Drug targets for lipid modification and risk of type 2 diabetes: a cis-Mendelian randomization study

Figures

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  Fig. 1. Study overview. Abbreviations: Apo, apolipoprotein; CAD, coronary artery disease; GRCh37, Genome Reference Consortium Human Build 37; GWAS, genome-wide association study; HbA1c, glycated haemoglobin; HDL, high density lipoprotein; HOMA-B/ IR, homeostatic model assessment of beta cell function/ insulin resistance; LDL, low density lipoprotein; SNP, single nucleotide polymorphism; T2D, type 2 diabetes; TG, triglycerides

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  Fig. 2. Mendelian randomization (MR) assumptions. Panel A. Mendelian randomization assumptions. Relevance (IV1): the instrument is strongly related to the exposure. Exchangeability (IV2): there is no confounding between the instrument and outcome (no path exists from confounders to instrument). Exclusion restriction (IV3): SNP effects on the outcome are exclusively mediated through the exposure (i.e. absence of horizontal pleiotropy, no alternative path exists from instrument to outcome). Under these assumptions, associations of SNP-instrumented exposure with an outcome provide unconfounded, causal estimates of the relation between an exposure and an outcome. Panel B. The cis-Mendelian randomization approach to drug target investigation is similar to traditional Mendelian randomization but uses only genetic instruments proximal to the genetic locus (cis-instruments). We used downstream lipid biomarkers as proxies for the drug target, e.g. associations of HMGCR-instrumented LDL-C decrease with T2D provides an estimate of the effect of HMGCR inhibition on T2D. Panel C. Correlation between genetic variants through linkage disequilibrium. If the variant in high linkage disequilibrium has a…

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  Fig. 3. Strength and direction of drug effects predicted by cis-Mendelian randomization (MR). Each panel represents a genetic locus. Colored tiles represent statistical strength (-log10(p-value)) and direction (color) of the cis-MR estimate. Red color indicates positive effects: drug target inhibition is predicted to increase outcome risk, while blue color indicates negative effects: drug target inhibition is predicted to reduce outcome risk, and finally white color indicates neutral effects: drug target inhibition does not affect outcome. MR p-values < 10–10 are truncated. Tiles remain grey in case of unavailability of instruments. Circles represent results from genetic colocalization under the single causal variant assumption. Larger size indicates higher posterior probability (0–1) of a single shared causal variant (hypothesis 4, h4) between exposure and outcome, thus stronger support for the MR estimate. Lipid exposures represent the lipids that were used as weights, oriented towards canonical drug effect (i.e. HDL increase, LDL decrease, TG decrease), for the analysis. In this analysis, we used independent cis-instruments (p-value < 10–5, clumping LD r2 < 0.001 with LD calculated…

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  Fig. 4. Predicted drug effect estimates from cis-Mendelian randomization, presented as odds ratio (OR) per SD in lipid weights with 95%CI for main binary outcome (type 2 diabetes, T2D, and coronary artery disease, CAD). We used independent cis-instruments (p-value < 10–5, clumping LD r2 < 0.001 within 1 Mb, within 100 kb of the genetic locus). MR estimates are based on the Wald ratio (SNP outcome divided by SNP exposure effect, in case of a single instrument) or random-effects inverse variance weighted meta-analysis of Wald ratios (in case of multiple instruments). Lipid exposures represent the lipids that were used as weights, with estimates oriented towards canonical drug effect (i.e. HDL increase, LDL decrease, TG decrease)