Population Differences in Genetic Risk for Age-Related Macular Degeneration and Implications for Genetic Testing

Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA.
Archives of ophthalmology (Impact Factor: 4.4). 01/2012; 130(1):116-7. DOI: 10.1001/archopthalmol.2011.1370
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Available from: Jonathan l. Haines, Apr 03, 2014
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    • "The AMD-associated variants in CFH, C2, C3, CFB, and ARMS2 have been established in populations worldwide [10,12,19,20,22,37,38]. However, genetic risk and the frequency of associated genetic polymorphisms differ across ethnicities [15]. Thus, when we compared the frequency of the seven genotyped SNPs in our control population group with two Mexican Amerindian groups (Zapotecos and Mayas) and individuals from three continental groups included in the HapMap International Project, Caucasians, Asians (Chinese and Japanese population), and individuals from a Nigerian region, we observed significant differences for rs1061170 (Tyr402His) in CFH between Mexican Mestizos and those populations (Appendix 5). "
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    ABSTRACT: To evaluate the contribution of genetic variants of complement factor H (CFH), complement component 2 and 3 (C2 and C3), complement factor B (CFB), and age-related maculopathy susceptibility 2 (ARMS2) to age-related macular degeneration (AMD) risk in the Mexican Mestizo population. Analysis included 282 unrelated Mexican patients with advanced AMD, 205 healthy controls, and 280 population controls. Stereoscopic fundus images were graded on the Clinical Age-Related Maculopathy System (CARMS). We designed a resequencing strategy using primers with M13 adaptor for the 23 exons of the CFH gene in a subgroup of 96 individuals clinically evaluated: 48 AMD cases and 48 age- and sex-matched healthy controls. Single nucleotide polymorphisms (SNPs) in C3 (Arg80Gly and Pro292Leu), C2 (rs547154), CFB (Leu9His), and ARMS2 (Ala69Ser) were genotyped in all patients, healthy and population controls using TaqMan assay. All evaluated individuals were Mexican Mestizos, and their genetic ancestry was validated using 224 ancestry informative markers and calculating Fst values. The CFH resequencing revealed 19 SNPs and a common variant in the intron 2 splice acceptor site; three CFH haplotypes inferred from individual genotypes, showed significant differences between cases and controls. The risk alleles in C3 (rs1047286, odds ratio [OR]=2.48, 95% confidence interval [CI]=1.64-3.75, p=1.59E-05; rs2230199, OR=2.15, 95% CI=1.48-3.13, p=6.28E-05) and in ARMS2 (rs10490924, OR=3.09, 95% CI=2.48-3.86, p=5.42E-23) were strongly associated with risk of AMD. The protective effect of alleles in C2 (rs547154) and CFB (rs4151667) showed a trend but was not significantly associated after correction for multiple testing. Our results show that ARMS2 and C3 are major contributors to advanced AMD in Mexican patients, while the contributions of CFH, C2, and CFB are minor to those of other populations, reveling significant ethnic differences in minor allele frequencies. We provide evidence that two specific common haplotypes in the CFH gene predispose individuals to AMD, while another may confer reduced risk of disease in this admixed population.
    Full-text · Article · Jan 2014 · Molecular vision
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    ABSTRACT: In recent years, there has been increasing evidence of ethnic differences in the epidemiology, risk factors, clinical presentation and manifestation of age-related macular degeneration (AMD). Although phenotypically very similar to AMD, polypoidal choroidal vasculopathy has a very different natural history, treatment response to anti-VEGF agents and photodynamic therapy and marked ethnic differences in disease prevalence. Despite these differences, there is supporting evidence, particularly from a genetics perspective, that links these two disease entities. In this review, the authors compare and contrast AMD and polypoidal choroidal vasculopathy with particular reference to ethnic variation, genetic disease risk assessment and potential for pharmacogenetic interventions. With advances in massively parallel next-generation sequencing and decreased cost of such technologies, investigators will be able to more thoroughly assess rare variants and their contribution to disease susceptibility.
    Full-text · Article · Apr 2013 · Expert Review of Ophthalmology
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    ABSTRACT: Age-related macular degeneration (AMD) is the main cause of blindness in the developed world. The etiology of AMD is multifactorial due to the interaction between genetic and environmental factors. IL-8 has a role in inflammation and angiogenesis; we report the genetic characterization of IL-8 allele architecture and evaluate the role of SNPs or haplotypes in the susceptibility to wet AMD, case-control study. Case-control study including 721 AMD patients and 660 controls becoming from Italian population. Genotyping was carried out by Real Time-PCR. Differences in the frequencies were estimated by the chi-square test. Direct sequencing was carried out by capillary electrophoresis trough ABI3130xl. rs2227306 showed a p-value of 4.15*10(-5) and an Odds Ratio (OR) for T allele of 1.39 [1.19-1.62]. After these positive results, we sequenced the entire IL-8 regulatory and coding regions of 60 patients and 30 controls stratified for their genotype at rs2227306. We defined two different haplotypes involving rs4073 (A/T), rs2227306 (C/T), rs2227346 (C/T) and rs1126647 (A/T): A-T-T-T (p-value: 2.08*10(-9); OR: 1.68 [1.43-1.97]) and T-C-C-A (p-value: 7.07*10(-11); OR: 0.60 [0.51-0.70]). To further investigate a potential functional role of associated haplotypes, we performed an expression study on RNA extracted from whole blood of 75 donors to verify a possible direct correlation between haplotype and gene expression, failing to reveal significant differences. These results suggest a possible secondary role of IL-8 gene in the development of the disease. This paper outlines the importance of association between inflammation and AMD. Moreover IL-8 is a new susceptibility genomic biomarker of AMD.
    Full-text · Article · Jul 2013 · PLoS ONE
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