Yonsei Med J.  2015 Mar;56(2):332-339. 10.3349/ymj.2015.56.2.332.

Association of the Single-Nucleotide Polymorphism and Haplotype of the Complement Receptor 1 Gene with Malaria

• Lan Y
• Wei CD
• Chen WC
• Wang JL
• Wang CF
• Pan GG
• Wei YS
• Nong LG

• KMID: 2070007
• DOI: http://doi.org/10.3349/ymj.2015.56.2.332

Abstract

PURPOSE
Although the polymorphisms of erythrocyte complement receptor type 1 (CR1) in patients with malaria have been extensively studied, a question of whether the polymorphisms of CR1 are associated with severe malaria remains controversial. Furthermore, no study has examined the association of CR1 polymorphisms with malaria in Chinese population. Therefore, we investigated the relationship of CR1 gene polymorphism and malaria in Chinese population.
MATERIALS AND METHODS
We analyzed polymorphisms of CR1 gene rs2274567 G/A, rs4844600 G/A, and rs2296160 C/T in 509 patients with malaria and 503 controls, using the Taqman genotyping assay and PCR-direct sequencing.
RESULTS
There were no significant differences in the genotype, allele and haplotype frequencies of CR1 gene rs2274567 G/A, rs4844600 G/A, and rs2296160 C/T polymorphisms between patients with malaria and controls. Furthermore, there was no association of polymorphisms in the CR1 gene with the severity of malaria in Chinese population.
CONCLUSION
These findings suggest that CR1 gene rs2274567 G/A, rs4844600 G/A, and rs2296160 C/T polymorphisms may not be involved in susceptibility to malaria in Chinese population.

Keyword

Erythrocyte complement receptor type 1; gene; polymorphism; haplotype; malaria

MeSH Terms

Adult
Alleles
Asian Continental Ancestry Group
Case-Control Studies
China
Erythrocytes/parasitology
Female
Genetic Predisposition to Disease
Genotype
*Haplotypes
Humans
Malaria/ethnology/*genetics
Male
Middle Aged
Polymorphism, Single Nucleotide/*genetics
Promoter Regions, Genetic/*genetics
Receptors, Complement/blood/*genetics
Taq Polymerase
Receptors, Complement
Taq Polymerase

Figure

• 

  Fig. 1 PCR-direct sequencing. CR1 gene rs2274567 site genotype GG, GA, and AA (A). CR1 gene rs4844600 site genotype GG, GA, and AA (B). CR1 gene rs2296160 site genotype CC, CT, and TT (C). PCR, polymerase chain reaction; CR1, complement receptor type 1.

Reference

1. Mayor S. WHO report shows progress in efforts to reduce malaria incidence. BMJ. 2008; 337:a1678.

2. Schofield L, Grau GE. Immunological processes in malaria pathogenesis. Nat Rev Immunol. 2005; 5:722–735.

3. Mackintosh CL, Beeson JG, Marsh K. Clinical features and pathogenesis of severe malaria. Trends Parasitol. 2004; 20:597–603.

4. Stoute JA, Odindo AO, Owuor BO, Mibei EK, Opollo MO, Waitumbi JN. Loss of red blood cell-complement regulatory proteins and increased levels of circulating immune complexes are associated with severe malarial anemia. J Infect Dis. 2003; 187:522–525.

5. Waitumbi JN, Opollo MO, Muga RO, Misore AO, Stoute JA. Red cell surface changes and erythrophagocytosis in children with severe plasmodium falciparum anemia. Blood. 2000; 95:1481–1486.

6. Vorup-Jensen T, Boesen T. Protein ultrastructure and the nanoscience of complement activation. Adv Drug Deliv Rev. 2011; 63:1008–1019.

7. Lapin ZJ, Höppener C, Gelbard HA, Novotny L. Near-field quantification of complement receptor 1 (CR1/CD35) protein clustering in human erythrocytes. J Neuroimmune Pharmacol. 2012; 7:539–543.

8. Nuutila J, Jalava-Karvinen P, Hohenthal U, Kotilainen P, Pelliniemi TT, Nikoskelainen J, et al. Use of complement regulators, CD35, CD46, CD55, and CD59, on leukocytes as markers for diagnosis of viral and bacterial infections. Hum Immunol. 2013; 74:522–530.

9. Awandare GA, Spadafora C, Moch JK, Dutta S, Haynes JD, Stoute JA. Plasmodium falciparum field isolates use complement receptor 1 (CR1) as a receptor for invasion of erythrocytes. Mol Biochem Parasitol. 2011; 177:57–60.

10. Stoute JA. Complement receptor 1 and malaria. Cell Microbiol. 2011; 13:1441–1450.

11. Newbold C, Craig A, Kyes S, Rowe A, Fernandez-Reyes D, Fagan T. Cytoadherence, pathogenesis and the infected red cell surface in Plasmodium falciparum. Int J Parasitol. 1999; 29:927–937.

12. Spadafora C, Awandare GA, Kopydlowski KM, Czege J, Moch JK, Finberg RW, et al. Complement receptor 1 is a sialic acid-independent erythrocyte receptor of Plasmodium falciparum. PLoS Pathog. 2010; 6:e1000968.

13. Fernandez-Arias C, Lopez JP, Hernandez-Perez JN, Bautista-Ojeda MD, Branch O, Rodriguez A. Malaria inhibits surface expression of complement receptor 1 in monocytes/macrophages, causing decreased immune complex internalization. J Immunol. 2013; 190:3363–3372.

14. Thomas BN, Diallo DA, Noumsi GT, Moulds JM. Circulating Immune Complex Levels are Associated with Disease Severity and Seasonality in Children with Malaria from Mali. Biomark Insights. 2012; 7:81–86.

15. Cockburn IA, Mackinnon MJ, O'Donnell A, Allen SJ, Moulds JM, Baisor M, et al. A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria. Proc Natl Acad Sci U S A. 2004; 101:272–277.

16. Nagayasu E, Ito M, Akaki M, Nakano Y, Kimura M, Looareesuwan S, et al. CR1 density polymorphism on erythrocytes of falciparum malaria patients in Thailand. Am J Trop Med Hyg. 2001; 64:1–5.

17. Rout R, Dhangadamajhi G, Mohapatra BN, Kar SK, Ranjit M. High CR1 level and related polymorphic variants are associated with cerebral malaria in eastern-India. Infect Genet Evol. 2011; 11:139–144.

18. Mahajan RC, Narain K, Mahanta J. Anaemia & expression levels of CD35, CD55 & CD59 on red blood cells in Plasmodium falciparum malaria patients from India. Indian J Med Res. 2011; 133:662–664.

19. Tham WH, Schmidt CQ, Hauhart RE, Guariento M, Tetteh-Quarcoo PB, Lopaticki S, et al. Plasmodium falciparum uses a key functional site in complement receptor type-1 for invasion of human erythrocytes. Blood. 2011; 118:1923–1933.

20. Soares SC, Abé-Sandes K, Nascimento Filho VB, Nunes FM, Silva WA Jr. Genetic polymorphisms in TLR4, CR1 and Duffy genes are not associated with malaria resistance in patients from Baixo Amazonas region, Brazil. Genet Mol Res. 2008; 7:1011–1019.

21. Rowe JA, Raza A, Diallo DA, Baby M, Poudiougo B, Coulibaly D, et al. Erythrocyte CR1 expression level does not correlate with a HindIII restriction fragment length polymorphism in Africans; implications for studies on malaria susceptibility. Genes Immun. 2002; 3:497–500.

22. Cockburn IA, Rowe JA. Erythrocyte complement receptor 1 (CR1) expression level is not associated with polymorphisms in the promoter or 3' untranslated regions of the CR1 gene. Int J Immunogenet. 2006; 33:17–20.

23. Teeranaipong P, Ohashi J, Patarapotikul J, Kimura R, Nuchnoi P, Hananantachai H, et al. A functional single-nucleotide polymorphism in the CR1 promoter region contributes to protection against cerebral malaria. J Infect Dis. 2008; 198:1880–1891.

24. John SW, Weitzner G, Rozen R, Scriver CR. A rapid procedure for extracting genomic DNA from leukocytes. Nucleic Acids Res. 1991; 19:408.

25. Shi YY, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res. 2005; 15:97–98.

26. Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001; 68:978–989.

27. Kirchgatter K, Portillo Hdel A. Association of severe noncerebral Plasmodium falciparum malaria in Brazil with expressed PfEMP1 DBL1 alpha sequences lacking cysteine residues. Mol Med. 2002; 8:16–23.

28. Valle-Delgado JJ, Urbán P, Fernàndez-Busquets X. Demonstration of specific binding of heparin to Plasmodium falciparum-infected vs. non-infected red blood cells by single-molecule force spectroscopy. Nanoscale. 2013; 5:3673–3680.

29. Doumbo OK, Thera MA, Koné AK, Raza A, Tempest LJ, Lyke KE, et al. High levels of Plasmodium falciparum rosetting in all clinical forms of severe malaria in African children. Am J Trop Med Hyg. 2009; 81:987–993.

30. Krych-Goldberg M, Moulds JM, Atkinson JP. Human complement receptor type 1 (CR1) binds to a major malarial adhesin. Trends Mol Med. 2002; 8:531–537.

31. Rowe JA, Rogerson SJ, Raza A, Moulds JM, Kazatchkine MD, Marsh K, et al. Mapping of the region of complement receptor (CR) 1 required for Plasmodium falciparum rosetting and demonstration of the importance of CR1 in rosetting in field isolates. J Immunol. 2000; 165:6341–6346.

32. Rowe JA, Moulds JM, Newbold CI, Miller LH. P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1. Nature. 1997; 388:292–295.

33. Stoute JA. Complement-regulatory proteins in severe malaria: too little or too much of a good thing? Trends Parasitol. 2005; 21:218–223.

34. Carlson J, Helmby H, Hill AV, Brewster D, Greenwood BM, Wahlgren M. Human cerebral malaria: association with erythrocyte rosetting and lack of anti-rosetting antibodies. Lancet. 1990; 336:1457–1460.

35. Treutiger CJ, Hedlund I, Helmby H, Carlson J, Jepson A, Twumasi P, et al. Rosette formation in Plasmodium falciparum isolates and anti-rosette activity of sera from Gambians with cerebral or uncomplicated malaria. Am J Trop Med Hyg. 1992; 46:503–510.

36. Heddini A, Pettersson F, Kai O, Shafi J, Obiero J, Chen Q, et al. Fresh isolates from children with severe Plasmodium falciparum malaria bind to multiple receptors. Infect Immun. 2001; 69:5849–5856.

37. Rowe A, Obeiro J, Newbold CI, Marsh K. Plasmodium falciparum rosetting is associated with malaria severity in Kenya. Infect Immun. 1995; 63:2323–2326.

38. Xiang L, Rundles JR, Hamilton DR, Wilson JG. Quantitative alleles of CR1: coding sequence analysis and comparison of haplotypes in two ethnic groups. J Immunol. 1999; 163:4939–4945.

39. Waitumbi JN, Donvito B, Kisserli A, Cohen JH, Stoute JA. Age-related changes in red blood cell complement regulatory proteins and susceptibility to severe malaria. J Infect Dis. 2004; 190:1183–1191.

40. Sinha S, Jha GN, Anand P, Qidwai T, Pati SS, Mohanty S, et al. CR1 levels and gene polymorphisms exhibit differential association with falciparum malaria in regions of varying disease endemicity. Hum Immunol. 2009; 70:244–250.