Association of homocysteine with type 2 diabetes: a meta-analysis implementing Mendelian randomization approach

Abstract

Background: We tested the hypothesis that elevated homocysteine (Hcy) level is causally associated with increased risk of type 2 diabetes mellitus (T2DM).

Results: The meta-analysis and Mendelian randomization analysis were performed among 4011 cases and 4303 controls. The absolute pooled mean Hcy concentration in subjects with MTHFR 677TT was 5.55 μmol/L (95% CI, 1.33 to 9.77) greater than that in subjects with MTHFR 677CC in T2DM. Overall, the T allele of the MTHFR 677 C > T conferred a greater risk for T2DM [Random effect (RE) OR = 1.31(1.17-1.64), I² = 41.0%, p = 0.055]. The random effect (RE) pooled OR associated with T2DM for MTHFR 677TT relative to the 677CC was [RE OR = 1.38(1.18-1.62)]. The fixed-effect pooled OR of the association for the MTHFR 677 TT vs CT was 1.29 (95% CI, 1.09-1.51). MTHFR 677 TT showed a significantly higher risk for T2DM compared with MTHFR 677 CC + CT [Fixed effect (FE) OR = 1.32(1.14-1.54), I² = 0.0%, p = 0.686]. The absolute pooled mean Hcy concentration in individuals with T2DM was 0.94 μmol/L (95% CI, 0.40-1.48) greater than that in control subjects. The estimated causal OR associated with T2DM was 1.29 for 5 μmol/L increment in Hcy.

Conclusions: Our findings provided strong evidence on the causal association of Hcy level with the development of T2DM.

Figure 1

PRISMA flow diagram for selection of studies in the meta-analysis.

Figure 2

Summary estimates for the effect size (ES) in plasma Hcy between the MTHFR genotypes (TT vs CC) in type 2 diabetes patients. ^aT2DM patients with nephropathy, ^bT2DM patients without nephropathy.

Figure 3

Summary estimates for the effect size (ES) in plasma Hcy between the MTHFR genotypes (TT vs CT) in type 2 diabetes patients. ^aT2DM patients with nephropathy, ^bT2DM patients without nephropathy.

Figure 4

Summary estimates for the OR of MTHFR 677 C > T in genotype contrasts (TT vs CC), the OR with the 95% confidence interval is shown. Studies are displayed by descending order of publication year.

Figure 5

Summary estimates for the OR of MTHFR 677 C > T in allele contrasts (T vs C), the OR with the 95% confidence interval is shown. Studies are displayed by descending order of publication year.

Figure 6

Forest plot of standardized mean difference (SMD) in Hcy between subjects with and without type 2 diabetes in included studies. ^aT2DM patients with nephropathy, ^bT2DM patients without nephropathy.

Figure 7

The potential causal relation between Hcy and T2DM risk was explored by using Mendelian randomization. Calculation of an unconfounded estimate of the effect of an increase in Hcy of 1 μmol/L on the risk of T2DM based on the concept of Mendelian randomization.