Mendelian Randomization Analysis of Hemoglobin A1c as a Risk Factor for Coronary Artery Disease

Abstract

Objective: Observational studies show that higher hemoglobin A_1c (A1C) predicts coronary artery disease (CAD). It remains unclear whether this association is driven entirely by glycemia. We used Mendelian randomization (MR) to test whether A1C is causally associated with CAD through glycemic and/or nonglycemic factors.

Research design and methods: To examine the association of A1C with CAD, we selected 50 A1C-associated variants (log₁₀ Bayes factor ≥6) from an A1C genome-wide association study (GWAS; n = 159,940) and performed an inverse-variance weighted average of variant-specific causal estimates from CAD GWAS data (CARDIoGRAMplusC4D; 60,801 CAD case subjects/123,504 control subjects). We then replicated results in UK Biobank (18,915 CAD case subjects/455,971 control subjects) and meta-analyzed all results. Next, we conducted analyses using two subsets of variants, 16 variants associated with glycemic measures (fasting or 2-h glucose) and 20 variants associated with erythrocyte indices (e.g., hemoglobin [Hb]) but not glycemic measures. In additional MR analyses, we tested the association of Hb with A1C and CAD.

Results: Genetically increased A1C was associated with higher CAD risk (odds ratio [OR] 1.61 [95% CI 1.40, 1.84] per %-unit, P = 6.9 × 10^-12). Higher A1C was associated with increased CAD risk when using only glycemic variants (OR 2.23 [1.73, 2.89], P = 1.0 × 10^-9) and when using only erythrocytic variants (OR 1.30 [1.08, 1.57], P = 0.006). Genetically decreased Hb, with concomitantly decreased mean corpuscular volume, was associated with higher A1C (0.30 [0.27, 0.33] %-unit, P = 2.9 × 10^-6) per g/dL and higher CAD risk (OR 1.19 [1.04, 1.37], P = 0.02).

Conclusions: Genetic evidence supports a causal link between higher A1C and higher CAD risk. This relationship is driven not only by glycemic but also by erythrocytic, glycemia-independent factors.

Figure 1

Causal effect on CAD risk in CARDIoGRAMplusC4D and UKBB of increased A1C instrumented by all A1C-associated genetic variants, glycemic-only A1C variants, and erythrocytic-only A1C variants. MR analyses were performed by the IVW method. Effect estimates are OR of CAD per %-unit increase in A1C.

Figure 2

MR diagram of glycemic and erythrocytic factors underlying the genetic relationship between A1C and CAD risk. Genetically decreased Hb with concomitantly decreased MCV was associated with higher A1C and higher odds of CAD (Table 2). Hb and LDL had bidirectional associations: increased LDL was associated with 0.06 g/dL decrease in Hb per SD change in LDL (P = 0.002), and decreased Hb was associated with 0.21 SD increase in LDL (P = 2.7 × 10⁻¹⁰). Generally, increased A1C when instrumented by all 50 A1C genetic variants was associated with higher LDL by 0.49 SD (P = 5.4 × 10⁻³⁶) per 1%-unit in A1C and higher odds of CAD (OR 1.61, P = 6.9 × 10⁻¹²) per 1%-unit in A1C. Increased A1C when instrumented by 20 erythrocytic A1C variants was associated with higher LDL by 0.57 SD (P = 2.3 × 10⁻²⁴) per 1%-unit in A1C and higher odds of CAD (OR 1.30, P = 0.004) per 1%-unit in A1C. The causal association of higher LDL with higher CAD risk has been shown in the literature (22,23) and so the MR analysis was not performed.