LPA kringle IV type 2 is associated with type 2 diabetes in a Chinese population with very high cardiovascular risk

Abstract

The connection between lipoprotein (a) [Lp(a)] levels and the risks of cardiovascular disease and diabetes remains poorly understood. Lp(a) is encoded by the LPA gene, and evidence suggests that the kringle IV type 2 (KIV-2) variant is particularly important to Lp(a) isoform size. A large isoform size, represented as a high number of KIV-2 repeats in LPA, is associated with low serum Lp(a) concentrations and an increased risk of type 2 diabetes. We investigated the associations among Lp(a) concentrations, LPA KIV-2 repeats, and type 2 diabetes in a Chinese population of 1,863 consecutive patients with very high cardiovascular risk, as identified by coronary angiography. Individuals with Lp(a) levels in the top tertile [67.86 (35.34-318.50) mg/dl] had a lower risk of diabetes compared with those in the bottom tertile [7.38 (0.60-12.91) mg/dl]. There was an inverse association between the number of KIV-2 repeats and serum Lp(a) concentrations. This study demonstrated that a high number of LPA KIV-2 repeats are associated with increased risk of type 2 diabetes in a Chinese population with very high cardiovascular risk, which suggests that large Lp(a) isoform size, associated with low Lp(a) concentration, has a causal effect on type 2 diabetes.

Keywords: Mendelian randomization; gene expression; genetics; glucose; lipids; lipoprotein (a); lipoproteins; polymorphisms.

Fig. 1.

Association of Lp(a) levels with prevalent type 2 diabetes. Data are shown as OR (95% CI). P for trend is from logistic regression model with tertiles. Model 1, unadjusted; model 2, adjusted for age, sex, and BMI; model 3, as in model 2 and additionally adjusted for smoking status, drinking status, systolic blood pressure, diastolic blood pressure, antihypertensive medication, and significant coronary stenosis (≥50%); model 4, as in model 3 and additionally adjusted for total cholesterol, triglyceride, LDL-C, HDL-C, apoA-I, apoB, and lipid-lowering drugs.

Fig. 2.

Association of Lp(a) levels with the number of KIV-2 repeats in LPA. A: The inverse correlation between the number of KIV-2 repeats, as measured by $\overline{\Delta {\text{C}}_{\text{T}}}$, and serum Lp(a) concentrations (natural-log transformed) in the study population (n = 1,428). B: Serum Lp(a) concentrations by the tertiles of $\overline{\Delta {\text{C}}_{\text{T}}}$ in the study population (n = 1,428). The upper, middle, and lower lines represent the 90th percentile, median, and 10th percentile of serum Lp(a) levels, respectively. The bottom and the top of the box represent the 25th and 75th percentiles of serum Lp(a) levels, respectively.

Fig. 3.

Association of the number of KIV-2 repeats in LPA with prevalent type 2 diabetes. Data are shown as OR (95% CI). P for trend is from logistic regression model with tertiles. Model 1, unadjusted; model 2, adjusted for age, sex, and BMI; model 3, as in model 2 and additionally adjusted for smoking status, drinking status, systolic blood pressure, diastolic blood pressure, antihypertensive medication, and significant coronary stenosis (≥50%); model 4, as in model 3 and additionally adjusted for total cholesterol, triglyceride, LDL-C, HDL-C, apoA-I, apoB, and lipid-lowering drugs; model 5, as in model 4 and additionally adjusted for Lp(a).

Fig. 4.

Instrumental variable analysis estimate of the association of genetically elevated Lp(a) levels with risk of type 2 diabetes using the number of KIV-2 repeats in LPA as an instrument. Risk estimates for the tertiles of Lp(a) levels were calculated by logistic regression analyses using the first tertile as the reference. T1, the first tertile; T2, the second tertile; T3, the third tertile. *The multifactorial analysis adjusted for age, sex, BMI, smoking status, drinking status, systolic blood pressure, diastolic blood pressure, antihypertensive medication, significant coronary stenosis, total cholesterol, triglyceride, LDL-C, HDL-C, apoA-I, apoB, and lipid-lowering drugs.