Inflammation is now considered critical in the pathogenesis of myocardial infarction. One of the mechanisms regulating the inflammatory process is the ubiquitin-proteasome system. We investigated whether variants of the 20S proteasome are associated with susceptibility to myocardial infarction and found a common SNP (minor allele frequency of 0.35) in the proteasome subunit α type 6 gene (PSMA6) conferring risk of myocardial infarction in the Japanese population (χ2 = 21.1, P = 0.0000044, 2,592 affected individuals versus 2,851 controls). We replicated this association in another panel of myocardial infarction and control subjects, although its relevance to other ethnic groups remains to be clarified. The SNP, located in the 5′ untranslated region of exon 1 in this gene, enhanced the transcription of PSMA6. Moreover, suppression of PSMA6 expression using short interfering RNA in cultured cells reduced activation of the transcription factor NF-κB by stabilizing phosphorylated IκB. Our results implicate this PSMA6 SNP as a previously unknown genetic risk factor for myocardial infarction.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hansson, G.K. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 352, 1685–1695 (2005).
Yamada, Y. et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N. Engl. J. Med. 347, 1916–1923 (2002).
Ozaki, K. et al. Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction. Nat. Genet. 32, 650–654 (2002).
Wang, L., Fan, C., Topol, S.E., Topol, E.J. & Wang, Q. Mutation of MEF2A in an inherited disorder with features of coronary artery disease. Science 302, 1578–1581 (2003).
Helgadottir, A. et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat. Genet. 36, 233–239 (2004).
Ozaki, K. et al. Functional variation in LGALS2 confers risk of myocardial infarction and regulates lymphotoxin-α secretion in vitro. Nature 429, 72–75 (2004).
Cipollone, F. et al. A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke. J. Am. Med. Assoc. 291, 2221–2228 (2004).
Pajukanta, P. et al. 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 (2000).
Broeckel, U. et al. A comprehensive linkage analysis for myocardial infarction and its related risk factors. Nat. Genet. 30, 210–214 (2002).
Harrap, S.B. et al. Genome-wide linkage analysis of the acute coronary syndrome suggests a locus on chromosome 2. Arterioscler. Thromb. Vasc. Biol. 22, 874–878 (2002).
Wang, Q. et al. Premature myocardial infarction novel susceptibility locus on chromosome 1P34–36 identified by genomewide linkage analysis. Am. J. Hum. Genet. 74, 262–271 (2004).
Hauser, E.R. et al. A genomewide scan for early-onset coronary artery disease in 438 families: the GENECARD Study. Am. J. Hum. Genet. 75, 436–447 (2004).
Samani, N.J. et al. 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, 1011–1020 (2005).
Karin, M. & Delhase, M. The IκB kinase (IKK) and NF-κB: key elements of proinflammatory signalling. Semin. Immunol. 12, 85–98 (2000).
Maki, C.G., Huibregtse, J.M. & Howley, P.M. In vivo ubiquitination and proteasome-mediated degradation of p53(1). Cancer Res. 56, 2649–2654 (1996).
Salghetti, S.E., Kim, S.Y., & Tansey, W P. Destruction of Myc by ubiquitin-mediated proteolysis: cancer-associated and transforming mutations stabilize Myc. EMBO J. 18, 717–726 (1999).
Dimmeler, S., Breitschopf, K., Haendeler, J. & Zeiher, A.M. Dephosphorylation targets Bcl-2 for ubiquitin-dependent degradation: a link between the apoptosome and the proteasome pathway. J. Exp. Med. 189, 1815–1822 (1999).
Ross, R. Atherosclerosis—an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999).
Beinke, S. & Ley, S.C. Functions of NF-κB1 and NF-κB2 in immune cell biology. Biochem. J. 382, 393–409 (2004).
Coux, O., Tanaka, K. & Goldberg, A.L. Structure and functions of the 20S and 26S proteasomes. Annu. Rev. Biochem. 65, 801–847 (1996).
International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).
Haga, H., Yamada, R., Ohnishi, Y., Nakamura, Y. & Tanaka, T Gene-based SNP discover as part of the Japanese Millennium Genome project: identification of 190,562 genetic variations in the human genome. J. Hum. Genet. 47, 605–610 (2002).
Freedman, M.L. et al. Assessing the impact of population stratification on genetic association studies. Nat. Genet. 36, 388–393 (2004).
Lo, H.S. et al. Allelic variation in gene expression is common in the human genome. Genome Res. 13, 1855–1862 (2003).
Herrmann, J., Ciechanover, A., Lerman, L.O. & Lerman, A. The ubiquitin-proteasome system in cardiovascular diseases—a hypothesis extended. Cardiovasc. Res. 61, 11–21 (2004).
Meiners, S. et al. Ubiquitin-proteasome pathway as a new target for the prevention of restenosis. Circulation 105, 483–489 (2002).
Pye, J. et al. Proteasome inhibition ablates activation of NF-κB in myocardial reperfusion and reduces reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 284, H919–H926 (2003).
Elliott, P.J., Zollner, T.M. & Boehncke, W.H. Proteasome inhibition: a new anti-inflammatory strategy. J. Mol. Med. 81, 235–245 (2003).
Pritchard, J.K. & Rosenberg, N.A. Use of unlinked genetic markers to detect population stratification in association studies. Am. J. Hum. Genet. 65, 220–228 (1999).
den Dunnen, J.T. & Antonarakis, S.E. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum. Mutat. 15, 7–12 (2000).
We thank M. Takahashi, M. Yoshii, S. Abiko, W. Yamanobe, M. Omotezako, Y. Ariji, R. Ohishi, M. Watabe, K. Tabei and S. Manabe for their assistance and A. Suzuki and K. Kobayashi for advice on allele-specific gene expression experiments. We also thank all the other members of SNP Research Center, RIKEN and OACIS for their contribution to the completion of our study. We are also grateful to members of The Rotary Club of Osaka-Midosuji District 2660 Rotary International in Japan for supporting our study. This work was supported in part by grants from the Takeda Science Foundation, the Uehara Science Foundation and the Japanese Millennium Project.
Association analyses between myocardial infarction and SNPs in genes encoding 20S proteasome α and β subunits. (PDF 140 kb)
Pairwise LD coefficients (upper; r2; lower; D1) among SNPs in PSMA6 region. (PDF 25 kb)
Association analyses of haplotypes in PSMA6 region with MI. (PDF 24 kb)
No association of HT, smoking and past history of MI with the PSMA6 SNP. (PDF 33 kb)
Clinical parameters of MI patients and the PSMA6 SNP genotype. (PDF 17 kb)
Replication of association with the second panel. (PDF 36 kb)
Primer sequences used in the study. (PDF 9 kb)
About this article
Association between functional variant of inflammatory system gene (PSMA6) and end-stage kidney disease
International Urology and Nephrology (2016)