No Sex Differences in the Frequencies of Common Single Nucleotide Polymorphisms Associated with Age-Related Macular Degeneration.
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ABSTRACT: Purpose
Since some studies have reported differences in the association of age-related macular degeneration (AMD) with biological sex, we set out to determine whether the difference in the disease susceptibility is afforded by common single nucleotide polymorphisms (SNPs) associated with AMD.Methods
We genotyped 2067 Caucasian subjects from the Age-Related Eye Disease Study cohort for commonly associated AMD SNPs, including those in CFH (rs1061170, rs1410996, and rs3766404), ARMS2 (rs10490924), and C3 (rs2230199) using either a Sequenom MassARRAY MALDI-TOF mass spectrometer or using Taqman genotyping reagents. A Cox proportional hazards model was used to determine the effect of genotype, age, sex, and smoking status on the development of AMD.Results
All tested SNPs genotyped are associated strongly with AMD (p < 0.0001), in concordance with previous studies. However, we found no observable differences in any of the SNPs studied when categorized by sex. Interactions between SNPs and sex were found to be not statistically significant (p = 0.38-0.79).Conclusions
The difference between male and female incidence of AMD is not explained by the most commonly AMD-associated SNPs, though it does not exclude the possibility that other, less common SNPs contribute to this difference.
SUBMITTER: Popp NA
PROVIDER: S-EPMC8324397 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe prevalence of age-related macular degeneration (AMD) varies from 6.8 to 18.3% for all forms of AMD and from 0.6 to 2.6% for late AMD according to race, suggesting the existence of genetic differences among races. The purpose of this study was to determine the genetic causes of differences in the prevalence of AMD among individuals of different races.MethodsWe collected 138 AMD-associated single nucleotide polymorphisms (SNPs) from a genome-wide association studies catalog. Their population-level allele frequencies were derived based on the 1000 Genomes Project and Korean Reference Genome Database. We used Fisher's exact tests to assess whether the effect allele at a given SNP was significantly enriched or depleted in the database.ResultsEuropean, American, and South Asian populations showed similar heatmap patterns, whereas East Asian, and Korean populations had distinct patterns. Korean populations exhibited patterns that were different from those of the other groups; rs5754227 (SYN3), rs1626340 (TGFBR1/COL15A1), rs3750846(ARMS2/HTRA1), and rs9564692 (B3GALTL) were enriched, whereas rs2230199 (C3) and rs73036519 (EXOC3L2/MARK4) were depleted in Koreans; these SNPs are associated with late AMD. The genetic risk score calculated from allele frequencies was not less in East Asians than in Europeans.ConclusionThe prevalence of AMD is lower in Asians than in Europeans. However, our study showed that genetic risk scores in East Asians were similar to those in Europeans, which may explain why the global projected number of people with AMD by 2040 is in largest for East Asians, including Koreans.
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Project description:PurposeTenomodulin (TNMD) is located in the X-chromosome encoding a putative angiogenesis inhibitor which is expressed in retina. Associations of single nucleotide polymorphisms of TNMD with the prevalence of age-related macular degeneration (AMD) were examined.MethodsSix markers covering 75% of the common sequence variation in the coding region of TNMD and 10 kb up- and downstream were genotyped in a sample consisting of 89 men and 175 women with exudative AMD, 18 men and 25 women with atrophic AMD, and 55 men and 113 women without AMD. All participants were over 65 years old and did not have diabetes mellitus. Due to the chromosomal locus, the association of genotypes with AMD was assessed genderwise.ResultsThree markers, rs1155974, rs2073163, and rs7890586, were associated with a risk of AMD in women. In comparison to women with other genotypes, the women who were homozygous for the minor allele (genotypes rs1155974-TT or rs2073163-CC) had 2.6 fold (p=0.021) or 1.9 fold (p=0.067) risk for having AMD, respectively. These differences were due to the unequal prevalence of exudative AMD. In comparison to women who were homozygous for the major alleles, the women with rs1155974-TT genotype had a 2.8 fold risk (p=0.021 in additive model; p=0.022 in recessive model) for exudative AMD, and the women with rs2073163-CC genotype had a 1.8 fold risk (p=0.09 in additive model; p=0.038 in recessive model). Furthermore, women carrying the rare rs7890586-AA genotype had a significantly smaller risk for having AMD than women with the other genotypes (odds ratio 0.083; p=0.001 in recessive model), but due to the low frequency of this genotype, this finding must be interpreted cautiously. The false discovery rate was <10% for all of the aforementioned results.ConclusionsOn the basis of the putative antiangiogenic role of TNMD and the present genetic associations of TNMD with AMD in women, we suggest that TNMD could be a novel candidate gene for AMD. These results should be confirmed in further studies.
| S-EPMC2669446 | biostudies-literature
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Project description:Associations between vascular endothelial growth factor (VEGF) polymorphisms (rs833061, rs1413711, and rs3025039) and risk of age-related macular degeneration (AMD) have been extensively studied, but the currently available results are contentious rather than conclusive. Therefore, we performed the present meta-analysis to further assess the associations. Literature search in PubMed, Embase, and Web of Science databases was conducted until April 2013. The strength of the associations between VEGF polymorphisms and AMD risk was estimated by pooled odds ratios (ORs) and 95% confidence intervals (CIs). Both models of fixed effects and random effects were performed to summarize the pooled ORs. All data were analyzed by Stata software 12.0. The meta-analysis results based on nine case-control studies with 2427 cases and 2037 controls showed that rs833061 had protective effects on AMD risk (TT vs. CT+CC: OR=0.58, 95% CI=0.41-0.81), whereas rs1413711 (TT vs. CT+CC: OR=1.46, 95% CI=1.10-1.93) and rs3025039 (TT vs. CC: OR=1.87, 95% CI=1.15-3.02; TT vs. CT+CC: OR=2.09, 95% CI=1.30-3.37) represented as risk factors for AMD. Subgroup analysis by ethnicity suggested significantly reduced risk in Caucasians (TT vs. CT+CC: OR=0.60, 95% CI=0.36-0.99; T vs. C: OR=0.89, 95% CI=0.78-1.00) and Asians (TT+CT vs. CC: OR=0.57, 95% CI=0.34-0.96; TT vs. CT+CC: OR=0.54, 95% CI=0.33-0.90) for rs833061, yet elevated risk in Caucasians (TT vs. CT+CC: OR=2.05, 95% CI=1.24-3.38) for rs1413711 and in Asians (TT vs. CC: OR=2.06, 95% CI=1.24-3.43; TT vs. CC: OR=2.34, 95% CI=1.42-3.89) for rs3025039. In stratified analysis by type of AMD, rs833061 was observed to decrease wet AMD risk, while rs1413711 and rs3025039 were found to increase the risk of wet AMD. Based on the currently available data, this meta-analysis suggests that the VEGF polymorphisms may be associated with risk of AMD, particularly wet AMD.
| S-EPMC3976594 | biostudies-literature
Project description:PurposeAge-related macular degeneration (AMD) is an acquired degenerative disease of the retina classified into early, intermediate, and advanced AMD. A key factor in the pathogenesis of AMD is the complement system. The interaction of age and sex with the complement system may affect the risk of developing AMD. The purpose of this study was to determine if there were sex-specific differences in levels of complement factors among patients with the intermediate phenotype of AMD (iAMD) and explore the correlation between age and complement proteins.MethodsWe studied complement factors in patients with iAMD and controls without AMD. Nonparametric, rank-based linear regressions including a sex by AMD interaction were used to compare levels for each analyte. Correlations between age and complement proteins were evaluated using the Spearman rank correlation coefficient.ResultsWe found significantly higher levels of factor B and factor I in females compared with males with iAMD, whereas no differences were seen in complement levels in male and female controls. The ratios of Ba/factor B, C3a/C3, C4b/C4, and C5a/C5 were not different in males and females with iAMD.ConclusionsWe demonstrate disparities in a subset of systemic complement factors between females and males with iAMD, but apparent complement turnover as measured by ratios of activation fragments to intact molecules was not different between these groups. The results suggest that complement system levels, including complement regulator factor I, exhibits sex-related differences in patients with iAMD and highlights that stratification by sex might be helpful in the interpretation of clinical trials of anticomplement therapy.
| S-EPMC9145081 | biostudies-literature
Project description:Purpose:Smoking and the incidence of age-related macular degeneration (AMD) have been linked to an overactive complement system. Here, we examined in a retrospective cohort study whether AMD-associated single nucleotide polymorphisms (SNPs), smoking, ethnicity, and disease status are correlated with blood complement levels. Methods:Population: The study involved 91 AMD patients and 133 controls, which included 73% Americans of European descent (EUR) and 27% Americans of African descent (AFR) in South Carolina. Readouts: Participants were genotyped for 10 SNPs and systemic levels of complement factor H (CFH) activity, and the complement activation products C3a, C5a, and Bb were assessed. Main Outcome Measures: Univariate and multivariable logistic regression models were used to examine associations between AMD status and distinct readouts. Results:AMD affects EUR individuals more than AFRs. EUR but not AFR AMD subjects revealed higher levels of Factors C3a and Bb. In all subjects, a 10-unit increase in C3a levels was associated with an approximately 10% increase in the odds of being AMD-positive, and C3a and Bb were associated with smoking. While CFH activity levels were not correlated with AMD, a significant interaction was evident between patient age and CFH activity. Finally, EURs had lower odds of AMD with enhanced copies of rs1536304 (VEGFA) and higher odds with more copy numbers of rs3766404 (CFH). Conclusions:Our results support previous studies of systemic complement components being potential biomarkers for AMD, but they suggest that smoking and disease do not synergistically affect complement levels. We also suggest a novel susceptibility and protective haplotypes in the South Carolinian AMD population. Our studies indicate that augmented complement activation associated with advanced AMD could be attributed to a decrease in CFH activity in younger patients.
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