Biopolym. Cell. 2014; 30(5):377-387.
Molecular Biomedicine
Genetic variants in the PSMA6, PSMC6 and PSMA3 genes associated with childhood asthma in Latvian and Taiwanese populations
1Paramonova N., 2Wu L. Shi-Shin, 3, 4Rumba-Rozenfelde I., 5Wang J. -Y., 1, 6Sjakste N., 1Sjakste T.
  1. Genomics and Bioinformatics, Institute of Biology
    University of Latvia
    3, Miera Str., Salaspils, Latvia, LV-2169
  2. Institute of Biomedicine, Tzu-Chi University
    701, Zhongyang Rd., Sec 3., Hualien 97004, Taiwan
  3. Faculty of Medicine,
    University of Latvia
    1a, Sharlotes Str., Riga, Latvia, LV-1001
  4. University Children Hospital
    20, Juglas Str., Riga, Latvia, LV-1079
  5. Division of Allergy and Clinical Immunology, College of Medicine,
    National Cheng Kung University
    1, University Road, Tainan City 701, Tainan, Taiwan
  6. Latvian Institute of Organic Synthesis
    21, Aizkraukles Str., Riga, Latvia, LV-1006


Proteasomes mediate functional realization of signaling proteins implicated in asthma pathogenesis. Aim. To evaluate main and sex-specific association between the PSMA6, PSMC6 and PSMA3 proteasomal genes variations and childhood asthma in Latvians and Taiwanese. Methods. SNPs rs2277460, rs1048990, rs2295826, rs2295827 and rs2348071 were genotyped in 102 Latvian and 159 Taiwanese cases for comparison with genetic diversity in populations (191 and 1097 subjects respectively). Results. Haplotype CGACG showed strong (P < 0.0001) association with asthma risk in both populations. All loci heterozygous genotypes and haplotype CCGTA were identified as asthma risk factors in Latvians; rs1048990 and rs2348071 GG homozygotes and rs2295826 and rs2295827 heterozygotes showed asthma risk and protective effect in Taiwanese females respectively. The multi locus genotypes homozygous for alleles being common in Latvian population were identified as protective in Latvians and disease susceptible in Taiwanese. Conclusions. Our results suggest an association of the 14q13-23 proteasomal genes polymorphisms with the childhood asthma in Latvians and Taiwanese and high-light risk and/or protective factors being the same or different between the populations.
Keywords: chromosome 14q13-23, SNPs, PSMA6, PSMC6, PSMA3, childhood asthma

Supplementary data


[1] Broide DH. Molecular and cellular mechanisms of allergic disease. J Allergy Clin Immunol. 2001;108(2 Suppl):S65-71.
[2] Galli SJ, Tsai M, Piliponsky AM. The development of allergic inflammation. Nature. 2008;454(7203):445-54.
[3] Wu LS, Sjakste T, Sakalauskas R, Sitkauskiene B, Paramonova N, Gasiuniene E, Jan RL, Wang JY. The burden of allergic asthma in children: a landscape comparison based on data from Lithuanian, Latvian, and Taiwanese populations. Pediatr Neonatol. 2012;53(5):276-82.
[4] Leung TF, Ko FW, Sy HY, Tsui SK, Wong GW. Differences in asthma genetics between Chinese and other populations. J Allergy Clin Immunol. 2014;133(1):42-8.
[5] Birrell MA, Hardaker E, Wong S, McCluskie K, Catley M, De Alba J, Newton R, Haj-Yahia S, Pun KT, Watts CJ, Shaw RJ, Savage TJ, Belvisi MG. Ikappa-B kinase-2 inhibitor blocks inflammation in human airway smooth muscle and a rat model of asthma. Am J Respir Crit Care Med. 2005;172(8):962-71.
[6] Edwards MR, Bartlett NW, Clarke D, Birrell M, Belvisi M, Johnston SL. Targeting the NF-kappaB pathway in asthma and chronic obstructive pulmonary disease. Pharmacol Ther. 2009;121(1):1-13.
[7] Gagliardo R, Chanez P, Mathieu M, Bruno A, Costanzo G, Gougat C, Vachier I, Bousquet J, Bonsignore G, Vignola AM. Persistent activation of nuclear factor-kappaB signaling pathway in severe uncontrolled asthma. Am J Respir Crit Care Med. 2003;168(10):1190-8.
[8] Konstantinova IM, Tsimokha AS, Mittenberg AG. Role of proteasomes in cellular regulation. Int Rev Cell Mol Biol. 2008;267:59-124.
[9] Wang X, Guerrero C, Kaiser P, Huang L. Proteomics of proteasome complexes and ubiquitinated proteins. Expert Rev Proteomics. 2007;4(5):649-65.
[10] Yano M, Kanesaki Y, Koumoto Y, Inoue M, Kido H. Chaperone activities of the 26S and 20S proteasome. Curr Protein Pept Sci. 2005;6(2):197-203.
[11] Albright JM, Romero J, Saini V, Sixt SU, Bird MD, Kovacs EJ, Gamelli RL, Peters J, Majetschak M. Proteasomes in human bronchoalveolar lavage fluid after burn and inhalation injury. J Burn Care Res. 2009;30(6):948-56.
[12] Majetschak M, Sorell LT, Patricelli T, Seitz DH, Knoferl MW. Detection and possible role of proteasomes in the bronchoalveolar space of the injured lung. Physiol Res. 2009;58(3):363-72.
[13] Sixt SU, Peters J. Extracellular alveolar proteasome: possible role in lung injury and repair. Proc Am Thorac Soc. 2010;7(1):91-6.
[14] Zemeckien? Z, Vitkauskien? A, Sjakste T, Sitkauskien? B, Sakalauskas R. Proteasomes and proteasomal gene polymorphism in association with inflammation and various diseases. Medicina (Kaunas). 2013;49(5):207-13.
[15] Hakonarson H, Bjornsdottir US, Halapi E, Palsson S, Adalsteinsdottir E, Gislason D, Finnbogason G, Gislason T, Kristjansson K, Arnason T, Birkisson I, Frigge ML, Kong A, Gulcher JR, Stefansson K. A major susceptibility gene for asthma maps to chromosome 14q24. Am J Hum Genet. 2002;71(3):483-91.
[16] Malerba G, Patuzzo C, Trabetti E, Lauciello MC, Galavotti R, Pescollderungg L, Whalen MB, Zanoni G, Martinati LC, Boner AL, Pignatti PF. Chromosome 14 linkage analysis and mutation study of 2 serpin genes in allergic asthmatic families. J Allergy Clin Immunol. 2001;107(4):654-8.
[17] Mansur AH, Bishop DT, Holgate ST, Markham AF, Morrison JF. Linkage/association study of a locus modulating total serum IgE on chromosome 14q13-24 in families with asthma. Thorax. 2004;59(10):876-82.
[18] Munthe-Kaas MC, Gerritsen J, Carlsen KH, Undlien D, Egeland T, Skinningsrud B, T?rres T, Carlsen KL. Eosinophil cationic protein (ECP) polymorphisms and association with asthma, s-ECP levels and related phenotypes. Allergy. 2007;62(4):429-36.
[19] Tulah AS, Begh? B, Barton SJ, Holloway JW, Sayers I. Leukotriene B4 receptor locus gene characterisation and association studies in asthma. BMC Med Genet. 2012;13:110.
[20] Ungv?ri I, Hull?m G, Antal P, Kiszel PS, G?zsi A, Hadadi ?, Vir?g V, Haj?s G, Millinghoffer A, Nagy A, Kiss A, Semsei ?F, Temesi G, Melegh B, Kisfali P, Sz?ll M, Bikov A, G?lffy G, Tam?si L, Falus A, Szalai C. Evaluation of a partial genome screening of two asthma susceptibility regions using bayesian network based bayesian multilevel analysis of relevance. PLoS One. 2012;7(3):e33573.
[21] Zhang Y, Moffatt MF, Cookson WO. Genetic and genomic approaches to asthma: new insights for the origins. Curr Opin Pulm Med. 2012;18(1):6-13.
[22] Sjakste T, Eglite J, Sochnevs A, Marga M, Pirags V, Collan Y, Sjakste N. Microsatellite genotyping of chromosome 14q13.2-14q13 in the vicinity of proteasomal gene PSMA6 and association with Graves' disease in the Latvian population. Immunogenetics. 2004;56(4):238-43.
[23] Sjakste T, Trapina I, Rumba-Rozenfelde I, Lunin R, Sugoka O, Sjakste N. Identification of a novel candidate locus for juvenile idiopathic arthritis at 14q13.2 in the Latvian population by association analysis with microsatellite markers. DNA Cell Biol. 2010;29(9):543-51.
[24] Sjakste T, Paramonova N, Rumba-Rozenfelde I, Trapina I, Sugoka O, Sjakste N. Juvenile Idiopathic Arthritis Subtype- and Sex-specific Associations with Genetic Variants in the PSMA6/PSMC6/PSMA3 Gene Cluster. Pediatr Neonatol. 2014;55(5):393-403.
[25] Sjakste T, Kalis M, Poudziunas I, Pirags V, Lazdins M, Groop L, Sjakste N. Association of microsatellite polymorphisms of the human 14q13.2 region with type 2 diabetes mellitus in Latvian and Finnish populations. Ann Hum Genet. 2007;71(Pt 6):772-6.
[26] Sjakste T, Poudziunas I, Ninio E, Perret C, Pirags V, Nicaud V, Lazdins M, Evanss A, Morrison C, Cambien F, Sjakste N. SNPs of PSMA6 gene--investigation of possible association with myocardial infarction and type 2 diabetes mellitus. Genetika. 2007;43(4):553-9.
[27] Wang H, Jiang M, Zhu H, Chen Q, Gong P, Lin J, Lu J, Qiu J. Quantitative assessment of the influence of PSMA6 variant (rs1048990) on coronary artery disease risk. Mol Biol Rep. 2013;40(2):1035-41.
[28] Sjakste T, Paramonova N, Wu LS-S, Zemeckiene Z, Sitkauskiene B, Sakalauskas R, Wange J-Y, Sjakste N. PSMA6 (rs2277460, rs1048990), PSMC6 (rs2295826, rs2295827) and PSMA3 (rs2348071) genetic diversity in Latvians, Lithuanians and Taiwanese. Meta Gene. 2014;2:283–98.
[29] Rozas J. DNA sequence polymorphism analysis using DnaSP. Methods Mol Biol. 2009;537:337-50.
[30] Lewis CM. Genetic association studies: design, analysis and interpretation. Brief Bioinform. 2002;3(2):146-53.
[31] Loisel DA, Tan Z, Tisler CJ, Evans MD, Gangnon RE, Jackson DJ, Gern JE, Lemanske RF Jr, Ober C. IFNG genotype and sex interact to influence the risk of childhood asthma. J Allergy Clin Immunol. 2011;128(3):524-31.
[32] Qian F, Zhang Q, Zhou L, Ma G, Jin G, Huang Q, Yin K. Association between polymorphisms in IL17F and male asthma in a Chinese population. J Investig Allergol Clin Immunol. 2012;22(4):257-63.
[33] Hunninghake GM, Soto-Quir?s ME, Avila L, Kim HP, Lasky-Su J, Rafaels N, Ruczinski I, Beaty TH, Mathias RA, Barnes KC, Wilk JB, O'Connor GT, Gauderman WJ, Vora H, Baurley JW, Gilliland F, Liang C, Sylvia JS, Klanderman BJ, Sharma SS, Himes BE, Bossley CJ, Israel E, Raby BA, Bush A, Choi AM, Weiss ST, Celed?n JC. TSLP polymorphisms are associated with asthma in a sex-specific fashion. Allergy. 2010;65(12):1566-75.
[34] Raby BA, Lazarus R, Silverman EK, Lake S, Lange C, Wjst M, Weiss ST. Association of vitamin D receptor gene polymorphisms with childhood and adult asthma. Am J Respir Crit Care Med. 2004;170(10):1057-65.
[35] Seibold MA, Wang B, Eng C, Kumar G, Beckman KB, Sen S, Choudhry S, Meade K, Lenoir M, Watson HG, Thyne S, Williams LK, Kumar R, Weiss KB, Grammer LC, Avila PC, Schleimer RP, Burchard EG, Brenner R. An african-specific functional polymorphism in KCNMB1 shows sex-specific association with asthma severity. Hum Mol Genet. 2008;17(17):2681-90.
[36] Sivakumaran S, Agakov F, Theodoratou E, Prendergast JG, Zgaga L, Manolio T, Rudan I, McKeigue P, Wilson JF, Campbell H. Abundant pleiotropy in human complex diseases and traits. Am J Hum Genet. 2011;89(5):607-18.
[37] Lee SH, Park JS, Park CS. The search for genetic variants and epigenetics related to asthma. Allergy Asthma Immunol Res. 2011;3(4):236-44.
[38] Thompson SD, Barnes MG, Griffin TA, Grom AA, Glass DN. Heterogeneity in juvenile idiopathic arthritis: impact of molecular profiling based on DNA polymorphism and gene expression patterns. Arthritis Rheum. 2010;62(9):2611-5.
[39] Hallstrand TS, Fischer ME, Wurfel MM, Afari N, Buchwald D, Goldberg J. Genetic pleiotropy between asthma and obesity in a community-based sample of twins. J Allergy Clin Immunol. 2005;116(6):1235-41.
[40] Murphy A, Tantisira KG, Soto-Quir?s ME, Avila L, Klanderman BJ, Lake S, Weiss ST, Celed?n JC. PRKCA: a positional candidate gene for body mass index and asthma. Am J Hum Genet. 2009;85(1):87-96.
[41] Lee SH, Lee EB, Shin ES, Lee JE, Cho SH, Min KU, Park HW. The Interaction Between Allelic Variants of CD86 and CD40LG: A Common Risk Factor of Allergic Asthma and Rheumatoid Arthritis. Allergy Asthma Immunol Res. 2014;6(2):137-41.
[42] Ram?rez-Bello J, Jim?nez-Morales S, Espinosa-Rosales F, G?mez-Vera J, Guti?rrez A, Vel?zquez Cruz R, Baca V, Orozco L. Juvenile rheumatoid arthritis and asthma, but not childhood-onset systemic lupus erythematosus are associated with FCRL3 polymorphisms in Mexicans. Mol Immunol. 2013;53(4):374-8.
[43] Trapina I, Rumba-Rozenfelde I, Sjakste N, Sokolovska J, Sugoka O, Sjakste T. Association study of genetic variants in the 14q11– 14q13 proteasomal genes cluster with juvenile idiopathic arthritis (JIA) in Latvian population. Proceedings of the Latvian Academy of Sciences. Section B. 2009; 63(4–5):214–31.
[44] Kupca S, Sjakste T, Paramonova N, Sugoka O, Rinkuza I, Trapina I, Daugule I, Sipols AJ, Rumba-Rozenfelde I. Association of obesity with proteasomal gene polymorphisms in children. J Obes. 2013;2013:638154.
[45] Kalnina J, Paramonova N, Sjakste N, Sjakste T. Study of association between polymorphisms in the PSMB5 (rs11543947) and PSMA3 (rs2348071) genes and multiple sclerosis in Latvians. Biopolym Cell. 2014; 30(4):305–9.
[46] Jean-Philippe J, Paz S, Caputi M. hnRNP A1: the Swiss army knife of gene expression. Int J Mol Sci. 2013;14(9):18999-9024.
[47] Guo R, Li Y, Ning J, Sun D, Lin L, Liu X. HnRNP A1/A2 and SF2/ASF regulate alternative splicing of interferon regulatory factor-3 and affect immunomodulatory functions in human non-small cell lung cancer cells. PLoS One. 2013;8(4):e62729.
[48] Wu ZH, Shi Y. When ubiquitin meets NF-?B: a trove for anti-cancer drug development. Curr Pharm Des. 2013;19(18):3263-75.
[49] Dozmorov M, Wu W, Chakrabarty K, Booth JL, Hurst RE, Coggeshall KM, Metcalf JP. Gene expression profiling of human alveolar macrophages infected by B. anthracis spores demonstrates TNF-alpha and NF-kappab are key components of the innate immune response to the pathogen. BMC Infect Dis. 2009;9:152.
[50] Ozaki K, Sato H, Iida A, Mizuno H, Nakamura T, Miyamoto Y, Takahashi A, Tsunoda T, Ikegawa S, Kamatani N, Hori M, Nakamura Y, Tanaka T. A functional SNP in PSMA6 confers risk of myocardial infarction in the Japanese population. Nat Genet. 2006;38(8):921-5.
[51] Sj?lander A, Birgander R, Saha N, Beckman L, Beckman G. p53 polymorphisms and haplotypes show distinct differences between major ethnic groups. Hum Hered. 1996;46(1):41-8.
[52] Kopp A. Dmrt genes in the development and evolution of sexual dimorphism. Trends Genet. 2012;28(4):175-84.
[53] Imhof A, Wolffe AP. Transcription: gene control by targeted histone acetylation. Curr Biol. 1998;8(12):R422-4.
[54] Johnson CA, Turner BM. Histone deacetylases: complex transducers of nuclear signals. Semin Cell Dev Biol. 1999;10(2):179-88.
[55] Adcock IM, Ito K, Barnes PJ. Histone deacetylation: an important mechanism in inflammatory lung diseases. COPD. 2005;2(4):445-55.
[56] Chiappara G, Chanez P, Bruno A, Pace E, Pompeo F, Bousquet J, Bonsignore G, Gjomarkaj M. Variable p-CREB expression depicts different asthma phenotypes. Allergy. 2007;62(7):787-94.
[57] Viemari JC. Noradrenergic modulation of the respiratory neural network. Respir Physiol Neurobiol. 2008;164(1-2):123-30.
[58] Clark RI, Tan SW, P?an CB, Roostalu U, Vivancos V, Bronda K, Pil?tov? M, Fu J, Walker DW, Berdeaux R, Geissmann F, Dionne MS. MEF2 is an in vivo immune-metabolic switch. Cell. 2013;155(2):435-47.