Variants in the non-coding region of the TLR2 gene associated with infectious subphenotypes in pediatric sickle cell anemia
- 249 Downloads
Sickle cell anemia (SCA) is characterized by chronic hemolysis, severe vasoocclusive crises (VOCs), and recurrent often severe infections. A cohort of 95 SCA pediatric patients was the background for genotype-to-phenotype association of the patient’s infectious disease phenotype and three non-coding polymorphic regions of the TLR2 gene, the −196 to −174 indel, SNP rs4696480, and a (GT)n short tandem repeat. The infectious subphenotypes included (A) recurrent respiratory infections and (B) severe bacterial infection at least once during the patient’s follow-up. The absence of the haplotype [Del]-T-[n ≥ 17] (Hap7) in homozygocity protected against subphenotype (B), in a statistically significant association, resisting correction for multiple testing. For the individual loci, the same association tendencies were observed as in the haplotype, including a deleterious association between the SNP rs4696480 T allele and subphenotype (A), whereas the A/A genotype was protective, and a deleterious effect of the A/T genotype with subphenotype (B), as well as including the protective effect of −196 to −174 insert (Ins) and deleterious effect of the deletion (Del) in homozygocity, against subphenotype (B). Moreover, a reduction in the incidence rate of severe bacterial infection was associated to a rise in the hemolytic score, fetal hemoglobin levels (prior to hydroxyurea treatment), and 3.7-kb alpha-thalassemia. Interestingly, differences between the effects of the two latter covariables favoring a reduction in the incidence rate of subphenotype (B) contrast with a resulting increase in relation to subphenotype (A). These results could have practical implications in health care strategies to lower the morbidity and mortality of SCA patients.
KeywordsSickle cell anemia TLR2 Genetic variants Viral and bacterial infection Hemolytic component Genotype-to-phenotype association
We are grateful to the patients and their families. We also thank Dominique Labie for having suggested this topic of research. We thank INSA’s “Unidade de Tecnologia e Inovacão” as well as Andreia Coelho and Emanuel Ferreira for their technical support. We thank Eric David Bosne for the insight in PCA. We also thank Audrey V. Grant, Baltazar Nunes, Paula Faustino, and Vera C.M. David for their helpful suggestions in the elaboration of the study. This study was carried out with financial support from FCT/MEC through national funds and co-financed by FEDER, under the Partnership Agreement PT2020, in the project with reference UIDMULTI/00211/2013, and was partially funded by FCT grants PIC/IC/83084/2007 and the Centro de Investigação em Genética Molecular Humana (CIGMH).
Conceived and designed the experiments: S David, A Dias, A Morais, J Lavinha. Suggested methodologies: S David, A Dias, A Morais, A Sakuntabhai, J Lavinha. Genotyped: S David. Reorganized the database: S David. Analyzed the data: S David, P Aguiar. Carried out the investigation: S David. Provided the resources: A Dias, A Morais, J Lavinha. Wrote the paper: S David. Reviewed the paper: P Aguiar, J Lavinha, A Sakuntabhai. All authors approved the final version of the paper.
Compliance with ethical standards
Conflict of interests
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
- Hishida A, Matsuo K, Goto Y, Naito M, Wakai K, Tajima K, Hamajima N (2010) No associations of toll-like receptor 2 (TLR2)-196 to-174del polymorphism with the risk of Helicobacter pylori seropositivity, gastric atrophy, and gastric cancer in Japanese. Gastric Cancer 13(4):251–257CrossRefPubMedGoogle Scholar
- Ioana M, Ferwerda B, Plantinga TS, Stappers M, Oosting M, McCall M, Cimpoeru A, Burada F, Panduru N, Sauerwein R, Doumbo O (2012) Different patterns of toll-like receptor 2 polymorphisms in populations of various ethnic and geographic origins. Infect Immun 80(5):1917–1922CrossRefPubMedPubMedCentralGoogle Scholar
- Miedema KGE, Tissing WJE, Te Poele EM, Kamps WA, Alizadeh BZ, Kerkhof M, De Jongste JC, Smit HA, De Pagter AP, Bierings M, Boezen HM (2012) Polymorphisms in the TLR6 gene associated with the inverse association between childhood acute lymphoblastic leukemia and atopic disease. Leukemia 26(6):1203–1210CrossRefPubMedGoogle Scholar
- Nischalke HD, Berger C, Aldenhoff K, Thyssen L, Gentemann M, Grünhage F, Lammert F, Nattermann J, Sauerbruch T, Spengler U, Appenrodt B (2011) Toll-like receptor (TLR) 2 promoter and intron 2 polymorphisms are associated with increased risk for spontaneous bacterial peritonitis in liver cirrhosis. J Hepatol 55(5):1010–1016CrossRefPubMedGoogle Scholar
- Nischalke HD, Coenen M, Berger C, Aldenhoff K, Müller T, Berg T, Krämer B, Körner C, Odenthal M, Schulze F, Grünhage F (2012) The toll-like receptor 2 (TLR2)-196 to-174 del/ins polymorphism affects viral loads and susceptibility to hepatocellular carcinoma in chronic hepatitis C. Int J Cancer 130(6):1470–1475CrossRefPubMedGoogle Scholar
- Nouraie M, Lee JS, Zhang Y, Kanias T, Zhao X, Xiong Z, Oriss TB, Zeng Q, Kato GJ, Gibbs JSR, Hildesheim ME (2013) The relationship between the severity of hemolysis, clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and Europe. Haematologica 98(3):464–472CrossRefPubMedPubMedCentralGoogle Scholar
- de Oliviera Nascimento L, Massari P, Wetzler LM (2012) The role of TLR2 in infection and immunity. Front Immunol 3:79Google Scholar
- Rostane H, Busson M, Diallo D (2012) Le risque d’infections bactériennes sévères au cours de la maladie drépanocytaire est influencé par un polymorphisme du promoteur du gène TLR-2. Congrès Soc Franc Hématol 2012; Globule rouge et fer# 138. Hématologie 18(suppl 1):26Google Scholar
- Team, RC (2013) R: a language and environment for statistical computing. R Foundation for Statistical Computing, ViennaGoogle Scholar
- Trinchieri G (2010) Type I interferon: friend or foe? J Exp Med. doi: 10.1084/jem.20101664
- Velez DR, Wejse C, Stryjewski ME, Abbate E, Hulme WF, Myers JL, Estevan R, Patillo SG, Olesen R, Tacconelli A, Sirugo G (2010) Variants in toll-like receptors 2 and 9 influence susceptibility to pulmonary tuberculosis in Caucasians, African-Americans, and West Africans. Hum Genet 127(1):65–73CrossRefPubMedGoogle Scholar
- Zeng HM, Pan KF, Zhang Y, Zhang L, Ma JL, Zhou T, Su HJ, Li WQ, Li JY, Gerhard M, Classen M (2011) Genetic variants of toll-like receptor 2 and 5, helicobacter pylori infection, and risk of gastric cancer and its precursors in a Chinese population. Cancer Epidemiol Prev Biomark 20(12):2594–2602CrossRefGoogle Scholar