The online version of this article (doi:10.1186/1475-2840-11-138) contains supplementary material, which is available to authorized users.
Gijs WD Landman, Jana V van Vliet-Ostaptchouk contributed equally to this work.
The authors state that they have no conflicts of interest.
GWDL: researched data, contributed to discussion, drafted manuscript. JVvVO: carried out the molecular genetic studies, participated in the sequence alignment, contributed to discussion and the drafting of the manuscript. NK, KJJvH, ID, ROBG, CW, HS, MHH and HJGB: contributed to discussion, reviewed manuscript. KHG: researched data/ statistician, reviewed manuscript. All authors read and approved the final manuscript. Both GWDL and JVvVO contributed equally to this paper.
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.
Mit LU, Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Diabetes Genetics Initiative of Broad Institute of H Novartis Institutes of BioMedical R: Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007, 316 (5829): 1331-1336. CrossRef
Helgadottir A, Thorleifsson G, Magnusson KP, Gretarsdottir S, Steinthorsdottir V, Manolescu A, Jones GT, Rinkel GJ, Blankensteijn JD, Ronkainen A: The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet. 2008, 40 (2): 217-224. CrossRefPubMed
Virani SS, Brautbar A, Lee VV, MacArthur E, Morrison AC, Grove ML, Nambi V, Frazier L, Wilson JM, Willerson JT: Chromosome 9p21 single nucleotide polymorphisms are not associated with recurrent myocardial infarction in patients with established coronary artery disease. Circ J. 2012, 76 (4): 950-956. PubMedCentralCrossRefPubMed
Wang W, Peng W, Zhang X, Lu L, Zhang R, Zhang Q, Wang L, Chen Q, Shen W: Chromosome 9p21.3 polymorphism in a Chinese Han population is associated with angiographic coronary plaque progression in non-diabetic but not in type 2 diabetic patients. Cardiovasc Diabetol. 2010, 9: 33. PubMedCentralCrossRefPubMed
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997, 20 (7): 1183-1197. CrossRef
Brito EC, Lyssenko V, Renstrom F, Berglund G, Nilsson PM, Groop L, Franks PW: Previously associated type 2 diabetes variants may interact with physical activity to modify the risk of impaired glucose regulation and type 2 diabetes: a study of 16,003 Swedish adults. Diabetes. 2009, 58 (6): 1411-1418. PubMedCentralCrossRefPubMed
Musunuru K, Post WS, Herzog W, Shen H, O’Connell JR, McArdle PF, Ryan KA, Gibson Q, Cheng YC, Clearfield E: Association of single nucleotide polymorphisms on chromosome 9p21.3 with platelet reactivity: a potential mechanism for increased vascular disease. Circ Cardiovasc Genet. 2010, 3 (5): 445-453. PubMedCentralCrossRefPubMed
Beekman M, Nederstigt C, Suchiman HE, Kremer D, van der Breggen R, Lakenberg N, Alemayehu WG, de Craen AJ, Westendorp RG, Boomsma DI: Genome-wide association study (GWAS)-identified disease risk alleles do not compromise human longevity. Proc Natl Acad Sci U S A. 2010, 107 (42): 18046-18049. PubMedCentralCrossRefPubMed
Shea J, Agarwala V, Philippakis AA, Maguire J, Banks E, Depristo M, Thomson B, Guiducci C, Onofrio RC, Kathiresan S: Comparing strategies to fine-map the association of common SNPs at chromosome 9p21 with type 2 diabetes and myocardial infarction. Nat Genet. 2011, 43 (8): 801-805. PubMedCentralCrossRefPubMed
- Association between 9p21 genetic variants and mortality risk in a prospective cohort of patients with type 2 diabetes (ZODIAC-15)
Gijs WD Landman
Jana V van Vliet-Ostaptchouk
Kornelis JJ van Hateren
Klaas H Groenier
Rijk OB Gans
Marten H Hofker
Henk JG Bilo
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Mail Icon II