Open Access Original investigation

Association between 9p21 genetic variants and mortality risk in a prospective cohort of patients with type 2 diabetes (ZODIAC-15)

Gijs WD Landman1*, Jana V van Vliet-Ostaptchouk23, Nanne Kleefstra145, Kornelis JJ van Hateren1, Iefke Drion1, Klaas H Groenier6, Rijk OB Gans5, Harold Snieder7, Marten H Hofker2 and Henk JG Bilo158

Author Affiliations

1 Diabetes Center, Isala Clinics, PO Box 10400, 8000 GK, Zwolle, The Netherlands

2 Molecular Genetics, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

3 Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

4 Langerhans, Medical Research Group, Zwolle, the Netherlands

5 Department of Internal Medicine, University Medical Center Groningen, Groningen, the Netherlands

6 Department of General Practice, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

7 Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

8 Department of Internal Medicine, Isala Clinics, Zwolle, the Netherlands

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Cardiovascular Diabetology 2012, 11:138  doi:10.1186/1475-2840-11-138

Published: 7 November 2012

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.

Keywords:
Type 2 Diabetes; CVD; Mortality; 9p21; Genetics; SNP