title: DNA sequence variants in PPARGC1A, a gene encoding a coactivator of the ω-3 LCPUFA sensing PPAR-RXR transcription complex, are associated with NV AMD and AMD-associated loci in genes of complement and VEGF signaling pathways.
abstract: BACKGROUND
  Increased intake of ω-3 long-chain polyunsaturated fatty acids (LCPUFAs) and use of peroxisome proliferator activator receptor (PPAR)-activating drugs are associated with attenuation of pathologic retinal angiogenesis. ω-3 LCPUFAs are endogenous agonists of PPARs. We postulated that DNA sequence variation in PPAR gamma (PPARG) co-activator 1 alpha (PPARGC1A), a gene encoding a co-activator of the LCPUFA-sensing PPARG-retinoid X receptor (RXR) transcription complex, may influence neovascularization (NV) in age-related macular degeneration (AMD).
  
  
  METHODS
  We applied exact testing methods to examine distributions of DNA sequence variants in PPARGC1A for association with NV AMD and interaction of AMD-associated loci in genes of complement, lipid metabolism, and VEGF signaling systems. Our sample contained 1858 people from 3 elderly cohorts of western European ancestry. We concurrently investigated retinal gene expression profiles in 17-day-old neonatal mice on a 2% LCPUFA feeding paradigm to identify LCPUFA-regulated genes both associated with pathologic retinal angiogenesis and known to interact with PPARs or PPARGC1A.
  
  
  RESULTS
  A DNA coding variant (rs3736265) and a 3'UTR-resident regulatory variant (rs3774923) in PPARGC1A were independently associated with NV AMD (exact P = 0.003, both SNPs). SNP-SNP interactions existed for NV AMD (P<0.005) with rs3736265 and a AMD-associated variant in complement factor B (CFB, rs512559). PPARGC1A influences activation of the AMD-associated complement component 3 (C3) promoter fragment and CFB influences activation and proteolysis of C3. We observed interaction (P ≤ 0.003) of rs3736265 with a variant in vascular endothelial growth factor A (VEGFA, rs3025033), a key molecule in retinal angiogenesis. Another PPARGC1A coding variant (rs8192678) showed statistical interaction with a SNP in the VEGFA receptor fms-related tyrosine kinase 1 (FLT1, rs10507386; P ≤ 0.003). C3 expression was down-regulated 2-fold in retinas of ω-3 LCPUFA-fed mice - these animals also showed 70% reduction in retinal NV (P ≤ 0.001).
  
  
  CONCLUSIONS
  Ligands and co-activators of the ω-3 LCPUFA sensing PPAR-RXR axis may influence retinal angiogenesis in NV AMD via the complement and VEGF signaling systems. We have linked the co-activator of a lipid-sensing transcription factor (PPARG co-activator 1 alpha, PPARGC1A) to age-related macular degeneration (AMD) and AMD-associated genes.
authors: Clinical Trials Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA. jpsangio@post.harvard.edu
authors: John Paul
authors: JP
authors: SanGiovanni
authors: Jing
authors: J
authors: Chen
authors: Przemyslaw
authors: P
authors: Sapieha
authors: Christopher M
authors: CM
authors: Aderman
authors: Andreas
authors: A
authors: Stahl
authors: Traci E
authors: TE
authors: Clemons
authors: Emily Y
authors: EY
authors: Chew
authors: Lois E H
authors: LE
authors: Smith
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015331:Cohort Studies; D003165:Complement System Proteins / Q000235:genetics*; D015525:Fatty Acids, Omega-3 / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020641:Polymorphism, Single Nucleotide; D012160:Retina / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D015525:Fatty Acids, Omega-3; D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D003165:Complement System Proteins