Alleles in the HtrA Serine Peptidase 1 Gene Alter the Risk of Neovascular Age-Related Macular Degeneration
Received 2 July 2007; received in revised form 14 September 2007; accepted 22 October 2007. published online 03 January 2008.
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.
Available online: December 27, 2007.
1Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.
2Laboratory of Statistical Genetics, Rockefeller University, New York, New York.
3Associated Retinal Consultants, PC, William Beaumont Hospital, Royal Oak, Michigan.
4Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
Correspondence to Margaret M. DeAngelis, PhD, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114.
Manuscript no. 2007-874.
The authors have no conflict of interest in any materials mentioned in the article.
Supported by grants from the Ruth and Milton Steinbach Fund, New York, New York; Lincy Foundation, Beverly Hills, California; Massachusetts Lions, New Bedford, Massachusetts; Friends of the Massachusetts Eye and Ear Infirmary (MEEI), Boston, Massachusetts; Genetics of Age-Related Macular Degeneration Fund, MEEI, Boston, Massachusetts; Research to Prevent Blindness, New York, New York; Natural Science Foundation of China, Beijing, China (project no. 30730057); and National Institutes of Health, Bethesda, Maryland (nos. EY014458, EY14104, MH44292).
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