ratio of 7.4 for ARMD (P = 2.9 x 10(-11)). In a longitudinal study in the disease-free cohort, the age-adjusted hazard ratio was 2.8 (P = 2.4 x 10(-7)). The life-time hazard ratio was 3.4 (P = 2.1 x 10(-16)). We found no association of Y402H with development of referable diabetic retinal disease. The ARMD-associated Y402H variant in CFH does not appear to be associated with diabetic retinal disease, although complement activation is involved in the pathoaetiology of both conditions.

Complement Component C3 and Risk of Age-Related Macular Degeneration

To explore the association between polymorphisms in the complement component 3 (C3) gene and age-related macular degeneration (AMD), and to investigate the modifying effect of complement factor H (CFH) Y402H, LOC387715 A69S and smoking. Pooled data from the prospective, population-based Rotterdam Study (enrolment between 1990 and 1993, and 3 follow-up examinations between September 1, 1993, and December 31, 2004) and an independent case-control study from the Netherlands. The Rotterdam Study comprised a total of 6418 persons aged >or=55 years who had gradable fundus photographs. The case-control study consisted of 357 unrelated AMD patients and 173 control individuals aged >or=55 years. The variants R102G and P314L of the C3 gene, CFH Y402H and LOC387715 A69S, were genotyped in all study participants. Information on cigarette smoking was obtained by interview at baseline. Early and late stages of prevalent and incident AMD, graded according to the international classification and grading system for AMD. We found a population frequency of 0.217 for R102G and 0.211 for P314L in the Rotterdam Study. Both alleles significantly increased the risk of early AMD and all subtypes of late AMD, and this risk seemed to be independent of CFH Y402H, LOC387715 A69S, and smoking. Detailed analysis showed that the haplotype carrying both alleles had the highest frequency difference between cases and controls (P=0.006). We estimated a total population-attributable risk of 14.6%. A meta-analysis of all currently available data yielded a pooled odds ratio (OR) of 1.61 (95% confidence interval [CI], 1.46-1.78) for the R102G allele, and an OR of 1.50 (95% CI, 1.31-1.71) for the P314L allele. Our study showed a significant association between variants in the C3 gene and AMD and further highlights the crucial role of the complement pathway in the etiology of AMD.

Pharmacogenetics of complement factor H (Y402H) and treatment of exudative age-related macular degeneration with ranibizumab

Aims:To determine whether complement factor H (CFH) genotypes have a pharmacogenetic effect on the treatment of exudative age-related macular degeneration (AMD) with ranibizumab.Methods:A retrospective study of 156 patients with exudative...

Genetic variants in three genes and smoking show strong associations with susceptibility to exudative age-related macular degeneration in a Chinese population

The present study was undertaken to replicate the associations of representative polymorphisms in three genes (complement factor H (CFH), complement factor B (BF) and HtrA serine peptidase 1 (HTRA1)) with exudative age-related macular degeneration (AMD) in a Han Chinese population, and to test if the modifiable environmental factors affect AMD susceptibility associated with different type of genotype in these genes. An age, gender and ethnicity matched case-control study was conducted to genotype the representative single neucleotide polymorphisms (SNPs) loci including rs1061170 and rs1410996 in CFH, rs641153 and rs4151667 in BF and rs11200638 in HTRA1 gene in 144 exudative AMD patients and 126 normal controls using PCR-RFLP and direct resequencing. The demographic characteristics and behavioral risk factors were also recorded. Allelic and genotypic associations for individual SNP and joint associations with two loci were performed. The gene-gene and gene-environment interactions were analyzed using multivariate non-conditional Logistic regression analysis. The C risk allele frequencies for CFH Y402H (rs1061170) in cases and controls were 12.5% and 5.4% respectively, which were much lower than those in Caucasians (P < 0.001). Compared with TT homozygous genotype, the CT heterozygous genotype was positively associated with AMD with odds ratio (OR) of 3.23 (1.36 - 5.07). However, the population attributable risk (PAR) of C allele was only 3.3% (1.4% - 4.3%). rs1410996 was also associated with AMD independent of Y402H. The ORs of exudative AMD for individuals carrying one copy risk allele and two copy risk alleles were 2.57 (1.21 - 5.45) and 4.76 (2.15 - 10.55) respectively, with correspondent PARs of 28.3% (2.0% - 40.5%) and 38.2% (21.8% - 45.4%). rs11200638 in HTRA1 was another susceptible locus for AMD and the risk homozygotes were significantly susceptible for exudutive AMD (OR = 3.98, 1.88 - 8.43) with PAR of 38.9% (24.3% - 45.8%). Education status and cigarette smoking were also related to exudative AMD. After controlling for environmental risk factors, CFH and HTRA1 SNPs were independently associated with exudative AMD, with OR of 3.50 (1.45 - 8.45) for CT genotype in Y402H, 3.34 (1.33 - 8.36) for GG genotype in rs1410996 and 3.85 (1.58 - 9.42) for AA genotype in rs11200638 respectively. The interaction analysis between gene and environmental factors showed that smoking synergistically increased susceptibility of AMD for heterozygotes of rs1410996, with OR(interaction) of 7.33 (P(interaction) = 0.029). In a Han Chinese population, CFH and HTRA1 polymorphisms appear to be independently and possibly additively hereditary contributors to exudative AMD. Y402H polymorphism conferred a significant but relatively lower contribution in Chinese than in Caucasians with a low frequency of risk allele. The gene-environment interaction may be a best way to encourage those with a high genetic risk to prevent AMD by avoiding modifiable factors until there is effective treatment for AMD.