Genetic variants near TIMP3 and high-density lipoprotein–associated loci influence susceptibility to age-related macular degeneration

Abstract

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10 −75), ARMS2 (P < 10 −59), C2/CFB (P < 10 −20), C3 (P < 10 −9 ), and CFI (P < 10 −6). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 × 10), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 × 10 −7; CETP, P = 7.4 × 10 −7 ) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c-associated alleles near LPL (P = 3.0 × 10 −3) and ABCA1 (P = 5.6 × 10 −4). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.genome-wide association study | single nucleotide polymorphism A ge-related macular degeneration (AMD) is a progressive neurodegenerative disease and a common cause of blindness in the elderly population, particularly in developed countries (1). The disease affects primarily the macular region of the retina, which is necessary for sharp central vision. An early hallmark of AMD is the appearance of drusen, which are extracellular deposits of proteins and lipids under the retinal pigment epithelium (RPE). As the disease progresses, drusen grow in size and number. In advanced stages of AMD, atrophy of the RPE (geographic atrophy) and/or development of new blood vessels (neovascularization) result in death of photoreceptors and central vision loss.

Influence of TIMP3/SYN3 polymorphisms on the phenotypic presentation of age-related macular degeneration

“…8,9 Three additional tag-SNPs were selected in a 100-kb region spanning rs9621532. To find the three SNPs, we set the minor allele frequency cutoff to 0.01 and R 2 linkage disequilibrium (LD) with rs9621532 40.8. rs1427384 in the 3 0 -UTR region of TIMP3 was also included in this study based on silicon analysis, which indicates the SNP is located in a microRNA-binding site (SNP function prediction, http://snpinfo.niehs.nih.gov/snpfunc.htm).…”

“…8 Based on a pre-defined two-sided alpha of 0.05, there was 495% power to detect a ± 3% departure from an rs9621532 allele frequency of 5.7% in each of the three sample sets. Study power remained 480% after stratifying the cases to nAMD in the NEI and AREDS cohorts but not in BMES.…”

“…Recently, a large-scale GWAS with thousands of cases and controls reported several additional AMD-associated loci, including rs9621532 near the tissue inhibitor of metalloproteinase 3 (TIMP3) and synapsin III (SYN3) region of chromosome 22q12.3. 8,9 The TIMP3 gene is located within an intron of SYN3 and is transcribed in the opposite direction. The SNP is located approximately 100-kb upstream of TIMP3 within the same intron of SYN3 ( Figure 1a).…”

NRF2 and Age-Dependent RPE Degeneration

“…Functional polymorphisms in the promoter region of NRF2 have been reported (Marzec et al, 2007). However, according to the GWAS data (Chen et al, 2010), NRF2 is not a major risk allele of AMD and SNPs of NRF2 are unlikely to be a major genetic factor. A recent study showed that age-dependent decline of NRF2 function could be caused by upstream regulatory mechanisms, such as GSK-3, that control its localization and activity (Tomobe et al, 2011).…”

Review of nutrient actions on age-related macular degeneration

“…Due to the interaction between genetic and environmental factors, the etiology of AMD is multifactorial [4]. As with other complex diseases, recent genome-wide studies have established and confirmed many genetic variants associated with a higher risk for AMD [5][6][7][8][9]. In this review, we summarize the effects that dietary practices and nutritional supplements have on the susceptibility of AMD.…”