Abstract
Aims/hypothesisMicrovascular disease in type 2 diabetes is a significant cause of end-stage renal disease, blindness and peripheral neuropathy. The strict control of known risk factors, e.g. lifestyle, hyperglycaemia, hypertension and dyslipidaemia, reduces the incidence of microvascular complications, but a residual risk remains. Lipoprotein (a) [Lp(a)] is a strong risk factor for macrovascular disease in the general population. We hypothesised that plasma Lp(a) levels and the LPA gene SNPs rs10455872 and rs3798220 are associated with the incident development of microvascular complications in type 2 diabetes.MethodsAnalyses were performed of data from the DiaGene study, a prospective study for complications of type 2 diabetes, collected in the city of Eindhoven, the Netherlands (n = 1886 individuals with type 2 diabetes, mean follow-up time = 6.97 years). To assess the relationship between plasma Lp(a) levels and the LPA SNPs with each newly developed microvascular complication (retinopathy n = 223, nephropathy n = 246, neuropathy n = 236), Cox proportional hazards models were applied and adjusted for risk factors for microvascular complications (age, sex, mean arterial pressure, non-HDL-cholesterol, HDL-cholesterol, BMI, duration of type 2 diabetes, HbA1c and smoking).ResultsNo significant associations of Lp(a) plasma levels and the LPA SNPs rs10455872 and rs3798220 with prevalent or incident microvascular complications in type 2 diabetes were found. In line with previous observations the LPA SNPs rs10455872 and rs3798220 did influence the plasma Lp(a) levels.Conclusions/interpretationOur data show no association between Lp(a) plasma levels and the LPA SNPs with known effect on Lp(a) plasma levels with the development of microvascular complications in type 2 diabetes. This indicates that Lp(a) does not play a major role in the development of microvascular complications. However, larger studies are needed to exclude minimal effects of Lp(a) on the development of microvascular complications.
Highlights
Microvascular complications greatly reduce the quality of life of individuals with type 2 diabetes
What is already known about this subject? Lipoprotein(a) [Lp(a)] is a causal risk factor for the development of macrovascular complications in the general population, as confirmed by Mendelian randomisation studies New therapies have emerged to potentially decrease Lp(a) levels The risk factor profiles associated with the development of macro- and microvascular disease in type 2 diabetes are similar to each other
Even when people with type 2 diabetes receive optimal treatment according to the current standards, there is a residual risk of development and progression of complications [4, 5]
Summary
Study design The overall aim of the DiaGene study is to unravel the aetiology of type 2 diabetes and its complications, by identifying risk factors, e.g. genomic, glycomic and lipidomic factors. A total of 1850 type 2 diabetic individuals with successfully measured Lp(a) plasma levels were included in the analyses. Cox proportional hazards models were used to prospectively assess the association between Lp(a) as an independent variable and each microvascular complication endpoint as a dependent variable. Model 2 was adjusted for the following additional risk factors for microvascular complications: MAP, non-HDL-cholesterol, HDL-cholesterol, HbA1c, BMI, duration of type 2 diabetes and smoking. We applied Psplines (penalised cubic B-splines) in both the logistic regression as well as Cox models [34] This involves selecting a high number of equidistant knots, followed by a penalty term, which is optimised via generalised cross validation to avoid overfitting. Models 1 and 2 described above were applied to assess the relationship between the SNPs and each microvascular endpoint. ESM Table 1 provides an overview of conducted post hoc power analyses [35,36,37]
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