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Associations of smoking, body mass index, dietary lutein, and the LIPC gene variant rs10468017 with advanced age-related macular degeneration.

ABSTRACT: A novel locus in the hepatic lipase (LIPC) gene was found to be significantly related to advanced age-related macular degeneration (AMD) in our genome-wide association study. We evaluated its association and interaction with previously identified genetic variants and modifiable factors.Participants in the Age-Related Eye Disease Study with advanced AMD (n=545 cases) or no AMD (n=275 controls) were evaluated. AMD status was determined using fundus photography. Covariates included cigarette smoking, body mass index (BMI), and dietary lutein. Individuals were genotyped for the rs10468017 polymorphism in LIPC as well as seven previously identified AMD genetic loci. Unconditional logistic regression analyses were then performed.The TT genotype of the LIPC variant was associated with a reduced risk of AMD, with odds ratios (OR) of 0.50 (95% confidence interval (CI) 0.20-0.90) and p=0.014 for the TT genotype versus the CC genotype, controlling for age, gender, smoking, body mass index (BMI), and nutritional factors. Controlling for seven other AMD genetic variants, the OR was 0.50, 95% (CI 0.20-1.1, p=0.077). The magnitude of the effect was similar for both atrophic and neovascular forms of AMD. Cigarette smoking and higher BMI increased the risk, while higher dietary lutein reduced the risk of advanced AMD, adjusting for genetic variants. There were no significant interactions between LIPC and smoking, BMI, or lutein. There was a possible association between LIPC and complement factor H (CFH) rs1410996, and a possible interaction effect between LIPC and both CFH rs10033900 and the complement factor I (CFI) variants in terms of risk of AMD.LIPC is associated with reduced risk of advanced AMD, independent of demographic and environmental variables. Both genetic susceptibility and behavioral and lifestyle factors modify the risk of developing AMD.

SUBMITTER: Seddon JM

PROVIDER: S-EPMC2994762 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Associations of smoking, body mass index, dietary lutein, and the LIPC gene variant rs10468017 with advanced age-related macular degeneration.

Seddon Johanna M JM Reynolds Robyn R Rosner Bernard B

Molecular vision 20101117

<h4>Objective</h4>A novel locus in the hepatic lipase (LIPC) gene was found to be significantly related to advanced age-related macular degeneration (AMD) in our genome-wide association study. We evaluated its association and interaction with previously identified genetic variants and modifiable factors.<h4>Methods</h4>Participants in the Age-Related Eye Disease Study with advanced AMD (n=545 cases) or no AMD (n=275 controls) were evaluated. AMD status was determined using fundus photography. Co ...[more]

PMID: 21139980

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Project description:PurposeLarge-scale genome-wide association studies (GWAS) have reported important single nucleotide polymorphisms (SNPs) with significant associations with age-related macular degeneration (AMD). However, their role in disease development remains elusive. This study aimed to assess SNP-metabolite associations (i.e., metabolite quantitative trait loci [met-QTL]) and to provide insights into the biological mechanisms of AMD risk SNPs.DesignCross-sectional multicenter study (Boston, Massachusetts, and Coimbra, Portugal).ParticipantsPatients with AMD (n = 388) and control participants (n = 98) without any vitreoretinal disease (> 50 years).MethodsAge-related macular degeneration grading was performed using color fundus photographs according to the Age-Related Eye Disease Study classification scheme. Fasting blood samples were collected and evaluated with mass spectrometry for metabolomic profiling and Illumina OmniExpress for SNPs profiling. Analyses of met-QTL of endogenous metabolites were conducted using linear regression models adjusted for age, gender, smoking, 10 metabolite principal components (PCs), and 10 SNP PCs. Additionally, we analyzed the cumulative effect of AMD risk SNPs on plasma metabolites by generating genetic risk scores and assessing their associations with metabolites using linear regression models, accounting for the same covariates. Modeling was performed first for each cohort, and then combined by meta-analysis. Multiple comparisons were accounted for using the false discovery rate (FDR).Main outcome measuresPlasma metabolite levels associated with AMD risk SNPs.ResultsAfter quality control, data for 544 plasma metabolites were included. Meta-analysis of data from all individuals (AMD patients and control participants) identified 28 significant met-QTL (β = 0.016-0.083; FDR q-value < 1.14 × 10-2), which corresponded to 5 metabolites and 2 genes: ASPM and LIPC. Polymorphisms in the LIPC gene were associated with phosphatidylethanolamine metabolites, which are glycerophospholipids, and polymorphisms in the ASPM gene with branched-chain amino acids. Similar results were observed when considering only patients with AMD. Genetic risk score-metabolite associations further supported a global impact of AMD risk SNPs on the plasma metabolome.ConclusionsThis study demonstrated that genomic-metabolomic associations can provide insights into the biological relevance of AMD risk SNPs. In particular, our results support that the LIPC gene and the glycerophospholipid metabolic pathway may play an important role in AMD, thus offering new potential therapeutic targets for this disease.

Dataset Information

Associations of smoking, body mass index, dietary lutein, and the LIPC gene variant rs10468017 with advanced age-related macular degeneration.

Publications

Associations of smoking, body mass index, dietary lutein, and the LIPC gene variant rs10468017 with advanced age-related macular degeneration.

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