Molecular Biology Reports

, Volume 40, Issue 2, pp 1035–1041 | Cite as

Quantitative assessment of the influence of PSMA6 variant (rs1048990) on coronary artery disease risk



The proteasome system is a proteolytic pathway that regulates the expression of genes involved in inflammation. Recently, an association of a functional sequence variation, -8C/G, in the human proteasome subunit a type 6 gene (PSMA6) with the susceptibility to coronary artery disease (CAD) was reported. After that, several validation studies have been conducted among various ethnic populations, but the results have been inconsistent. To investigate this inconsistency and derive a more precise estimation of the relationship, a meta-analysis of 15,991 cases and 16,784 controls from 10 case–control studies was performed. Potential sources of heterogeneity including ethnicity, sample size and HWE status of study were also assessed. In a combined analysis, the summary per-allele OR for CAD of the -8C/G polymorphism was 1.09 (95 % CI: 1.02–1.16; P = 0.006). In the subgroup analysis by ethnicity, significantly increased risks were found in East Asians for the polymorphism; while no significant associations were found among Caucasians and other ethnic population in all genetic models. When restricted to studies concerning myocardial infarction patients, significant associations were detected in all genetic models. Furthermore, significant difference of PSMA6 mRNA expression was found between genotypes. In conclusion, this meta-analysis suggests that G allele of PSMA6-8C/G polymorphism is a risk factor associated with increased CAD susceptibility, but these associations vary in different ethnic populations.


Coronary artery disease Myocardial infarction PSMA6 Polymorphism Meta-analysis 



Coronary artery disease


Myocardial infarction


Proteasome subunit α type 6


Confidence interval


Hardy–Weinberg equilibrium


Odds ratio

Supplementary material

11033_2012_2146_MOESM1_ESM.doc (44 kb)
Supplementary material 1 (DOC 43 kb)


  1. 1.
    Yamada Y, Izawa H, Ichihara S, Takatsu F, Ishihara H, Hirayama H, Sone T, Tanaka M, Yokota M (2002) Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med 347:1916–1923PubMedCrossRefGoogle Scholar
  2. 2.
    Broeckel U, Hengstenberg C, Mayer B et al (2002) A comprehensive linkage analysis for myocardial infarction and its related risk factors. Nat Genet 30:210–214PubMedCrossRefGoogle Scholar
  3. 3.
    Topol EJ, Smith J, Plow EF, Wang QK (2006) Genetic susceptibility to myocardial infarction and coronary artery disease. Hum Mol Genet 15:R117–R123PubMedCrossRefGoogle Scholar
  4. 4.
    Libby P (2002) Atherosclerosis in inflammation. Nature 420:868–874PubMedCrossRefGoogle Scholar
  5. 5.
    Herrmann J, Ciechanover A, Lerman LO, Lerman A (2004) The ubiquitin–proteasome system in cardiovascular diseases-a hypothesis extended. Cardiovasc Res 61:11–21PubMedCrossRefGoogle Scholar
  6. 6.
    Meiners S, Laule M, Rother W et al (2002) Ubiquitin–proteasome pathway as a new target for the prevention of restenosis. Circulation 105:483–489PubMedCrossRefGoogle Scholar
  7. 7.
    Elliott PJ, Zollner TM, Boehncke WH (2003) Proteasome inhibition: a new anti-inflammatory strategy. J Mol Med 8:235–245Google Scholar
  8. 8.
    Ozaki K, Sato H, Iida A et al (2006) A functional SNP in PSMA6 confers risk of myocardial infarction in the Japanese population. Nat Genet 38:921–925PubMedCrossRefGoogle Scholar
  9. 9.
    Holm K, Melum E, Franke A, Karlsen TH (2010) SNPexp—a web tool for calculating and visualizing correlation between HapMap genotypes and gene expression levels. BMC Bioinformatics 11:600PubMedCrossRefGoogle Scholar
  10. 10.
    International HapMap Consortium (2003) The International HapMap Project. Nature 426:789–796CrossRefGoogle Scholar
  11. 11.
    Stranger BE, Forrest MS, Dunning M et al (2007) Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315:848–853PubMedCrossRefGoogle Scholar
  12. 12.
    Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748PubMedGoogle Scholar
  13. 13.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188PubMedCrossRefGoogle Scholar
  14. 14.
    Woolf B (1955) On estimating the relation between blood group and disease. Ann Hum Genet 19:251–253PubMedCrossRefGoogle Scholar
  15. 15.
    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634PubMedCrossRefGoogle Scholar
  16. 16.
    Sjakste T, Poudziunas I, Ninio E et al (2007) SNPs of PSMA6 gene–investigation of possible association with myocardial infarction and type 2 diabetes mellitus. Genetika 43:553–559PubMedGoogle Scholar
  17. 17.
    Takashima N, Shioji K, Kokubo Y, Okayama A, Goto Y, Nonogi H, Iwai N (2007) Validation of the association between the gene encoding proteasome subunit alpha type 6 and myocardial infarction in a Japanese population. Circ J 71:495–498PubMedCrossRefGoogle Scholar
  18. 18.
    Bennett DA, Xu P, Clarke R, Zondervan K, Parish S, Palmer A, Cardon L, Peto R, Lathrop M, Collins R (2008) The exon 1-8C/G SNP in the PSMA6 gene contributes only a small amount to the burden of myocardial infarction in 6,946 cases and 2,720 controls from a United Kingdom population. Eur J Hum Genet 16:480–486PubMedCrossRefGoogle Scholar
  19. 19.
    Barbieri M, Marfella R, Rizzo MR, Boccardi V, Siniscalchi M, Schiattarella C, Siciliano S, Lemme P, Paolisso G (2008) The −8 UTR C/G polymorphism of PSMA6 gene is associated with susceptibility to myocardial infarction in type 2 diabetic patients. Atherosclerosis 201:117–123PubMedCrossRefGoogle Scholar
  20. 20.
    Liu X, Wang X, Shen Y, Wu L, Ruan X, Lindpaintner K, Yusuf S, Engert JC, Anand S, Tan X, Liu L (2009) The functional variant rs1048990 in PSMA6 is associated with susceptibility to myocardial infarction in a Chinese population. Atherosclerosis 206:199–203PubMedCrossRefGoogle Scholar
  21. 21.
    Banerjee I, Pandey U, Hasan OM, Parihar R, Tripathi V, Ganesh S (2009) Association between inflammatory gene polymorphisms and coronary artery disease in an Indian population. J Thromb Thrombolysis 27:88–94PubMedCrossRefGoogle Scholar
  22. 22.
    Alsmadi O, Muiya P, Khalak H, Al-Saud H, Meyer BF, Al-Mohanna F, Alshahid M, Dzimiri N (2009) Haplotypes encompassing the KIAA0391 and PSMA6 gene cluster confer a genetic link for myocardial infarction and coronary artery disease. Ann Hum Genet 73:475–483PubMedCrossRefGoogle Scholar
  23. 23.
    Hinohara K, Nakajima T, Sasaoka T, Sawabe M, Lee BS, Ban J, Park JE, Izumi T, Kimura A (2009) Replication studies for the association of PSMA6 polymorphism with coronary artery disease in East Asian populations. J Hum Genet 54:248–251PubMedCrossRefGoogle Scholar
  24. 24.
    Ikeda S, Tanaka N, Arai T, Chida K, Muramatsu M, Sawabe M (2012) Polymorphisms of LTA, LGALS2, and PSMA6 genes and coronary atherosclerosis: a pathological study of 1503 consecutive autopsy cases. Atherosclerosis 221:458–460PubMedCrossRefGoogle Scholar
  25. 25.
    Kozak M (1997) Recognition of AUG and Alternative Initiator Codos Is Augmented by G in Position +4 but is not Generally Affected by the Nucleotides in Position +5 and +6. EMBO J 16:2482–2492PubMedCrossRefGoogle Scholar
  26. 26.
    Kozak M (2002) Pushing the limits of the scanning mechanism for initiation of translation. Gene 299:1–34PubMedCrossRefGoogle Scholar
  27. 27.
    Goldberg AL (2003) Protein degradation and protection against misfolded or damaged proteins. Nature 426:895–899PubMedCrossRefGoogle Scholar
  28. 28.
    Coux O, Tanaka K, Goldberg AL (1996) Structure and functions of the 20S and 26S proteasomes. Annu Rev Biochem 65:801–847PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  1. 1.Department of CardiologyShanghai Pudong New Area Gongli HospitalShanghaiPeople’s Republic of China
  2. 2.Departments of NeurologyShanghai Pudong New Area Gongli HospitalShanghaiPeople’s Republic of China
  3. 3.Department of CardiologyShanghai Xuhui Central HospitalShanghaiPeople’s Republic of China

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