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D. Chen, Y. Sun; Study of Three Genetic Variations in 10q26.13 With RNA Expression Levels of ARMS2 (LOC387715) and HTRA1. Invest. Ophthalmol. Vis. Sci. 2009;50(13):6013.
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The ARMS2/HTRA1 locus in chromosome 10q26.13 has been associated consistently with age-related macular degeneration (AMD) in populations throughout the world. Genetic variations in this locus including single nucleotide polymorphism (SNP) rs10490924, Indel (del443ins54) and SNP rs11200638 have been reported to explain the association of this locus for AMD susceptibility, and are in high linkage disequilibrium (LD). Fritsche et al (2008) reported that the Indel was associated with decreasing the expression of ARMS2. We sought to determine if the three variants alter the expression of ARMS2 and HTRA1 RNA in normal human retinas.
The three genetic variations were genotyped in a 53 Caucasian normal donor eye globes (first 20 donors and then 33 donors). HTRA1 mRNA levels in our first 20 donor retinas were measured by TaqMan real-time quantitative RT-PCR (qRT-PCR), and normalized to that of reference HPRT1 mRNA from separate reactions. TaqMan qRT-PCR assay available for ARMS2 RNA failed to measure the RNA levels in our samples, so ARMS2 RNA levels in all 53 donor retinas were measured by UPL probe-detection-coupled qRT-PCR duplexed with measuring reference TBP mRNA in the same reaction under optimized conditions, and normalized to that of TBP mRNA level. qRT-PCR for each RNA sample was performed in triplicate, and the average was used to represent the RNA level in the sample. T-test (2 tails and type 3) were used for genotype association with RNA expression levels.
The reported AMD-risk genotypes of rs10490924, Indel and rs11200638 appeared having no effects on altering HTRA1 mRNA expression levels in our 20 donor retinas (P>0.4). However, they were significantly associated with decreasing ARMS2 RNA expression levels in our 53 donor retinas: 1) wt/indel and indel/indel of del443ins54 was significantly associated with decreasing (23% and 63% respectively) ARMS2 RNA expression level (wt/indel vs. wt/wt, P<7.2x10-4; wt/indel + indel/indel vs. wt/wt, P<4.2x10-4); and 2) the risk genotypes of rs10490924 and rs11200638 were similarly associated with decreasing ARMS2 RNA expression level due to the high LD across the locus.
The previously-reported AMD risk genotypes of the studied genetic variations in ARMS2/HTRA1 locus were significantly associated with decreasing ARMS2 RNA expression level but most likely not with altering HTRA1 RNA expression level in normal human retinas. Decreasing ARMS2 RNA expression may be the mechanism for the genetic variations of 10q26.13 region to influence AMD susceptibility, but this requires further study
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