Macular Degeneration: DeAngelis MM

Yan T, Yang YN, Cheng X, DeAngelis MM, Hoh J, Zhang H. · Department of Statistics and Finance, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China. · Ann Hum Genet. · Pubmed #19040657 No free full text.

Abstract: In practice, family-based design has been widely used in disease-gene association analysis. The major advantage of such design is that it is not subject to spurious association due to population structure such as population stratification (PS) and admixture. A disadvantage is that parental genotypes are hard to obtain if the disease is late onset for which a discordant-relative-pair design is useful. Designs of such kind include full-sib-pair, half-sib-pair, first-cousin-pair, and so on. The closer the relatedness of the pair, the less possible that they are subject to population stratification. On the other hand, the association test using close relative-pairs may be less powerful due to over-matching. Trade-off between these two factors (population structure and over-matching) is the major concern of this study. Some tests, namely McNemar's test, matched Cochran-Armitage trend tests (CATTs), matched maximum efficient robust test (MERT), and Bhapkar's test, are used for testing disease-gene association based on relative-pair designs. These tests are shown to be valid in the presence of PS but not admixture. Numerical studies show that the McNemar's test, additive CATT, MERT, and Bhapkar's test are robust in power, but none of them is uniformly more powerful than the others. In most simulations, the power of any of the tests increases as the pair is more distant. The proposed methods are applied to two real examples.

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.

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.

DeAngelis MM, Lane AM, Shah CP, Ott J, Dryja TP, Miller JW. · Ocular Molecular Genetics Institute, Harvard Medical School, Boston, MA 02114, USA. · Arch Ophthalmol. · Pubmed #15078676 No free full text.

Abstract: OBJECTIVE: To search for factors that contribute to the development of neovascular age-related macular degeneration (AMD). METHODS: In a matched-pair case-control study, we studied sib pairs in which the index sibling had neovascular AMD in at least 1 eye and the unaffected sibling had normal maculae (or at most only a few small drusen) and was past the age at which the index case was diagnosed. Factors studied included sex, iris color, education, alcohol consumption, body mass index, vitamin use, smoking history, hypercholesterolemia, aspirin use, hypertension, other cardiovascular disease, any autoimmune disease, and non-insulin-dependent diabetes mellitus. Conditional logistic regression was performed to identify predictors of neovascular AMD. RESULTS: On the basis of 73 sib pairs, multivariate regression analysis revealed a statistically significant 2% increase in risk of neovascular AMD with each pack-year of smoking (odds ratio, 1.02; 95% confidence interval, 1.01-1.04; P =.007). Suggestive but nonsignificant associations were also observed for mean lifetime alcohol consumption, adult lifetime body mass index, and hypertension in multivariate regression analyses. CONCLUSION: Using extremely discordant sib pairs to study risk factors for AMD, a novel approach in epidemiological design, we found evidence that smoking is a risk factor for neovascular AMD.