Two common variants on 9p21 affect mortality risk in type 2 diabetes patients (ZODIAC-15)

Abstract

Background and aims: Recent genome wide association (GWA) studies identified two single nucleotide polymorphisms (SNP), rs10811661 and rs10757278 in the same region on the 9p21 chromosome to be consistently and independently associated with the risk of developing type 2 diabetes (T2DM) and cardiovascular disease, respectively. We examined the SNPs in relation to the risk of total and cardiovascular mortality in a population based cohort of T2DM patients. Materials and methods: The ZODIAC study is a prospective cohort study of T2DM patients treated in primary care in the Netherlands. Rs10811661 and rs10757278 were genotyped in 914 subjects from the ZODIAC study and 920 healthy Dutch controls. Associations of the SNPs with mortality were assessed by use of Cox proportional hazard analyses. Results: After a median follow-up of 9.5 years 358 out of 914 patients had died. The adjusted Hazard Ratio's (HR) for total mortality for patients homozygote and heterozygote for the wild type allele of rs10811661 was 1.34 (95% CI 1.06-1.69, p=0.01) compared to individuals homozygous for the risk allele. For rs10757278 total mortality was lower among patients heterozygous and homozygous for the wild-type allele than in homozygous carriers for the risk allele (HR 0.64 (95%CI 0.43-0.95), p=0.03, and HR 0.73 (95%CI 0.48-1.11), p=0.14, respectively). This effect was more pronounced in the lower tertile of HbA1c: the adjusted HR for patients heterozygous and homozygous for wild-type allele of rs10757278 was 0.48 (95%CI 0.28-0.83, p=0.01) and 0.48 (95%CI 0.27-0.85, p=0.01), respectively, compared with the patients homozygous for the risk allele. Conclusion: This prospective study shows a significant association between two common SNPs on 9p21 and mortality in type 2 diabetes patients.