Dataset Information

Mendelian Randomization Implicates High-Density Lipoprotein Cholesterol-Associated Mechanisms in Etiology of Age-Related Macular Degeneration.

ABSTRACT:

Purpose

Undertake a systematic investigation into associations between genetic predictors of lipid fractions and age-related macular degeneration (AMD) risk.

Design

Two-sample Mendelian randomization investigation using published data.

Participants

A total of 33 526 individuals (16 144 cases, 17 832 controls) predominantly of European ancestry from the International Age-related Macular Degeneration Genomics Consortium.

Methods

We consider 185 variants previously demonstrated to be associated with at least 1 of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides at a genome-wide level of significance, and test their associations with AMD. We particularly focus on variants in gene regions that are proxies for specific pharmacologic agents for lipid therapy. We then conduct a 2-sample Mendelian randomization investigation to assess the causal roles of LDL-cholesterol, HDL-cholesterol, and triglycerides on AMD risk. We also conduct parallel investigations for coronary artery disease (CAD) (viewed as a positive control) and Alzheimer's disease (a negative control) for comparison.

Main outcome measures

Diagnosis of AMD.

Results

We find evidence that HDL-cholesterol is a causal risk factor for AMD, with an odds ratio (OR) estimate of 1.22 (95% confidence interval [CI], 1.03-1.44) per 1 standard deviation increase in HDL-cholesterol. No causal effect of LDL-cholesterol or triglycerides was found. Variants in the CETP gene region associated with increased circulating HDL-cholesterol also associate with increased AMD risk, although variants in the LIPC gene region that increase circulating HDL-cholesterol have the opposite direction of association with AMD risk. Parallel analyses suggest that lipids have a greater role for AMD compared with Alzheimer's disease, but a lesser role than for CAD.

Conclusions

Some genetic evidence suggests that HDL-cholesterol is a causal risk factor for AMD risk and that increasing HDL-cholesterol (particularly via CETP inhibition) will increase AMD risk.

SUBMITTER: Burgess S

PROVIDER: S-EPMC5526457 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundLipid metabolism and particularly high-density lipoprotein (HDL) may be involved in the pathogenic mechanism of age-related macular degeneration (AMD). However, conflicting results have been reported in the associations of AMD with plasma HDL and other lipids, which may be confounded by the recently reported associations of AMD with HDL-related genes. We explored the association of AMD with plasma lipid levels and lipid-lowering medication use, taking into account most of HDL-related genes associated with AMD.MethodsThe Alienor study is a population-based study on age-related eye diseases performed in 963 elderly residents of Bordeaux (France). AMD was graded from non mydriatic color retinal photographs in three exclusive stages: no AMD (n = 430 subjects, 938 eyes); large soft distinct drusen and/or large soft indistinct drusen and/or reticular drusen and/or pigmentary abnormalities (early AMD, n = 176, 247); late AMD (n = 40, 61). Associations of AMD with plasma lipids (HDL, total cholesterol (TC), Low-density lipoprotein (LDL), and triglycerides (TG)) were estimated using Generalized Estimating Equation logistic regressions. Statistical analyses included 646 subjects with complete data.ResultsAfter multivariate adjustment for age, sex, educational level, smoking, BMI, lipid-lowering medication use, cardiovascular disease and diabetes, and for all relevant genetic polymorphisms (ApoE2, ApoE4, CFH Y402H, ARMS2 A69S, LIPC rs10468017, LIPC rs493258, LPL rs12678919, ABCA1 rs1883025 and CETP rs3764261), higher HDL was significantly associated with an increased risk of early (OR = 2.45, 95%CI: 1.54-3.90; P = 0.0002) and any AMD (OR = 2.29, 95%CI: 1.46-3.59; P = 0.0003). Association with late AMD was far from statistical significance (OR = 1.58, 95%CI: 0.48-5.17; p = 0.45). No associations were found for any stage of AMD with TC, LDL and TG levels, statin or fibrate drug use.ConclusionsThis study suggests that elderly patients with high HDL concentration may be at increased risk for AMD and, further, that HDL dysfunction might be implicated in AMD pathogenesis.

Project description:Dyslipidemia, particularly high-density lipoprotein cholesterol (HDL-C), has recently been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss. However, epidemiological studies have yielded conflicting results.We investigated the causal role of plasma lipid levels in AMD in multiethnic populations comprising 16 144 advanced AMD cases and 17 832 controls of European descent, together with 2219 cases and 5275 controls of Asian descent, using Mendelian randomization in three models. Model 1 is a conventional meta-analysis which does not account for pleiotropy of instrumental variable (IV) effects. Model 2 is a univariate, inverse variance weighted regression analysis that accounts for potential unbalanced pleiotropy using MR-Egger method. Finally, Model 3 is a multivariate regression analysis that addresses pleiotropy by MR-Egger method and by adjusting for effects on other lipid traits.A 1 standard deviation (SD) higher HDL-cholesterol level was associated with an odds ratio (OR) for AMD of 1.17 (95% confidence interval: 1.07-1.29) in Europeans (P = 6.88 × 10-4) and of 1.58 (1.24-2.00) in Asians (P = 2.92 × 10-4) in Model 3. The corresponding OR estimates were 1.30 (1.09-1.55) in Europeans (P = 3.18 × 10-3) and 1.42 (1.11-1.80) in Asians (P = 4.42 × 10-3) in Model 1, and 1.21 (1.11-1.31) in Europeans (P = 3.12 × 10-5) and 1.51 (1.20-1.91) in Asians (P = 7.61 × 10-4) in Model 2. Conversely, neither LDL-C (Europeans: OR = 0.96, P = 0.272; Asians: OR = 1.02, P = 0.874; Model 3) nor triglyceride levels (Europeans: OR = 0.91, P = 0.102; Asians: OR = 1.06, P = 0.613) were associated with AMD. We also assessed the association between lipid levels and polypoidal choroidal vasculopathy (PCV) in Asians, a subtype of AMD, and found a similar trend for association of PCV with HDL-C levels.Our study shows that high levels of plasma HDL-C are causally associated with an increased risk for advanced AMD in European and Asian populations, implying that strategies reducing HDL-C levels may be useful to prevent and treat AMD.

Project description:BACKGROUND:High circulating low-density lipoprotein cholesterol (LDL-C) is a major risk factor for atherosclerosis and age-associated cardiovascular events. Long-term dyslipidaemia could contribute to the development of frailty in older individuals through its role in determining cardiovascular health and potentially other physiological pathways. METHODS:We conducted Mendelian randomization (MR) analyses using genetic variants to estimate the effects of long-term LDL-C modification on frailty in UK Biobank (n?=?378,161). Frailty was derived from health questionnaire and interview responses at baseline when participants were aged 40 to 69?years, and calculated using an accumulation-of-deficits approach, i.e. the frailty index (FI). Several aggregated instrumental variables (IVs) using 50 and 274 genetic variants were constructed from independent single-nucleotide polymorphisms (SNPs) to instrument circulating LDL-C concentrations. Specific sets of variants in or near genes that encode six lipid-lowering drug targets (HMGCR, PCSK9, NPC1L1, APOB, APOC3, and LDLR) were used to index effects of exposure to related drug classes on frailty. SNP-LDL-C effects were available from previously published studies. SNP-FI effects were obtained using adjusted linear regression models. Two-sample MR analyses were performed with the IVs as instruments using inverse-variance weighted, MR-Egger, weighted median, and weighted mode methods. To address the stability of the findings, MR analyses were also performed using i) a modified FI excluding the cardiometabolic deficit items and ii) data from comparatively older individuals (aged ?60?years) only. Several sensitivity analyses were also conducted. FINDINGS:On average 0.14% to 0.23% and 0.16% to 0.31% decrements in frailty were observed per standard deviation reduction in LDL-C exposure, instrumented by the general IVs consisting of 50 and 274 variants, respectively. Consistent, though less precise, associations were observed in the HMGCR-, APOC3-, NPC1L1-, and LDLR-specific IV analyses. In contrast, results for PCSK9 were in the same direction but more modest, and null for APOB. All sensitivity analyses produced similar findings. INTERPRETATION:A genetically-predicted life-long lowering of LDL-C is associated with decreased frailty in midlife and older age, representing supportive evidence for LDL-C's role in multiple health- and age-related pathways. The use of lipid-lowering therapeutics with varying mechanisms of action may differ by the extent to which they provide overall health benefits.