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Variants in the non-coding region of the TLR2 gene associated with infectious subphenotypes in pediatric sickle cell anemia

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Abstract

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.

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Acknowledgements

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).

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Authors and Affiliations

  1. Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, Av. Padre Cruz, 1649-016, Lisbon, Portugal

    Susana David & João Lavinha

  2. Centro de Estudos de Ciência Animal, Instituto de Ciências e Tecnologias Agrárias e Agro-Alimentares, Universidade do Porto, Porto, Portugal

    Susana David

  3. Centro de Investigação em Saúde Pública, Escola Nacional de Saúde Publica, Universidade Nova de Lisboa, Lisbon, Portugal

    Pedro Aguiar

  4. Departamento de Epidemiologia, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisbon, Portugal

    Liliana Antunes

  5. Departamento de Pediatria, Hospital Prof Doutor Fernando Fonseca, Amadora, Portugal

    Alexandra Dias

  6. Departamento de Pediatria, Hospital de Santa Maria, Lisbon, Portugal

    Anabela Morais

  7. Unité de la Génétique Fonctionnelle des Maladies Infectieuses, Institut, Pasteur, Paris, France

    Anavaj Sakuntabhai

  8. Centre National de la Recherche Scientifique, URA3012, Paris, France

    Anavaj Sakuntabhai

  9. BioISI, Faculdade de Ciências, Universidade de Lisboa, Lisbon, Portugal

    João Lavinha

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  1. Susana David
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  2. Pedro Aguiar
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  3. Liliana Antunes
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Contributions

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.

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Correspondence to Susana David.

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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.

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David, S., Aguiar, P., Antunes, L. et al. Variants in the non-coding region of the TLR2 gene associated with infectious subphenotypes in pediatric sickle cell anemia. Immunogenetics 70, 37–51 (2018). https://doi.org/10.1007/s00251-017-1013-7

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