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Cigarette Smoking Strongly Modifies the Association of LOC387715 and Age-Related Macular Degeneration
Open accessAbstract
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.
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“Genetic studies also suggest modification of the susceptibility effect of ARMS2 by smoking (128), consistent with its involvement in mitochondrial function (66, 82).”
From Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration (2009) · cites this paper as [128]
In the citing paper
“A few studies have assessed gene/gene interaction as well as gene/environment interaction.73–75 No definitive interaction has yet been found.”
From Age-related macular degeneration (2008) · cites this paper as [74]
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2 of the 48 references couldn’t be matched to a known paper.
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Age-related macular degeneration
Jager, R. D., Mieler, W. F., & Miller, J. W. (2008) · New England Journal of Medicine · doi:10.1056/nejmra0801537 · Cited by 1,379
The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD
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“Likewise, the LOC387715 locus polymorphism that is associated with AMD risk is higher in smokers than either smoking or the polymorphism alone, is additional evidence of a pathogenic role of oxidative stress (Schmidt et al., 2006).”
BackgroundA Variant of the HTRA1 Gene Increases Susceptibility to Age-Related Macular Degeneration
Yang, Z., Camp, N. J., Sun, H., Tong, Z., Gibbs, D., Cameron, D. J., Chen, H., Zhao, Y., Pearson, E., Li, X., et al. (2006) · Science · doi:10.1126/science.1133811 · Cited by 796
Age-related macular degeneration
de Jong, P. T. V. M. (2006) · New England Journal of Medicine · doi:10.1056/nejmra062326 · Cited by 787
Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts
Gehrs, K. M., Anderson, D. H., Johnson, L. V., & Hageman, G. S. (2006) · Annals of Medicine · doi:10.1080/07853890600946724 · Cited by 650
“In addition, a significant statistical relationship between the LOC387715 variant and a history of cigarette smoking has been found (232).”
Background
Metadata
- Authors
- Schmidt, S., Hauser, M. A., Scott, W. K., Postel, E. A., Agarwal, A., Gallins, P., Wong, F., Chen, Y. S., Spencer, K., Schnetz-Boutaud, N., Haines, J. L., & Pericak-Vance, M. A.
- Affiliations
- Duke Medical Center (US)
- Vanderbilt University Medical Center (US)
- Corresponding author
- Schmidt, Silke
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2006-05
- Volume
- 78
- Issue
- 5
- Pages
- 852-864
- ISSN
- 0002-9297 (ISSN-L)
- OpenAlex
- W2131861979
- Cited by
- 335
- References
- 48
- Citations by year
- 2025: 2 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 7 · 2019: 2 · 2018: 7 · 2017: 4 · 2016: 8 · 2015: 13 · 2014: 27 · 2013: 28 · 2012: 30
- FWCI
- 41.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council
- National Institute on Aging (AG-11268, P60AG011268)
- National Eye Institute (R03EY015216, R01EY012118, EY015216, U10EY012118, EY12118)
- National Center for Research Resources (M01RR000095, RR00095)
- NIH Clinical Center
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
- Keywords
- age-related macular degeneration, LOC387715, cigarette smoking, gene-environment interaction, chromosome 10q26, complement factor H, genetic susceptibility, population attributable risk
- MeSH terms
- Aged, Aged, 80 and over, Chromosomes, Human, Pair 10, Female, Gene Frequency, Haplotypes, Homozygote, Humans, Genetic Linkage, Macular Degeneration, Male, Middle Aged, Proteins, Smoking, Genetic Variation, Case-Control Studies, Complement Factor H, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
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