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Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration.

ABSTRACT: We used iterative association mapping to identify a susceptibility gene for age-related macular degeneration (AMD) on chromosome 10q26, which is one of the most consistently implicated linkage regions for this disorder. We employed linkage analysis methods, followed by family-based and case-control association analyses, using two independent data sets. To identify statistically the most likely AMD-susceptibility allele, we used the Genotype-IBD Sharing Test (GIST) and conditional haplotype analysis. To incorporate the two most important known AMD risk factors--smoking and the Y402H variant of the complement factor H gene (CFH)--we used logistic regression modeling to test for gene-gene and gene-environment interactions in the case-control data set and used the ordered-subset analysis to account for genetic linkage heterogeneity in the family-based data set. Our results strongly implicate a coding change (Ala69Ser) in the LOC387715 gene as the second major identified AMD-susceptibility allele, confirming earlier suggestions. This variant's effect on AMD is statistically independent of CFH and is of similar magnitude to the effect of Y402H. The overall effect is driven primarily by a strong association in smokers, since we observed significant evidence for a statistical interaction between the LOC387715 variant and a history of cigarette smoking. This gene-environment interaction is supported by statistically independent family-based and case-control analysis methods. We estimate that CFH, LOC387715, and cigarette smoking together explain 61% of the population-attributable risk (PAR) of AMD. The adjusted PAR percentage estimates are 20% for smoking, 36% for LOC387715, and 43% for CFH. We demonstrate, for the first time, that a genetic susceptibility coupled with a modifiable lifestyle factor such as cigarette smoking confers a significantly higher risk of AMD than either factor alone.

SUBMITTER: Schmidt S

PROVIDER: S-EPMC1474047 | biostudies-literature | 2006 May

REPOSITORIES: biostudies-literature

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Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration.

Schmidt Silke S Hauser Michael A MA Scott William K WK Postel Eric A EA Agarwal Anita A Gallins Paul P Wong Frank F Chen Yu Sarah YS Spencer Kylee K Schnetz-Boutaud Nathalie N Haines Jonathan L JL Pericak-Vance Margaret A MA

American journal of human genetics 20060320 5

We used iterative association mapping to identify a susceptibility gene for age-related macular degeneration (AMD) on chromosome 10q26, which is one of the most consistently implicated linkage regions for this disorder. We employed linkage analysis methods, followed by family-based and case-control association analyses, using two independent data sets. To identify statistically the most likely AMD-susceptibility allele, we used the Genotype-IBD Sharing Test (GIST) and conditional haplotype analy ...[more]

PMID: 16642439

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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.

Project description:PurposeVariants in complement factor H (CFH), the hypothetical LOC387715, and the high-temperature requirement A-1 (HTRA1) genes have been reported to be associated with age-related macular degeneration (AMD). The purpose of this study was to investigate the association of reported common single-nucleotide polymorphisms (SNPs) in CFH, LOC387715, and HTRA1 with exudative AMD in a northern Chinese population.MethodsA cohort of 121 unrelated patients with exudative AMD and 132 control subjects were enrolled in this study. Genomic DNA was extracted from blood leukocytes. Genotyping for SNPs rs1061170:T>C in CFH (Y402H), rs10490924:G>T in LOC387715 (A69S), and rs11200638:G>A in the promoter of HTRA1 was performed using a polymerase chain reaction (PCR) method followed by allele-specific restriction enzyme digestion and direct sequencing.ResultsThe Y402H variant in CFH was not associated with exudative AMD in our study population. Frequencies of Y402H was 10.3% in AMD cases and 8.0% in controls (p=0.353). Significant associations were detected for exudative AMD with SNPs rs10490924:G>T in LOC387715 (A69S), and rs11200638:G>A in the promoter of HTRA1. The risk T-allele frequency of rs10490924 in LOC387715 was 64.9% in cases versus 43.2% in controls (p<0.001). The odds ratio for risk of AMD was 1.56 (95% CI; 0.80-3.03) for the GT genotype and 5.45 (95% CI; 2.59-11.49) for the TT genotype. The A allele frequency of rs11200638 in the HTRA1 promoter was 67.8% in cases versus 42.4% in controls (p<0.001). The odds ratio was 2.75 (95% CI; 1.34-5.64) for the GA genotype and 7.90 (95% CI; 3.61-17.26) for the AA genotype. An odds ratio of 7.94 (95% CI; 3.49-18.04) was obtained for carriers with both TT genotype in LOC387715 and AA genotype in the HTRA1 promoter.ConclusionsOur data suggest that the LOC387715 and HTRA1 polymorphisms are associated with a higher risk of exudative AMD in northern Chinese. We found no association of CFH Y402H with exudative AMD. The low frequency of CFH Y402H variant was further confirmed in this study population.

Dataset Information

Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration.

Publications

Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration.

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