Genome Wide Association Study on AMD in Japanese Patients and Characterization of HtrA1 Transgenic Mice

Abstract

Purpose: : Recently, several susceptibility genes were shown to associate with age-related macular degeneration (AMD). However, many of the previous genetic studies have included both the dry-type and wet-type of AMD. In the present study, we tried to identify the genes which associate with only the severe wet-type of AMD in Japanese patients. In this study we also investigated the transgenic mice over expressing the HtrA1 cDNA to compare with the HtrA1 knockout mice.

Methods: : A case-control study was performed on 100 advanced wet-type AMD (average age 74.56 ± 0.88 years) and 200 controls (average age 71.00 ± 0.75 years). Genechip genotyping was preformed on the Affymetrix GeneChip Human Mapping 500K Array Set. Transgenic constructs which consist of the mouse HtrA1 sequence controlled under CAG promoter was generated. 10 month-old heterozygous HtrA1 (htra1+/-) mice were examined by fundus imaging and HE staining.

Results: : Only the LOC387715/HTRA1 region on chromosome 10 was significantly associated with the advanced wet-type AMD in the Japanese. In the transgenic mice study, fundus observation resulted with drusen-like abnormalities. Initial histological examination did not reveal typical drusen. However, partial absence of choroid was observed in transgenic mice. No obvious abnormality was observed in HtrA1 knockout mice.

Conclusions: : LOC387715/HTRA1 region is a unique locus that is strongly associated with the advanced wet-type AMD in Japanese. Overexpression of Htra1 gene affects the formation of the choroid membrane and may make it easy to raise a vascularization.

Keywords: age-related macular degeneration • genetics • transgenics/knock-outs