Elsevier

Ophthalmology

Volume 115, Issue 7, July 2008, Pages 1209-1215.e7
Ophthalmology

Original article
Alleles in the HtrA Serine Peptidase 1 Gene Alter the Risk of Neovascular Age-Related Macular Degeneration

https://doi.org/10.1016/j.ophtha.2007.10.032Get rights and content

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.

Section snippets

Patient Population

The protocol was reviewed and approved by the institutional review boards at the Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, and William Beaumont Hospital, Royal Oak, Michigan, and conforms to the tenets of the Declaration of Helsinki. Eligible patients were enrolled in this study after they gave informed consent in person, over the phone, or through the mail before answering a standardized questionnaire and donating 10 to 50 ml of venous blood. In most cases, the donation of

Results

We identified 23 variants including deletions. Only the SNPs that had a minor allele frequency of ≥5% in the affected and unaffected siblings combined were used for statistical analysis (n = 19) (Table 4 [available at http://aaojournal.org]). Using FBAT, 6 SNPs showed significant association with AMD risk after applying a Bonferroni correction (Table 6 [available at http://aaojournal.org]). Genotype and allele frequencies for each of these SNPs are given in Table 5 (available at //aaojournal.org

Discussion

Two of the 4 novel variants that we identified in HTRA1 have predicted functional effects on the pathophysiology of neovascular AMD. Variant rs2672598 created a binding site for the transcription factor ELK-1, whose activity was reported to be impaired in a patient with a premature form of aging and insulin resistance.27 We hypothesize, then, that if the risk allele of the promoter SNP rs11200638 results in increased expression of HTRA1,12, 13 then the minor allele of rs2672598 might exert a

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  • Cited by (0)

    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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