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A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration.

ABSTRACT: Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N?=?293) and AMD cases (White N?=?4210 Indian?=?134; Malay?=?140) and controls (White N?=?3229; Indian?=?117; Malay?=?2390) demonstrated that deletion CNP148 was protective against AMD, independent of SNPs at CFH. Regression analysis of seven common haplotypes showed three haplotypes, H1, H6 and H7, as conferring risk for AMD development. Being the most common haplotype H1 confers the greatest risk by increasing the odds of AMD by 2.75-fold (95% CI?=?[2.51, 3.01]; p?=?8.31×10(-109)); Caucasian (H6) and Indian-specific (H7) recombinant haplotypes increase the odds of AMD by 1.85-fold (p?=?3.52×10(-9)) and by 15.57-fold (P?=?0.007), respectively. We identified a 32-kb region downstream of Y402H (rs1061170), shared by all three risk haplotypes, suggesting that this region may be critical for AMD development. Further analysis showed that two SNPs within the 32 kb block, rs1329428 and rs203687, optimally explain disease association. rs1329428 resides in 20 kb unique sequence block, but rs203687 resides in a 12 kb block that is 89% similar to a noncoding region contained in ?CNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number.

SUBMITTER: Sivakumaran TA

PROVIDER: S-EPMC3192039 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration.

Sivakumaran Theru A TA Igo Robert P RP Kidd Jeffrey M JM Itsara Andy A Kopplin Laura J LJ Chen Wei W Hagstrom Stephanie A SA Peachey Neal S NS Francis Peter J PJ Klein Michael L ML Chew Emily Y EY Ramprasad Vedam L VL Tay Wan-Ting WT Mitchell Paul P Seielstad Mark M Stambolian Dwight E DE Edwards Albert O AO Lee Kristine E KE Leontiev Dmitry V DV Jun Gyungah G Wang Yang Y Tian Liping L Qiu Feiyou F Henning Alice K AK LaFramboise Thomas T Sen Parveen P Aarthi Manoharan M George Ronnie R Raman Rajiv R Das Manmath Kumar MK Vijaya Lingam L Kumaramanickavel Govindasamy G Wong Tien Y TY Swaroop Anand A Abecasis Goncalo R GR Klein Ronald R Klein Barbara E K BE Nickerson Deborah A DA Eichler Evan E EE Iyengar Sudha K SK

PloS one 20111012 10

Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N = 293) and AMD cases (W ...[more]

PMID: 22022419

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Project description:To examine if the gene encoding C-reactive protein (CRP), a biomarker of inflammation, confers risk for neovascular age-related macular degeneration (AMD) in the presence of other modifiers of inflammation, including body mass index (BMI), diabetes, smoking, and complement factor H (CFH) Y402 genotype. Additionally we examined the degree to which CRP common variation was in linkage disequilibrium (LD) within our cohort.We ascertained 244 individuals from 104 families where at least one member had neovascular AMD, and a sibling had normal maculae and was past the age of the index patient's diagnosis of neovascular AMD. We employed a direct sequencing approach to analyze the 5'-promoter region as well as the entire coding region and the 3'-untranslated region of the CRP gene. CFH Y402 genotype data was available for all participants. Lifestyle and medical factors were obtained via administration of a standardized questionnaire. The family-based association test, haplotype analysis, McNemar's test, and conditional logistic regression were used to determine significant associations and interactions. Haploview was used to calculate the degree of LD (r2) between all CRP variants identified.Six single nucleotide polymorphisms (SNPs; rs3091244, rs1417938, rs1800947, rs1130864, rs1205, and rs3093068) comprised one haplotype block of which only rs1130864 and rs1417938 were in high LD (r2=0.94). SNP rs3093068 was in LD but less so with rs3093059 (r2=0.83), which is not part of the haplotype block. Six SNPs made up six different haplotypes with > or = 5% frequency, none of which were significantly associated with AMD risk. No statistically significant association was detected between any of the nine common variants in CRP and neovascular AMD when considering disease status alone or when controlling for smoking exposure, BMI, diabetes, or CFH genotype. Significant interactions were not found between CRP genotypes and any of the risk factors studied. No novel CRP variation was identified.We provide evidence that if elevated serum/plasma levels of CRP are associated with neovascular AMD, it is likely not due to genetic variation within CRP, but likely due to variations in some other genetic as well as epidemiological factors.

Project description:BACKGROUND: Age-related macular degeneration (AMD) is the major cause of blindness in the elderly. Those with the neovascular end-stage of disease have irreversible loss of central vision. AMD is a complex disorder in which genetic and environmental factors play a role. Polymorphisms in the complement factor H (CFH) gene, LOC387715, and the HTRA1 promoter are strongly associated with AMD. Smoking also contributes to the etiology. We aimed to provide a model of disease risk based on these factors. METHODS AND FINDINGS: We genotyped polymorphisms in CFH and LOC387715/HTRA1 in a case-control study of 401 patients with neovascular AMD and 266 controls without signs of disease, and used the data to produce genetic risk scores for the European-descent population based on haplotypes at these loci and smoking history. CFH and LOC387715/HTRA1 haplotypes and smoking status exerted large effects on AMD susceptibility, enabling risk scores to be generated with appropriate weighting of these three factors. 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). Patients with neovascular macular degeneration had considerably higher scores than those without disease, and risk of blinding AMD rose to 15.5% in the tenth of the population with highest predicted risk. CONCLUSIONS: An individual's risk of developing AMD in old age can be predicted by combining haplotype data with smoking status. Until there is effective treatment for AMD, encouragement to avoid smoking in those at high genetic risk may be the best option. We estimate that total absence of smoking would have reduced the prevalence of severe AMD by 33%. Unless smoking habits change or preventative treatment becomes available, the prevalence of AMD will rise as a consequence of the increasing longevity of the population.

Dataset Information

A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration.

Publications

A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration.

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