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

TLDR

The study aims to expand the catalog of AMD‑associated loci, identify high‑risk individuals, and uncover cellular pathways for future therapies. The authors performed a genome‑wide association scan of AMD in 2,157 cases and 1,150 controls, then replicated top signals in an independent cohort of up to 7,749 cases and 4,625 controls by genotyping 30 candidate markers. The analysis confirmed known AMD loci (CFH, ARMS2, C2/CFB, C3, CFI), identified a new TIMP3 locus, and revealed strong associations with HDL‑related genes (LIPC, CETP, LPL, ABCA1), with multilocus risk scores correctly classifying 99 % of cases and 85 % of advanced AMD.

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 &lt; 10 −75 ), ARMS2 ( P &lt; 10 −59 ), C2/CFB ( P &lt; 10 −20 ), C3 ( P &lt; 10 −9 ), and CFI ( P &lt; 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 −11 ), 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.