Genes & Genomics

, 33:483 | Cite as

Cigarette smoking status has a modifying effect on the association between polymorphisms in KALRN and measures of cardiovascular risk in the diabetes heart study

  • Megan E. Rudock
  • Amanda. J. Cox
  • Julie T. Ziegler
  • Allison B. Lehtinen
  • Jessica J. Connelly
  • Barry I. Freedman
  • J. Jeffrey Carr
  • Carl D. Langefeld
  • Elizabeth R. Hauser
  • Benjamin D. Horne
  • Donald W. Bowden
Research Article

Abstract

All manifestations of cardiovascular disease (CVD) are substantially more common in patients with type 2 diabetes mellitus (T2DM) than in non-diabetic individuals. The current study evaluated KALRN, a gene previously linked to CVD, as a contributor to CVD in a sample enriched for T2DM. Specifically, the potential modifying effect of cigarette smoking was examined. A total of 28 SNPs in KALRN were genotyped in 1001 European Americans from 369 Diabetes Heart Study (DHS) families, as well as 762 population-based controls. The association between each SNP and both qualitative and quantitative CVD disease phenotypes was determined using generalized estimating equations and variance component models, respectively. Selected KALRN SNPs were found to be associated with both the qualitative (T2DM, CVD, metabolic syndrome) and quantitative traits (C-reactive protein and abdominal aortic calcified plaque). Interaction analysis and stratification were then used to test whether smoking modulates the genetic effects of KALRN. The strongest evidence of a modifying effect of smoking status was observed for rs9289231 and intima-media thickness (p=9.0x10−4) and abdominal aortic calcified plaque (p=3.0×10−4). Overall, following stratification by smoking status, the evidence of association with quantitative traits was more pronounced in smokers compared to non-smokers. The strongest association for smokers was between rs1720960 and abdominal aortic calcified plaque (p=2.6x10−5), while in non-smokers there was no observed association. KALRN variants are associated with measures of CVD and T2DM in the DHS sample with smoking status observed to have a significant modifying effect on these associations.

Keywords

Kalirin Polymorphisms Vascular Calcification Type 2 diabetes 

Supplementary material

13258_2011_69_MOESM1_ESM.pdf (15 kb)
Supplementary material, approximately 14.5 KB.

References

  1. Alam MR, Johnson RC, Darlington DN, Hand TA, Mains RE and Eipper BA (1997) Kalirin, a cytosolic protein with spectrin-like and GDP/GTP exchange factor-like domains that interacts with peptidylglycine alpha-amidating monooxygenase, an integral membrane peptide-processing enzyme. J. Biol. Chem. 272: 12667–12675.PubMedCrossRefGoogle Scholar
  2. Almasy L and Blangero J (1998) Multipoint quantitative-trait linkage analysis in general pedigrees. Am. J. Hum. Genet. 62: 1198–1211.PubMedCrossRefGoogle Scholar
  3. American Heart Association (2010) Heart disease & stroke statistics — 2010 update at-a-glance. American Heart Association.Google Scholar
  4. Asahara S, Kido Y, Shigeyama Y, Matsuda T, Takeda A, Inoue T, Shibutani Y, Koyanagi M, Uchida T and Kasuga M (2008) Rac1 regulates glucose-induced insulin secretion through modulation of cytoskeletal organization in beta cells. In: 68th Scientific Session of the American Diabetes Association. San Francisco, California.Google Scholar
  5. Barrett JC, Fry B, Maller J and Daly MJ (2005) Haploview: Analysis and visualization of LD and haplotype maps. Bioinformatics. 21: 263–265.PubMedCrossRefGoogle Scholar
  6. Bensen JT, Langefeld CD, Hawkins GA, Green LE, Mychaleckyj JC, Brewer CS, Kiger DS, Binford SM, Colicigno CJ, Allred DC, et al. (2003) Nucleotide variation, haplotype structure, and association with end-stage renal disease of the human interleukin-1 gene cluster. Genomics. 82: 194–217.PubMedCrossRefGoogle Scholar
  7. Bento JL, Palmer ND, Zhong M, Roh B, Lewis JP, Wing MR, Pandya H, Freedman BI, Langefeld CD, Rich SD, et al. (2008) Heterogeneity in gene loci associated with type 2 diabetes on human chromosome 20q13.1. Genomics. 92: 226–234.PubMedCrossRefGoogle Scholar
  8. Bowden DW, Cox AJ, Freedman BI, Hugenschimdt CE, Wagenknecht LE, Herrington D, Agarwal S, Register TD, Maldjian JA, Ng MC, et al. (2010) Review of the diabetes heart study (DHS) family of studies: A comprehensively examined sample for genetic and epidemiological studies of type 2 diabetes and its complications. Rev. Diabet. Stud. 7: 188–201.PubMedGoogle Scholar
  9. Bowden DW, Rudock M, Ziegler J, Lehtinen AB, Xu J, Wagenknecht LE, Herrington D, Rich SS, Freedman BI, Carr JJ, et al. (2006) Coincident linkage of type 2 diabetes, metabolic syndrome, and measures of cardiovascular disease in a genome scan of the diabetes heart study. Diabetes. 55: 1985–1994.PubMedCrossRefGoogle Scholar
  10. Broeckel U, Hengstenberg C, Mayer B, Holmer S, Martin LJ, Comuzzie AG, Blangero J, Nurnberg P, Reis A, Riegger GA, et al. (2002) A comprehensive linkage analysis for myocardial infarction and its related risk factors. Nat. Genet. 30: 210–214.PubMedCrossRefGoogle Scholar
  11. Carr JJ, Nelson JC, Wong ND, McNitt-Gray M, Arad Y, Jacobs DR, Jr., Sidney S, Bild DE, Williams OD and Detrano RC (2005) Calcified coronary artery plaque measurement with cardiac CT in population-based studies: Standardized protocol of multi-ethnic study of atherosclerosis (MESA) and coronary artery risk development in young adults (CARDIA) study. Radiology. 234: 35–43.PubMedCrossRefGoogle Scholar
  12. Carr JJ, Register TC, Hsu FC, Lohman K, Lenchik L, Bowden DW, Langefeld CD, Xu J, Rich SS, Wagenknecht LE, et al. (2008) Calcified atherosclerotic plaque and bone mineral density in type 2 diabetes: The diabetes heart study. Bone. 42: 43–52.PubMedCrossRefGoogle Scholar
  13. Centers for Disease Control and Prevention (2009) Diabetes data & trends. Department of Health and Human Services.Google Scholar
  14. Chakrabarti K, Lin R, Schiller NI, Wang Y, Koubi D, Fan YX, Rudkin Bb, Johnson GR and Schiller MR (2005) Critical role for kalirin in nerve growth factor signaling through TRKA. Mol. Cell. Biol. 25: 5106–5118.PubMedCrossRefGoogle Scholar
  15. De Bakker PI, Yelensky R, Pe’er I, Gabriel SB, Daly MJ and Altshuler D (2005) Efficiency and power in genetic association studies. Nat. Genet. 37: 1217–1223.PubMedCrossRefGoogle Scholar
  16. Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (2001) Executive summary of the third report of the National Cholesterol Education Program (NCEP) ex pert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 285: 2486–2497.CrossRefGoogle Scholar
  17. Farrall M, Green Fr, Peden JF, Olsson PG, Clarke R, Hellenius ML, Rust S, Lagercrantz J, Franzosi MG, Schulte H, et al. (2006) Genome-wide mapping of susceptibility to coronary artery disease identifies a novel replicated locus on chromosome 17. PLoS. Genet. 2: e72.PubMedCrossRefGoogle Scholar
  18. Francke S, Manraj M, Lacquemant C, Lecoeur C, Lepretre F, Passa P, Hebe A, Corset L, Yan SL, Lahmidi S, et al. (2001) A genome-wide scan for coronary heart disease suggests in Indo-Mauritians a susceptibility locus on chromosome 16p13 and replicates linkage with the metabolic syndrome on 3q27. Hum. Mol. Genet. 10: 2751–2765.PubMedCrossRefGoogle Scholar
  19. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, Defelice M, Lochner A, Faggart M, et al. (2002) The structure of haplotype blocks in the human genome. Science. 296: 2225–2229.PubMedCrossRefGoogle Scholar
  20. Harrap SB, Zammit KS, Wong ZY, Williams FM, Bahlo M, Tonkin AM and Anderson ST (2002) Genome-wide linkage analysis of the acute coronary syndrome suggests a locus on chromosome 2. Arterioscler. Thromb. Vasc. Biol. 22: 874–878.PubMedCrossRefGoogle Scholar
  21. Hauser ER, Crossman DC, Granger CB, Haines JL, Jones CJ, Mooser V, Mcadam B, Winkelmann BR, Wiseman AH, Muhlestein JB, et al. (2004) A genomewide scan for early-onset coronary artery disease in 438 families: The GENCARD study. Am. J. Hum. Genet. 75: 436–447.PubMedCrossRefGoogle Scholar
  22. Helgadottir A, Manolescu A, Thorleifsson G, Gretarsdottir S, Jonsdottir H, Thorsteinsdottir U, Samani NJ, Gudmundsson G, Grant SF, Thorgeirsson G, et al. (2004) The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat. Genet. 36: 233–239.PubMedCrossRefGoogle Scholar
  23. Hordijk PL (2006) Regulation of NADPH oxidases: The role of Rac proteins. Circ. Res. 98: 453–462.PubMedCrossRefGoogle Scholar
  24. Horne BD, Hauser ER, Wang L, Muhlestein JB, Anderson JL, Carlquist JF, Shah SH and Kraus WE (2009) Validation study of genetic associations with coronary artery disease on chromosome 3q13–21 and potential effect modification by smoking. Ann. Hum. Genet. 73: 551–558.PubMedCrossRefGoogle Scholar
  25. Hyder JA, Allison MA, Wong N, Papa A, Lang TF, Sirlin C, Gapstur SM, Ouyang P, Carr JJ and Criqui MH (2009) Association of coronary artery and aortic calcium with lumbar bone density: The MESA abdominal aortic calcium study. Am. J. Epidemiol. 169: 186–194.PubMedCrossRefGoogle Scholar
  26. Koh CG (2006) Rho GTPases and their regulators in neuronal functions and development. Neurosignals. 15: 228–237.PubMedCrossRefGoogle Scholar
  27. Kone BC, Kuncewicz T, Zhang W and Yu ZY (2003) Protein interactions with nitric oxide synthases: Controlling the right time, the right place, and the right amount of nitric oxide. Am. J. Physiol. Renal. Physiol. 285: F178–190.PubMedGoogle Scholar
  28. Lange La, Bowden DW, Langefeld CD, Wagenknecht LE, Carr JJ, Rich SS, Riley WA and Freedman BI (2002) Heritability of carotid artery intima-medial thickness in type 2 diabetes. Stroke. 33: 1876–1881.PubMedCrossRefGoogle Scholar
  29. Larson MG, Atwood LD, Benjamin EJ, Cupples LA, D’agostino RB, Sr., Fox CS, Govindaraju Dr, Guo CY, Heard-Costa NL, Hwang SJ, et al. (2007) Framingham heart study 100k project: Genome-wide associations for cardiovascular disease outcomes. BMC. Med. Genet. 8Suppl 1: S5.PubMedCrossRefGoogle Scholar
  30. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, Ford E, Furie K, Gillespie C et al. (2010) Heart disease and stroke statistics — 2010 update: A report from the American Heart Association. Circulation. 121: e46–e215.PubMedCrossRefGoogle Scholar
  31. Ma XM, Kiraly DD, Gaier ED, Wang Y, Kim EJ, Levine ES, Eipper BA and Mains RE (2008) Kalirin-7 is required for synaptic structure and function. J. Neurosci. 28: 12368–12382.PubMedCrossRefGoogle Scholar
  32. Noma K, Oyama N and Liao JK (2006) Physiological role of Rocks in the cardiovascular system. Am. J. Physiol. Cell. Physiol. 290: C661–668.PubMedCrossRefGoogle Scholar
  33. O’Connell JR and Weeks DE (1998) Pedcheck: A program for identification of genotype incompatibilities in linkage analysis. Am. J. Hum. Genet. 63: 259–266.PubMedCrossRefGoogle Scholar
  34. O’Donnell CJ, Cupples LA, D’agostino RB, Fox CS, Hoffmann U, Hwang SJ, Ingellson E, Liu C, Murabito JM, Polak JF, et al. (2007) Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI’s Framingham heart study. BMC. Med. Genet. 8Suppl 1: S4.PubMedCrossRefGoogle Scholar
  35. Pajukanta P, Cargill M, Viitanen L, Nuotio I, Kareinen A, Perola M, Terwilliger JD, Kempas E, Daly M, Lilja H, et al. (2000) Two loci on chromosomes 2 and X for premature coronary heart disease identified in early- and late-settlement populations of Finland. Am. J. Hum. Genet. 67: 1481–1493.PubMedCrossRefGoogle Scholar
  36. Samani NJ, Burton P, Mangino M, Ball SG, Balmforth AJ, Barrett J, Bishop T and Hall A (2005) A genomewide linkage study of 1,933 families affected by premature coronary artery disease: The British Heart Foundation (BHF) family heart study. Am. J. Hum. Genet. 77: 1011–1120.PubMedCrossRefGoogle Scholar
  37. Shiffman D, Rowland CM, Louie JZ, Luke MM, Bare LA, Bolonick JI, Young BA, Catanese JJ, Stiggins CF, Pullinger CR, et al. (2006) Gene variants of VAMP8 and HNRPUL1 are associated with early-onset myocardial infarction. Arterioscler. Thromb. Vasc. Biol. 26: 1613–1618.PubMedCrossRefGoogle Scholar
  38. The International Hapmap Consortium (2005) A haplotype map of the human genome. Nature. 437: 1299–1320.CrossRefGoogle Scholar
  39. Tzima E (2006) Role of small GTPases in endothelial cytoskeletal dynamics and the shear stress response. Circ. Res. 98: 176–185.PubMedCrossRefGoogle Scholar
  40. Wagenknecht LE, Langefeld CD, Freedman BI, Carr JJ and Bowden DW (2007) A comparison of risk factors for calcified atherosclerotic plaque in the coronary, carotid, and abdominal aortic arteries: The diabetes heart study. Am. J. Epidemiol. 166: 340–347.PubMedCrossRefGoogle Scholar
  41. Wang L, Hauser ER, Shah SH, Pericak-Vance MA, Haynes C, Crosslin D, Harris M, Nelson S, Hale AB, Granger CB, et al. (2007) Peakwide mapping on chromosome 3q13 identifies the kalirin gene as a novel candidate gene for coronary artery disease. Am. J. Hum. Genet. 80: 650–663.PubMedCrossRefGoogle Scholar
  42. Wang Q, Rao S, Shen GQ, Li L, Moliterno DJ, Newby LK, Rogers WJ, Cannata R, Zirzow E, Elston R, et al. (2004) Premature myocardial infarction novel susceptibility locus on chromosome 1p34–36 identified by genomewide linkage analysis. Am. J. Hum. Genet. 74: 262–271.PubMedCrossRefGoogle Scholar
  43. Wang X, Ria M, Kelmenson PM, Eriksson P, Higgins DC, Samnegard A, Petros C, Rollins J, Bennet AM, Wiman B, et al. (2005) Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. Nat. Genet. 37: 365–372.PubMedCrossRefGoogle Scholar
  44. Zeger SL and Liang KY (1986) Longitudinal data analysis for discrete and continuous outcomes. Biometrics. 42: 121–130.PubMedCrossRefGoogle Scholar

Copyright information

© The Genetics Society of Korea and Springer Netherlands 2011

Authors and Affiliations

  • Megan E. Rudock
    • 1
    • 2
    • 3
  • Amanda. J. Cox
    • 1
    • 2
    • 3
  • Julie T. Ziegler
    • 4
  • Allison B. Lehtinen
    • 1
    • 2
    • 3
  • Jessica J. Connelly
    • 5
  • Barry I. Freedman
    • 6
  • J. Jeffrey Carr
    • 7
  • Carl D. Langefeld
    • 4
  • Elizabeth R. Hauser
    • 5
  • Benjamin D. Horne
    • 8
  • Donald W. Bowden
    • 1
    • 2
    • 3
  1. 1.Center for Human GenomicsWake Forest School of MedicineWinston-SalemUSA
  2. 2.Center for Diabetes ResearchWake Forest School of MedicineWinston-SalemUSA
  3. 3.Department of BiochemistryWake Forest School of MedicineWinston-SalemUSA
  4. 4.Department of Biostatistical SciencesWake Forest School of MedicineWinston-SalemUSA
  5. 5.Center for Human Genetics, School of MedicineDuke University Medical CenterDurhamUSA
  6. 6.Department of Internal MedicineWake Forest School of MedicineWinston-SalemUSA
  7. 7.Department of Radiologic SciencesWake Forest School of MedicineWinston-SalemUSA
  8. 8.Cardiovascular Department, Intermountain Medical CenterUniversity of UtahSalt Lake CityUSA

Personalised recommendations