HTRA1 Promoter Polymorphism in Wet Age-Related Macular Degeneration

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.

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

“…Our findings validate that the 10q26 region is more strongly associated with neovascular AMD risk than the 1q32 region in which CFH resides. 12,13,32 Moreover, our results demonstrate that HTRA1 variants influence risk independent of CFH genotype and smoking, supporting the role for HTRA1 in a distinct pathway underlying AMD pathogenesis. …”

“…Previously reported oligonucleotide primers were used to amplify the coding region and flanking intronic sequences of exon 12 for PLEKHA1, 9 exon 9 of CFH, 4 and the promoter sequence for HTRA1. 12 For the putative LOC387715/ ARMS2 gene region (including both exons) and the 9 exons of HTRA1, oligonucleotide primers were selected using the Primer3 program (http:// primer3.sourceforge.net) to encompass the entire coding region and flanking intronic sequences (Table 3 [available at http://aaojournal.org]).…”

“…7 Although many reports have demonstrated that variant rs10490924 in hypothetical LOC387715/ ARMS2 gene is associated with all types of AMD, [8][9][10][11] it was recently shown that the single-nucleotide polymorphism (SNP) rs11200638 in the HTRA1 promoter, in linkage disequilibrium (LD) with rs10490924, is likely the causal variant. [12][13][14] Moreover, data from the Age-Related Eye Disease Study showed a significant association between the SNP rs1045216 in PLEKHA1 and increased risk of neovascular AMD. 11 In the study presented here, we genotyped 33 megabases of the 10q26 region (Table 1) in samples from unrelated patients with neovascular AMD who had one sibling with normal maculae and was past the age at which the affected sibling was diagnosed with neovascular AMD.…”

The pursuit of genome-wide association studies: where are we now?

“…Some promising findings were achieved, for example, two new candidate genes were identified for AMD, the CFH gene for the drysubtype and the HTRA1 gene was associated with the wet-subtype of AMD. 1,20 The associations of these two genes have been robustly replicated in subsequent studies. 21,22 The other significant finding was the identification of the interleukin (IL)23R gene for CD, which encodes a subunit of the receptor binding to IL23 (a proinflammatory cytokine).…”

Genetics paired with CT angiography in the setting of atherosclerosis

“…The first robustly replicated GWAS result for CAD was published by the Wellcome Trust Case Control Consortium (WTCCC) in 2007 despite two landmark studies published prior [22,23]. These studies link human chromosome 9p21.3 locus with CAD for the first time.…”