Macular Degeneration: Kim IK

Kim IK, Gragoudas ES. · No affiliation provided · Br J Ophthalmol. · Pubmed #19244026 No free full text.

This publication has no abstract.

Kim IK, Ji F, Morrison MA, Adams S, Zhang Q, Lane AM, Capone A, Dryja TP, Ott J, Miller JW, DeAngelis MM. · Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA. · Mol Vis. · Pubmed #18704199 links to  free full text

Abstract: PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Zhang H, Morrison MA, Dewan A, Adams S, Andreoli M, Huynh N, Regan M, Brown A, Miller JW, Kim IK, Hoh J, Deangelis MM. · Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA. · BMC Med Genet. · Pubmed #18541031 links to  free full text

Abstract: BACKGROUND: To examine if the significantly associated SNPs derived from the genome wide allelic association study on the AREDS cohort at the NEI (dbGAP) specifically confer risk for neovascular age-related macular degeneration (AMD). We ascertained 134 unrelated patients with AMD who had one sibling with an AREDS classification 1 or less and was past the age at which the affected sibling was diagnosed (268 subjects). Genotyping was performed by both direct sequencing and Sequenom iPLEX system technology. Single SNP analyses were conducted with McNemar's Test (both 2 x 2 and 3 x 3 tests) and likelihood ratio tests (LRT). Conditional logistic regression was used to determine significant gene-gene interactions. LRT was used to determine the best fit for each genotypic model tested (additive, dominant or recessive). RESULTS: Before release of individual data, p-value information was obtained directly from the AREDS dbGAP website. Of the 35 variants with P < 10-6 examined, 23 significantly modified risk of neovascular AMD. Many variants located in tandem on 1q32-q22 including those in CFH, CFHR4, CFHR2, CFHR5, F13B, ASPM and ZBTB were significantly associated with AMD risk. Of these variants, single SNP analysis revealed that CFH rs572515 was the most significantly associated with AMD risk (P < 10-6). Haplotype analysis supported our findings of single SNP association, demonstrating that the most significant haplotype, GATAGTTCTC, spanning CFH, CFHR4, and CFHR2 was associated with the greatest risk of developing neovascular AMD (P < 10-6). Other than variants on 1q32-q22, only two SNPs, rs9288410 (MAP2) on 2q34-q35 and rs2014307 (PLEKHA1/HTRA1) on 10q26 were significantly associated with AMD status (P = .03 and P < 10-6 respectively). After controlling for smoking history, gender and age, the most significant gene-gene interaction appears to be between rs10801575 (CFH) and rs2014307 (PLEKHA1/HTRA1) (P < 10-11). The best genotypic fit for rs10801575 and rs2014307 was an additive model based on LRT. After applying a Bonferonni correction, no other significant interactions were identified between any other SNPs. CONCLUSION: This is the first replication study on the NEI dbGAP SNPs, demonstrating that alleles on 1q, 2q and 10q may predispose an individual to AMD.

Deangelis MM, Ji F, Adams S, Morrison MA, Harring AJ, Sweeney MO, Capone A, Miller JW, Dryja TP, Ott J, Kim IK. · Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, USA. · Ophthalmology. · Pubmed #18164066 No free full text.

Abstract: OBJECTIVE: To examine if the genes encoding the pleckstrin homology domain-containing protein gene (PLEKHA1), hypothetical LOC387715/ARMS2 gene, and HtrA serine peptidase 1 gene (HTRA1) located on the long arm of chromosome 10 (10q26 region) confer risk for neovascular age-related macular degeneration (AMD) in an independent or interactive manner when controlling for complement factor H gene (CFH) genotype and smoking exposure. DESIGN: Retrospective matched-pair case-control study. PARTICIPANTS: Hospital clinic-based sample of 134 unrelated patients with neovascular AMD who have a sibling with normal maculae (268 subjects). METHODS: Disease status was ascertained by at least 2 investigators by review of fundus photographs and/or fluorescein angiography according to the Age-Related Eye Disease Study grading scale. If necessary, a home retinal examination was performed (n = 6). A combination of direct sequencing and analysis of 8 highly polymorphic microsatellite markers was used to genotype 33 megabases of the 10q26 region on leukocyte DNA. Smoking history was obtained via a standardized questionnaire and measured in pack-years. The family-based association test, haplotype analysis, multiple conditional logistic regression, and linkage analysis were used to determine significant associations. MAIN OUTCOME MEASURE: Neovascular AMD status. RESULTS: Of the 23 variants we identified in the 10q26 region, 6 were significant. Four of the 6 were novel and included 2 genotypes that reduced risk of AMD. Many single-nucleotide polymorphisms (SNPs), including the previously reported variants rs10490924 (hypothetical LOC387715/ARMS2) and rs11200638 (HTRA1), defined 2 significant haplotypes associated with increased risk of neovascular AMD. The coding HTRA1 SNP rs2293870, not part of the significant haplotypes containing rs10490924 and rs11200638, showed as strong an association with increased susceptibility to neovascular AMD. Linkage analysis supported our findings of SNP association (P<10(-15)). No significant interactions were found between any of the SNPs in the 10q26 and smoking or between these SNPs and CFH genotype. CONCLUSIONS: Independent of CFH genotype or smoking history, an individual's risk of AMD could be increased or decreased, depending on their genotype or haplotype in the 10q26 region.

DeAngelis MM, Ji F, Kim IK, Adams S, Capone A, Ott J, Miller JW, Dryja TP. · Department of Ophthalmology, Harvard Medical School, and Massachusetts Eye and Ear Infirmary, Boston, USA. · Arch Ophthalmol. · Pubmed #17210851 links to  free full text

Abstract: OBJECTIVE: To examine if the genes encoding complement factor H (CFH), apolipoprotein E (APOE), and elongation of very-long-chain fatty acids-like 4 (ELOVL4) confer risk of neovascular age-related macular degeneration (AMD) in an independent or interactive manner when controlling for smoking exposure. METHODS: We studied 103 unrelated patients with neovascular AMD who each had at least 1 sibling with normal maculae. Smoking histories were obtained. Genotyping was performed by analyzing amplified genomic fragments from CFH, APOE, and ELOVL4 by direct sequencing or by restriction endonuclease digests. Conditional logistic regression analysis was used to build a multifactor model. RESULTS: For CFH, only the CC genotype carried a statistically significant elevation of disease risk (odds ratio, 49.37; 95% confidence interval, 6.20-393.22; P<.001). No significant association was observed between neovascular AMD and APOE or ELOVL4. No significant interactions were found between smoking and having the CFH or APOE genotype nor were significant interactions found between the CFH, ELOVL4, and APOE genotypes. CONCLUSIONS: Smoking and having the CFH CC genotype independently increase risk of neovascular AMD. APOE and ELOVL4 genotypes do not seem to modify risk. CLINICAL RELEVANCE: Smoking 10 pack-years or more and having the CFH CC genotype increase one's risk of neovascular AMD 144-fold compared with smoking less than 10 pack-years and having the CT or TT genotype.