Macular Degeneration: Hoh J

DeWan A, Bracken MB, Hoh J. · Department of Epidemiology and Public Health, Yale University, 60 College Street, New Haven, CT 06520, USA. · Curr Opin Genet Dev. · Pubmed #17467263 No free full text.

Abstract: The discovery of strong associations of the His402 variant of complement factor H (CFH) and the change in the promoter region of HtrA serine peptidase 1 (HTRA1) with age-related macular degeneration (AMD) have altered our conception of the pathophysiology of this disease. The complement system has been placed at the center of a flurry of research interest, and a similar growth in attention to the serine proteases is not far behind. The specific role of these variants in causing AMD is unknown, but they will undoubtedly lead to a deeper understanding of the biological mechanisms and will point to new avenues for pharmacologic management. Furthermore, these variants will enable clinicians and investigators to identify people at high risk for this condition, thereby establishing the preconditions for preventing the disease.

Thakkinstian A, Han P, McEvoy M, Smith W, Hoh J, Magnusson K, Zhang K, Attia J. · Centre for Clinical Epidemiology and Biostatistics, School of Medical Practice and Population Health, University of Newcastle, NSW, Australia, and Clinical Epidemiology Unit, Ramathibodi Hospital, Bangkok, Thailand. · Hum Mol Genet. · Pubmed #16905558 links to  free full text

Abstract: Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world and complement factor H (CFH) polymorphism has been found to associated with the AMD. We performed a meta-analysis to estimate the magnitude of the gene effect and the possible mode of action. A meta-analysis of eight studies assessing association between the CFH Y402H polymorphism and AMD was performed. Data extraction and study quality assessment were performed in duplicate, and heterogeneity and publication bias were explored. There was strong evidence for association between CFH and AMD, with those having CC and TC genotypes being roughly six and 2.5 times more likely to have AMD than patients with TT genotype, suggesting a co-dominant, multiplicative genetic model. The population attributable risk for the CC/TC genotype is 58.9%, i.e. the CFH polymorphism is involved in over half of all AMD. This meta-analysis summarizes the strong evidence for an association between CFH and AMD and indicates a multiplicative model with each C allele increasing the odds of AMD by approximately 2.5-fold. This result is at least as important at the population level as ApoE4 and Alzheimer's disease, playing a role in almost 60% of AMD at the population level.

SanGiovanni JP, Arking DE, Iyengar SK, Elashoff M, Clemons TE, Reed GF, Henning AK, Sivakumaran TA, Xu X, DeWan A, Agrón E, Rochtchina E, Sue CM, Wang JJ, Mitchell P, Hoh J, Francis PJ, Klein ML, Chew EY, Chakravarti A. · National Eye Institute (NEI)/National Institutes of Health (NIH), Bethesda, Maryland, United States of America. · PLoS One. · Pubmed #19434233 links to  free full text

Abstract: BACKGROUND: Age-related macular degeneration (AMD), a chronic neurodegenerative and neovascular retinal disease, is the leading cause of blindness in elderly people of western European origin. While structural and functional alterations in mitochondria (mt) and their metabolites have been implicated in the pathogenesis of chronic neurodegenerative and vascular diseases, the relationship of inherited variants in the mitochondrial genome and mt haplogroup subtypes with advanced AMD has not been reported in large prospective cohorts. METHODOLOGY/PRINICIPAL FINDINGS: We examined the relationship of inherited mtDNA variants with advanced AMD in 1168 people using a three-stage design on samples from 12-year and 10-year prospective studies on the natural history of age-related eye disease. In Stage I we resequenced the entire genome in 99 elderly AMD-free controls and 215 people with advanced AMD from the 12-year study. A consistent association with AMD in 14 of 17 SNPs characterizing the mtDNA T haplogroup emerged. Further analysis revealed these associations were driven entirely by the T2 haplogroup, and characterized by two variants in Complex I genes (A11812G of MT-ND4 and A14233G of MT-ND6). We genotyped T haplogroups in an independent sample of 490 cases and 61 controls from the same study (Stage II) and in 56 cases and 246 controls from the 10-year study (Stage III). People in the T2 haplogroup were approximately 2.5 times more likely to have advanced AMD than their peers (odds ratio [OR] = 2.54, 95%CI 1.36-4.80, P<or=0.004) after considering the totality of evidence. Findings persisted after considering the impact of AMD-associated variants A69S and Y402H (OR = 5.19, 95%CI 1.19-22.69, P<or=0.029). CONCLUSION: Loci defining the mtDNA T2 haplogroup and Complex I are reasonable targets for novel functional analyses and therapeutic research in AMD.

Chowers I, Meir T, Lederman M, Goldenberg-Cohen N, Cohen Y, Banin E, Averbukh E, Hemo I, Pollack A, Axer-Siegel R, Weinstein O, Hoh J, Zack DJ, Galbinur T. · Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. · Mol Vis. · Pubmed #19065273 links to  free full text

Abstract: PURPOSE: Single nucleotide polymorphisms (SNPs) in the tightly linked LOC387715/ARMS2 and HTRA1 genes have been associated with age-related macular degeneration (AMD). We tested whether these SNPs are associated with AMD in Israeli populations, if they underlie variable phenotype and response to therapy in neovascular AMD (NVAMD), and if HTRA1 expression in vivo is associated with its promoter variant. METHODS: Genotyping for the rs10490924 SNP in LOC387715/ARMS2 and the rs11200638 SNP in HTRA1 was performed on 255 NVAMD patients and 119 unaffected controls from Ashkenazi and Sephardic Jewish, and from Arab origins which are the main ethnic groups composing the Israeli population. Genotyping was correlated with phenotype and response to therapy among 143 patients who underwent photodynamic therapy (PDT). HTRA1 mRNA levels in white blood cells (WBCs), measured by quantitative PCR, were correlated with genotype in 27 participants. RESULTS: Both SNPs were in almost complete linkage disequilibrium (D'=0.96-1). Homozygotes for the T allele of rs10490924 had an odds ratio (OR) of 8.6, with a 95% confidence interval (CI) of 3.5-20.8, and homozygotes for the A allele of rs11200638 had an OR of 10.7, with a 95% CI of 3.2-35.7, for having AMD (p<0.00001). There was no association among these SNPs and phenotype or response to PDT. HTRA1 mRNA levels in WBCs were not associated with rs11200638 genotypes. CONCLUSIONS: The rs10490924 SNP in LOC387715/ARMS2 and the rs11200638 SNP in HTRA1 are strongly associated with NVAMD in this Israeli population. These variants do not have a major contribution to the variable phenotype and response to PDT which characterize NVAMD.

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.

Francis PJ, Zhang H, Dewan A, Hoh J, Klein ML. · Macular Degeneration Center, Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA. · Mol Vis. · Pubmed #18682806 links to  free full text

Abstract: PURPOSE: To estimate the joint effects of single nucleotide polymorphisms (SNPs) in the genes complement factor H (CFH), HtrA serine peptidase 1 (HTRA1), and age-related maculopathy susceptibility 2 (LOC387715/ARMS2) in a Caucasian age related macular degeneration (AMD) case-control cohort. METHODS: We genotyped three SNPs, rs1061170 (exon 9, CFH), rs11200638 (HTRA1 promoter, -512 bp), and rs10490924 (6.6 kb upstream of HTRA1 in LOC387715/ARMS2) in 333 cases with advanced AMD (choroidal neovascularization [CNV] and geographic atrophy) and 171 age-matched examined controls. Association tests were performed for individual SNPs and jointly with the CFH SNP Y402H. Analyses for interaction were also performed. RESULTS: The linkage disequilibrium measure for two SNPs on 10q26, rs10490924 and rs11200638, is D'=0.8 and all four possible haplotypes of the two SNPs were detected in the samples. The allelic association test for rs11200638 on the promoter of HTRA1 yielded p-values less than 10(-10) for geographic atrophy, less than 10(-16) for neovascularization, and less than 10(-19) for the pooled phenotypes (with an odds ration [OR] of 3.973; 95% confidence interval [CI] 2.928, 5.390). Disease risk is conferred in a dosage-dependent fashion. Similar figures were observed for the LOC387715/ARMS2 SNP. No interaction was detected between either between the 10q26 SNPs or the CFH SNP. CONCLUSIONS: This is the first analysis to show that the two 10q26 SNPs are not in complete linkage disequilibrium. Our studies however show that both the HTRA1 and LOC387715/ARMS2 SNP appear to contribute equally to disease risk (both geographic atrophy and choroidal neovascularization) with no evidence of interaction with CFH.

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.

Bacolod MD, Schemmann GS, Wang S, Shattock R, Giardina SF, Zeng Z, Shia J, Stengel RF, Gerry N, Hoh J, Kirchhoff T, Gold B, Christman MF, Offit K, Gerald WL, Notterman DA, Ott J, Paty PB, Barany F. · Department of Microbiology, Weill Medical College of Cornell University, New York, NY 10021, USA. · Cancer Res. · Pubmed #18375840 links to  free full text

Abstract: Previous studies have shown that among populations with a high rate of consanguinity, there is a significant increase in the prevalence of cancer. Single nucleotide polymorphism (SNP) array data (Affymetrix, 50K XbaI) analysis revealed long regions of homozygosity in genomic DNAs taken from tumor and matched normal tissues of colorectal cancer (CRC) patients. The presence of these regions in the genome may indicate levels of consanguinity in the individual's family lineage. We refer to these autozygous regions as identity-by-descent (IBD) segments. In this study, we compared IBD segments in 74 mostly Caucasian CRC patients (mean age of 66 years) to two control data sets: (a) 146 Caucasian individuals (mean age of 80 years) who participated in an age-related macular degeneration (AMD) study and (b) 118 cancer-free Caucasian individuals from the Framingham Heart Study (mean age of 67 years). Our results show that the percentage of CRC patients with IBD segments (>or=4 Mb length and 50 SNPs probed) in the genome is at least twice as high as the AMD or Framingham control groups. Also, the average length of these IBD regions in the CRC patients is more than twice the length of the two control data sets. Compared with control groups, IBD segments are found to be more common among individuals of Jewish background. We believe that these IBD segments within CRC patients are likely to harbor important CRC-related genes with low-penetrance SNPs and/or mutations, and, indeed, two recently identified CRC predisposition SNPs in the 8q24 region were confirmed to be homozygous in one particular patient carrying an IBD segment covering the region.

Tam PO, Ng TK, Liu DT, Chan WM, Chiang SW, Chen LJ, DeWan A, Hoh J, Lam DS, Pang CP. · Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China. · Invest Ophthalmol Vis Sci. · Pubmed #18316707 links to  free full text

Abstract: PURPOSE: Mapping the genes for age-related macular degeneration (AMD) had not been successful until recent genome-wide association studies revealed Tyr402His in CFH and rs11200638 in HTRA1 as AMD-related genetic variants. This study was conducted to identify other critical factors in HTRA1 that are associated with exudative AMD. METHODS: The promoter, splice regions, and coding exons of HTRA1 were sequenced in 163 patients with exudative AMD and 183 sex- and age-matched control subjects. Also documented were the CFH genotype and smoking status. RESULTS: Four significant SNPs were found in the promoter and the first exon of HTRA1: rs11200638 (-625G>A), rs2672598 (-487T>C), rs1049331 (102C>T, Ala34Ala), and rs2293870 (108G>T, Gly36Gly) with respective P = 1.7 x 10(-14), 3.0 x 10(-10), 3.7 x 10(-12), and 3.7 x 10(-12). Among them, rs11200638 is the most significant associated SNP with a high odds ratio (OR) of 7.6 (95% CI: 3.94-14.51). One risk haplotype block across the promoter and exon 1, ACCTT, significantly predisposes to AMD (P = 6.68 x 10(-14)). In both models, significant independent additive effects were identified with smoking and rs800292 (184G>A, Val62Ile) of CFH. Smoking and rs11200638 (HTRA1) combined caused a 15.7-fold increased risk, whereas combined rs800292 and rs11200638 caused a 23.3-fold increased risk. An extremely high population attributable risk (PAR) of 78% was also found. CONCLUSIONS: A high impact of the additive effect of CFH and HTRA1 in the development of exudative AMD was shown. The HTRA1-smoking additive effect found in this study further suggests the importance of this environmental risk factor in AMD.

Ormsby RJ, Ranganathan S, Tong JC, Griggs KM, Dimasi DP, Hewitt AW, Burdon KP, Craig JE, Hoh J, Gordon DL. · Department of Microbiology and Infectious Diseases, Flinders Medical Centre and Flinders University of South Australia, Bedford Park, SA 5042, Australia. · Invest Ophthalmol Vis Sci. · Pubmed #18263814 links to  free full text

Abstract: PURPOSE: A Tyr-to-His (Y402H) sequence variant in the factor H (FH) and factor H-like protein (FHL-1) gene is strongly associated with an increased susceptibility for age-related macular degeneration (AMD). The purpose of this study was to understand how the Y402H variant in FH/FHL-1 contributes to the pathogenesis of AMD and, in particular, whether interactions mediated by FH/FHL-1, including binding to C-reactive protein (CRP), group A streptococcal M protein (GAS M6), heparin, and retinal pigment epithelial cells (RPE), are affected. METHODS: FH was purified from sera of patients homozygous for FH(Y402) or (H402), and recombinant FH fragments representing FHL-1 were generated. Proteins were analyzed for binding to CRP, GAS M6, heparin, and RPE cells. RESULTS: Binding of the FH and FH1 to seven polymorphic variants to CRP and M protein was reduced. The variant did not influence the interaction of FH with heparin but did reduce binding of FHL-1. Binding of the FH and FHL-1 polymorphic variant to RPE cells was not affected. CONCLUSIONS: The FH Y402H polymorphism associated with AMD causes a reduction in binding of FH and FHL-1 to CRP and M protein. Both variants show comparable binding to RPE cells, indicating that AMD is unlikely to manifest as a result of impaired host cell-surface recognition. The decreased interaction between FH and CRP, which is essential for the anti-inflammatory function of CRP, provides a possible pathophysiological explanation for the association of the Y402H variant with AMD.

Gibbs D, Yang Z, Constantine R, Ma X, Camp NJ, Yang X, Chen H, Jorgenson A, Hau V, Dewan A, Zeng J, Harmon J, Buehler J, Brand JM, Hoh J, Cameron DJ, Dixit M, Tong Z, Zhang K. · Department of Ophthalmology and Visual Science, Moran Eye Center, Building 533, Room 3160A, 15 North 2030 East, Salt Lake City, UT 84132, USA. · Vision Res. · Pubmed #18207215 No free full text.

Abstract: Age-related macular degeneration (AMD) is a complex disorder with genetic and environmental influences. The genetic influences affecting AMD are not well understood and few genes have been consistently implicated and replicated for this disease. A polymorphism (rs11200638) in a transcription factor binding site of the HTRA1 gene has been described, in previous reports, as being most significantly associated with AMD. In this paper, we investigate haplotype association and individual polymorphic association by genotyping additional variants in the AMD risk-associated region of chromosome 10q26. We demonstrate that rs11200638 in the promoter region and rs2293870 in exon 1 of HTRA1, are among the most significantly associated variants for advanced forms of AMD.

Yoshida T, DeWan A, Zhang H, Sakamoto R, Okamoto H, Minami M, Obazawa M, Mizota A, Tanaka M, Saito Y, Takagi I, Hoh J, Iwata T. · National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan. · Mol Vis. · Pubmed #17438519 links to  free full text

Abstract: PURPOSE: To study the effect of candidate single nucleotide polymorphisms (SNPs) on chromosome 10q26, recently shown to be associated with wet age-related macular degeneration (AMD) in Chinese and Caucasian cohorts, in a Japanese cohort. METHODS: Using genomic DNA isolated from peripheral blood of wet AMD cases and age-matched controls, we genotyped two SNPs, rs10490924, and rs11200638, on chromosome 10q26, 6.6 kb and 512 bp upstream of the HTRA1 gene, respectively, using temperature gradient capillary electrophoresis (TGCE) and direct sequencing. Association tests were performed for individual SNPs and jointly with SNP complement factor H (CFH) Y402H. RESULTS: The two SNPs, rs10490924 and rs11200638, are in complete linkage disequilibrium (D'=1). Previous sequence comparisons among seventeen species revealed that the genomic region containing rs11200638 was highly conserved while the region surrounding rs10490924 was not. The allelic association test for rs11200638 yielded a p-value <10(-11). SNP rs11200638 conferred disease risk in an autosomal recessive fashion: Odds ratio was 10.1 (95% CI 4.36, 23.06), adjusted for SNP CFH 402, for those carrying two copies of the risk allele, whereas indistinguishable from unity if carrying only one risk allele. CONCLUSIONS: The HTRA1 promoter polymorphism, rs11200638, is a strong candidate with a functional consequence that predisposes Japanese to develop neovascular AMD.

Ennis S, Goverdhan S, Cree A, Hoh J, Collins A, Lotery A. · Genetic Epidemiology and Bioinformatics Group, Human Genetics Division (MP 808), Southampton General Hospital, Southampton, UK. · Br J Ophthalmol. · Pubmed #17314151 No free full text.

Abstract: AIM: To present results from a nested association study of the complement factor H (CFH) gene region using a novel methodology that uses a high-resolution genetic linkage disequilibrium map to estimate a point location for a causal mutation. METHOD: Age-related macular degeneration (AMD) case-control data from a genomewide single-nucleotide polymorphism (SNP) panel were used to identify the target interval to be genotyped at higher density in a second independent panel. The pattern of linkage disequilibrium (LD) and segmental duplications across this region are described in detail. RESULT: Data were consistent with other studies in that strong association between the Y402H variant and AMD is observed. However, composite likelihood analysis, which combines association data from all SNPs in the region, and uses genetic locations on a high-resolution LD map, gave a point location for a causal variant between exons 1 and 2 of the CFH gene. CONCLUSION: The findings are consistent with evidence that, in addition to the widely described Y402H variant, there is at least one and, most probably, several other mutations in the CFH gene which determine disease manifestation in AMD. A genetic model in which multiple mutations contribute to a varying degree to disease aetiology has been previously well described in ophthalmic genetics, and is typified by the COL2A1 and ABCA4 genes.

Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, Cameron DJ, Chen H, Zhao Y, Pearson E, Li X, Chien J, Dewan A, Harmon J, Bernstein PS, Shridhar V, Zabriskie NA, Hoh J, Howes K, Zhang K. · Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. · Science. · Pubmed #17053109 links to  free full text

Abstract: Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the developed world and has a strong genetic predisposition. A locus at human chromosome 10q26 affects the risk of AMD, but the precise gene(s) have not been identified. We genotyped 581 AMD cases and 309 normal controls in a Caucasian cohort in Utah. We demonstrate that a single-nucleotide polymorphism, rs11200638, in the promoter region of HTRA1 is the most likely causal variant for AMD at 10q26 and is estimated to confer a population attributable risk of 49.3%. The HTRA1 gene encodes a secreted serine protease. Preliminary analysis of lymphocytes and retinal pigment epithelium from four AMD patients revealed that the risk allele was associated with elevated expression levels of HTRA1 mRNA and protein. We also found that drusen in the eyes of AMD patients were strongly immunolabeled with HTRA1 antibody. Together, these findings support a key role for HTRA1 in AMD susceptibility and identify a potential new pathway for AMD pathogenesis.

Dewan A, Liu M, Hartman S, Zhang SS, Liu DT, Zhao C, Tam PO, Chan WM, Lam DS, Snyder M, Barnstable C, Pang CP, Hoh J. · Department of Epidemiology and Public Health, Yale University, 60 College Street, New Haven, CT 06520, USA. · Science. · Pubmed #17053108 links to  free full text

Abstract: Age-related macular degeneration (AMD), the most common cause of irreversible vision loss in individuals aged older than 50 years, is classified as either wet (neovascular) or dry (nonneovascular). Inherited variation in the complement factor H gene is a major risk factor for drusen in dry AMD. Here we report that a single-nucleotide polymorphism in the promoter region of HTRA1, a serine protease gene on chromosome 10q26, is a major genetic risk factor for wet AMD. A whole-genome association mapping strategy was applied to a Chinese population, yielding a P value of <10(-11). Individuals with the risk-associated genotype were estimated to have a likelihood of developing wet AMD 10 times that of individuals with the wild-type genotype.

Zareparsi S, Branham KE, Li M, Shah S, Klein RJ, Ott J, Hoh J, Abecasis GR, Swaroop A. · Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA. · Am J Hum Genet. · Pubmed #15895326 links to  free full text

Abstract: Using a large sample of cases and controls from a single center, we show that a T-->C substitution in exon 9 (Y402H) of the complement factor H gene is strongly associated with susceptibility to age-related macular degeneration, the most common cause of blindness in the elderly. Frequency of the C allele was 0.61 in cases, versus 0.34 in age-matched controls (P<1x10(-24)). Genotype frequencies also differ markedly between cases and controls (chi2=112.68 [2 degrees of freedom]; P<1x10(-24)). A multiplicative model fits the data well, and we estimate the population frequency of the high-risk C allele to be 0.39 (95% confidence interval 0.36-0.42) and the genotype relative risk to be 2.44 (95% confidence interval 2.08-2.83) for TC heterozygotes and 5.93 (95% confidence interval 4.33-8.02) for CC homozygotes.

Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J. · Laboratory of Statistical Genetics, Rockefeller University, 1230 York Avenue, New York, NY 10021, USA. · Science. · Pubmed #15761122 links to  free full text

Abstract: Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. We report a genome-wide screen of 96 cases and 50 controls for polymorphisms associated with AMD. Among 116,204 single-nucleotide polymorphisms genotyped, an intronic and common variant in the complement factor H gene (CFH) is strongly associated with AMD (nominal P value <10(-7)). In individuals homozygous for the risk allele, the likelihood of AMD is increased by a factor of 7.4 (95% confidence interval 2.9 to 19). Resequencing revealed a polymorphism in linkage disequilibrium with the risk allele representing a tyrosine-histidine change at amino acid 402. This polymorphism is in a region of CFH that binds heparin and C-reactive protein. The CFH gene is located on chromosome 1 in a region repeatedly linked to AMD in family-based studies.