Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Allelic mRNA expression imbalance in C-type lectins reveals a frequent regulatory SNP in the human surfactant protein A (SP-A) gene

Genes & Immunity volume 14, pages 99–106 (2013)Cite this article

Subjects

Abstract

Genetic variation in C-type lectins influences infectious disease susceptibility but remains poorly understood. We used allelic mRNA expression imbalance (AEI) technology for surfactant protein (SP)-A1, SP-A2, SP-D, dendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN), macrophage mannose receptor (MRC1) and Dectin-1, expressed in human macrophages and/or lung tissues. Frequent AEI, an indicator of regulatory polymorphisms, was observed in SP-A2, SP-D and DC-SIGN. AEI was measured for SP-A2 in 38 lung tissues using four marker single-nucleotide polymorphisms (SNPs) and was confirmed by next-generation sequencing of one lung RNA sample. Genomic DNA at the SP-A2 DNA locus was sequenced by Ion Torrent technology in 16 samples. Correlation analysis of genotypes with AEI identified a haplotype block, and, specifically, the intronic SNP rs1650232 (30% minor allele frequency); the only variant consistently associated with an approximately twofold change in mRNA allelic expression. Previously shown to alter a NAGNAG splice acceptor site with likely effects on SP-A2 expression, rs1650232 generates an alternative splice variant with three additional bases at the start of exon 3. Validated as a regulatory variant, rs1650232 is in partial linkage disequilibrium with known SP-A2 marker SNPs previously associated with risk for respiratory diseases including tuberculosis. Applying functional DNA variants in clinical association studies, rather than marker SNPs, will advance our understanding of genetic susceptibility to infectious diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Sorensen TI, Nielsen GG, Andersen PK, Teasdale TW . Genetic and environmental influences on premature death in adult adoptees. N Engl J Med 1988; 318: 727–732.

    Article  CAS  Google Scholar 

  2. Cooke GS, Hill AV . Genetics of susceptibility to human infectious disease. Nat Rev Genet 2001; 2: 967–977.

    Article  CAS  Google Scholar 

  3. Hill AV . Aspects of genetic susceptibility to human infectious diseases. Annu Rev Genet 2006; 40: 469–486.

    Article  CAS  Google Scholar 

  4. Azad AK, Sadee W, Schlesinger LS . Innate immune gene polymorphisms in tuberculosis. Infect Immun 2012; 80: 3343–3359.

    Article  CAS  Google Scholar 

  5. Torrelles JB, Azad AK, Henning LN, Carlson TK, Schlesinger LS . Role of C-type lectins in mycobacterial infections. Curr Drug Targets 2008; 9: 102–112.

    Article  CAS  Google Scholar 

  6. McGreal EP, Miller JL, Gordon S . Ligand recognition by antigen-presenting cell C-type lectin receptors. Curr Opin Immunol 2005; 17: 18–24.

    Article  CAS  Google Scholar 

  7. Bray NJ, Buckland PR, Owen MJ, O’Donovan MC . Cis-acting variation in the expression of a high proportion of genes in human brain. Hum Genet 2003; 113: 149–153.

    PubMed  Google Scholar 

  8. Yan H, Yuan W, Velculescu VE, Vogelstein B, Kinzler KW . Allelic variation in human gene expression. Science 2002; 297: 1143.

    Article  CAS  Google Scholar 

  9. Johnson AD, Gong Y, Wang D, Langaee TY, Shin J, Cooper-DeHoff RM et al. Promoter polymorphisms in ACE (angiotensin I-converting enzyme) associated with clinical outcomes in hypertension. Clin Pharmacol Ther 2009; 85: 36–44.

    Article  CAS  Google Scholar 

  10. Zhang Y, Bertolino A, Fazio L, Blasi G, Rampino A, Romano R et al. Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. Proc Natl Acad Sci USA 2007; 104: 20552–20557.

    Article  CAS  Google Scholar 

  11. Johnson AD, Wang D, Sadee W . Polymorphisms affecting gene regulation and mRNA processing: broad implications for pharmacogenetics. Pharmacol Ther 2005; 106: 19–38.

    Article  CAS  Google Scholar 

  12. Johnson AD, Zhang Y, Papp AC, Pinsonneault JK, Lim JE, Saffen D et al. Polymorphisms affecting gene transcription and mRNA processing in pharmacogenetic candidate genes: detection through allelic expression imbalance in human target tissues. Pharmacogenet Genomics 2008; 18: 781–791.

    Article  CAS  Google Scholar 

  13. Lim JE, Pinsonneault J, Sadee W, Saffen D . Tryptophan hydroxylase 2 (TPH2) haplotypes predict levels of TPH2 mRNA expression in human pons. Mol Psychiatry 2007; 12: 491–501.

    Article  CAS  Google Scholar 

  14. Wang D, Guo Y, Wrighton SA, Cooke GE, Sadee W . Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J 2011; 11: 274–286.

    Article  Google Scholar 

  15. Wang G, Umstead TM, Phelps DS, Al Mondhiry H, Floros J . The effect of ozone exposure on the ability of human surfactant protein a variants to stimulate cytokine production. Environ Health Perspect 2002; 110: 79–84.

    Article  CAS  Google Scholar 

  16. Karinch AM, DeMello DE, Floros J . Effect of genotype on the levels of surfactant protein A mRNA and on the SP-A2 splice variants in adult humans. Biochem J 1997; 321: 39–47.

    Article  CAS  Google Scholar 

  17. Wang G, Guo X, Floros J . Human SP-A 3′-UTR variants mediate differential gene expression in basal levels and in response to dexamethasone. Am J Physiol Lung Cell Mol Physiol 2003; 284: L738–L748.

    Article  CAS  Google Scholar 

  18. Floros J, Lin HM, García A, Salazar MA, Guo X, DiAngelo S et al. Surfactant protein genetic marker alleles identify a subgroup of tuberculosis in a Mexican population. J Infect Dis 2000; 182: 1473–1478.

    Article  CAS  Google Scholar 

  19. Malik S, Greenwood CM, Eguale T, Kifle A, Beyene J, Habte A et al. Variants of the SFTPA1 and SFTPA2 genes and susceptibility to tuberculosis in Ethiopia. Hum Genet 2006; 118: 752–759.

    Article  CAS  Google Scholar 

  20. Hiller M, Huse K, Szafranski K, Jahn N, Hampe J, Schreiber S et al. Widespread occurrence of alternative splicing at NAGNAG acceptors contributes to proteome plasticity. Nat Genet 2004; 36: 1255–1257.

    Article  CAS  Google Scholar 

  21. Hiller M, Huse K, Szafranski K, Jahn N, Hampe J, Schreiber S et al. Single-nucleotide polymorphisms in NAGNAG acceptors are highly predictive for variations of alternative splicing. Am J Hum Genet 2006; 78: 291–302.

    Article  CAS  Google Scholar 

  22. Silveyra P, Raval M, Simmons B, DiAngelo S, Wang G, Floros J . The untranslated exon B of human surfactant protein A2 mRNAs is an enhancer for transcription and translation. Am J Physiol Lung Cell Mol Physiol 2011; 301: L795–L803.

    Article  CAS  Google Scholar 

  23. Liu J, Zhou Z, Hodgkinson CA, Yuan Q, Shen PH, Mulligan CJ et al. Haplotype-based study of the association of alcohol-metabolizing genes with alcohol dependence in four independent populations. Alcohol Clin Exp Res 2011; 35: 304–316.

    Article  CAS  Google Scholar 

  24. Jack DL, Cole J, Naylor SC, Borrow R, Kaczmarski EB, Klein NJ et al. Genetic polymorphism of the binding domain of surfactant protein-A2 increases susceptibility to meningococcal disease. Clin Infect Dis 2006; 43: 1426–1433.

    Article  CAS  Google Scholar 

  25. Pettigrew MM, Gent JF, Zhu Y, Triche EW, Belanger KD, Holford TR et al. Respiratory symptoms among infants at risk for asthma: association with surfactant protein A haplotypes. BMC Med Genet 2007; 8: 15.

    Article  Google Scholar 

  26. Saxena S, Kumar R, Madan T, Gupta V, Muralidhar K, Sarma PU . Association of polymorphisms in pulmonary surfactant protein A1 and A2 genes with high-altitude pulmonary edema. Chest 2005; 128: 1611–1619.

    Article  CAS  Google Scholar 

  27. Kang BK, Schlesinger LS . Characterization of mannose receptor-dependent phagocytosis mediated by Mycobacterium tuberculosis lipoarabinomannan. Infect Immun 1998; 66: 2769–2777.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang Y, Wang D, Johnson AD, Papp AC, Sadee W . Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem 2005; 280: 32618–32624.

    Article  CAS  Google Scholar 

  29. Wang D, Johnson AD, Papp AC, Kroetz DL, Sadee W . Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genomics 2005; 15: 693–704.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was in part supported by NIH Research Grant U01 GM092655 from the National Institute General Medical Sciences (WS) and Award Number UL1RR025755 from the National Center for Research Resources. It was also in part supported by NIH R01 AI059639 from the National Institute of Allergy and Infectious Diseases (LSS).

Author information

Author notes

  1. W Sadee and L S Schlesinger: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, College of Medicine, Columbus, OH, USA

    A K Azad & L S Schlesinger

  2. Departments of Pharmacology, Program in Pharmacogenomics, Psychiatry, and Medical Genetics, College of Public Health, Columbus, OH, USA

    A Curtis, A Papp, A Webb & W Sadee

  3. College of Pharmacy and Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA

    D Knoell

Authors
  1. A K Azad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Curtis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Papp
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Webb
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Knoell
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. W Sadee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L S Schlesinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L S Schlesinger.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on Genes and Immunity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Azad, A., Curtis, A., Papp, A. et al. Allelic mRNA expression imbalance in C-type lectins reveals a frequent regulatory SNP in the human surfactant protein A (SP-A) gene. Genes Immun 14, 99–106 (2013). https://doi.org/10.1038/gene.2012.61

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2012.61

Keywords

Search

Advanced search

Quick links