RGD Reference Report - FLT1 genetic variation predisposes to neovascular AMD in ethnically diverse populations and alters systemic FLT1 expression. - Rat Genome Database

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FLT1 genetic variation predisposes to neovascular AMD in ethnically diverse populations and alters systemic FLT1 expression.

Authors: Owen, LA  Morrison, MA  Ahn, J  Woo, SJ  Sato, H  Robinson, R  Morgan, DJ  Zacharaki, F  Simeonova, M  Uehara, H  Chakravarthy, U  Hogg, RE  Ambati, BK  Kotoula, M  Baehr, W  Haider, NB  Silvestri, G  Miller, JW  Tsironi, EE  Farrer, LA  Kim, IK  Park, KH  DeAngelis, MM 
Citation: Owen LA, etal., Invest Ophthalmol Vis Sci. 2014 May 8;55(6):3543-54. doi: 10.1167/iovs.14-14047.
RGD ID: 10402108
Pubmed: PMID:24812550   (View Abstract at PubMed)
PMCID: PMC4073997   (View Article at PubMed Central)
DOI: DOI:10.1167/iovs.14-14047   (Journal Full-text)

PURPOSE: Current understanding of the genetic risk factors for age-related macular degeneration (AMD) is not sufficiently predictive of the clinical course. The VEGF pathway is a key therapeutic target for treatment of neovascular AMD; however, risk attributable to genetic variation within pathway genes is unclear. We sought to identify single nucleotide polymorphisms (SNPs) associated with AMD within the VEGF pathway. METHODS: Using a tagSNP, direct sequencing and meta-analysis approach within four ethnically diverse cohorts, we identified genetic risk present in FLT1, though not within other VEGF pathway genes KDR, VEGFA, or VASH1. We used ChIP and ELISA in functional analysis. RESULTS: The FLT1 SNPs rs9943922, rs9508034, rs2281827, rs7324510, and rs9513115 were significantly associated with increased risk of neovascular AMD. Each association was more significant after meta-analysis than in any one of the four cohorts. All associations were novel, within noncoding regions of FLT1 that do not tag for coding variants in linkage disequilibrium. Analysis of soluble FLT1 demonstrated higher expression in unaffected individuals homozygous for the FLT1 risk alleles rs9943922 (P = 0.0086) and rs7324510 (P = 0.0057). In silico analysis suggests that these variants change predicted splice sites and RNA secondary structure, and have been identified in other neovascular pathologies. These data were supported further by murine chromatin immunoprecipitation demonstrating that FLT1 is a target of Nr2e3, a nuclear receptor gene implicated in regulating an AMD pathway. CONCLUSIONS: Although exact variant functions are not known, these data demonstrate relevancy across ethnically diverse genetic backgrounds within our study and, therefore, hold potential for global efficacy.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Kuhnt-Junius degeneration susceptibilityIAGP 10402108DNA:SNP::rs9943922 more ...RGD 
Kuhnt-Junius degeneration susceptibilityISOFLT1 (Homo sapiens)10402108; 10402108DNA:SNP::rs9943922 more ...RGD 

Objects Annotated

Genes (Rattus norvegicus)
Flt1  (Fms related receptor tyrosine kinase 1)

Genes (Mus musculus)
Flt1  (FMS-like tyrosine kinase 1)

Genes (Homo sapiens)
FLT1  (fms related receptor tyrosine kinase 1)


Additional Information