Abstract
The genomic region at 9p21 chromosome near the CDKN2A/CDKN2B genes is associated with type 2 diabetes(T2D) and cardiovascular disease(CVD). The effect of the 9p21 locus on long-term mortality in patients with T2D has yet to be determined.We examined three single nucleotide polymorphisms (SNPs) on 9p21, consistently and independently associated with T2D (rs10811661) or CVD (rs10757278, rs2383206), in relation to the risk of total and cardiovascular mortality in diabetic patients. We also aimed to replicate the previously observed interaction between rs2383206 and glycemic control on mortality.Genotypes for three SNPs were determined in 914 individuals from a prospective cohort of T2D patients of Dutch origin. Associations with mortality were assessed using Cox proportional hazard analyses.After a median follow-up of 9.5 years, 358 out of 914 patients had died. The hazard ratio (HR) for total mortality among individuals homozygous for the T2D-risk allele of rs10811661 compared to non-homozygous individuals was 0.74(95%CI 0.59-0.93). For the carriers of both CVD-risk alleles of rs10757278, the HR for total mortality was 1.31(95%CI 1.01-1.70). We found a significant interaction between rs2383206 and HbA1c on mortality, which was higher among patients with two CVD-risk alleles in the two lowest HbA1c tertiles (HR 1.68(95%CI 1.08-2.63); HR 1.48(95%CI 1.01-2.18).In conclusion, common variants on 9p21 were associated with mortality in patients with T2D in a Dutch population. The T2D SNP was inversely associated with mortality, while the CVD SNP increased the risk for mortality. We confirmed a possible, although different, synergistic relationship between HbA1c and rs2383206 on total mortality.
Highlights
Patients with type 2 diabetes (T2D) have a high risk for cardiovascular morbidity and mortality [1]
This prospective study shows that three genetic risk variants for T2D and cardiovascular disease (CVD) on 9p21 are associated with total mortality in patients with T2D
We found that the genetic risk variant for
Summary
Patients with type 2 diabetes (T2D) have a high risk for cardiovascular morbidity and mortality [1]. Genome-wide association (GWA) studies for T2D [2,3,4] and cardiovascular disease (CVD) have identified the same susceptibility locus on chromosome 9p21 [5,6] In this genomic region near the protein-coding genes CDKN2A and CDKN2B containing. Different pathophysiological pathways have been proposed, including the initiation and possibly progression of coronary atherosclerosis and development of multivessel coronary artery disease (CAD) [9,10,11]. One of these studies showed an effect of the 9p21 region on progression of plaques in the presence of already established CVD among non-diabetics, this effect was different in patients with T2D [11]. Whether the polymorphisms on 9p21 can predict overall or cardiovascular mortality in patients with T2D and how this association is modulated by glycemic control is still to be determined
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