Altered levels of IFN-γ, IL-4, and IL-5 depend on the TLR4 rs4986790 genotype in COPD smokers but not those exposed to biomass-burning smoke

Karla Jazmín Gutiérrez-Romero; Ramcés Falfán-Valencia; Alejandra Ramírez-Venegas; Rafael De Jesus Hernández-Zenteno; Fernando Flores-Trujillo; Raúl Sansores-Martínez; Espiridión Ramos-Martínez; Gloria Pérez-Rubio

doi:10.3389/fimmu.2024.1411408

Altered levels of IFN-γ, IL-4, and IL-5 depend on the TLR4 rs4986790 genotype in COPD smokers but not those exposed to biomass-burning smoke

Front Immunol. 2024 Jul 30:15:1411408. doi: 10.3389/fimmu.2024.1411408. eCollection 2024.

Authors

Karla Jazmín Gutiérrez-Romero¹, Ramcés Falfán-Valencia¹, Alejandra Ramírez-Venegas², Rafael De Jesus Hernández-Zenteno², Fernando Flores-Trujillo², Raúl Sansores-Martínez³, Espiridión Ramos-Martínez⁴, Gloria Pérez-Rubio¹

Affiliations

¹ HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.
² Tobacco Smoking and COPD Research Department, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.
³ Clínica de Enfermedades Respiratorias, Fundación Médica Sur, Mexico City, Mexico.
⁴ Experimental Medicine Research Unit, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico.

Abstract

Introduction: Chronic obstructive pulmonary disease (COPD) is associated with tobacco smoking and biomass-burning smoke exposure. Toll-like receptor 4 (TLR4) single-nucleotide polymorphisms (SNPs) may contribute to its pathogenesis. The study aimed to assess the association of rs4986790 and rs4986791 in the TLR4 gene in a Mexican mestizo population with COPD secondary to tobacco smoking (COPD-TS) and biomass-burning smoke (COPD-BBS) and to evaluate whether the genotypes of risk affect cytokine serum levels.

Materials and methods: We enrolled 2,092 participants and divided them into two comparisons according to their environmental exposure. SNPs were genotyped using TaqMan probes. Serum cytokine levels (IL-4, IL-5, IL-6, IL-10, and INF-γ) were quantified by ELISA.

Results: The rs4986790 AA genotype in COPD-TS was associated with a higher COPD risk (OR = 3.53). Haplotype analysis confirmed this association, identifying a block containing the rs4986790 allele (A-C, OR = 3.11). COPD-TS exhibited elevated IL-6, IL-4, and IL-5 levels compared with smokers without COPD (SWOC), whereas COPD-BBS displayed higher IFN-γ, IL-6, and IL-10 levels. The AA carriers in the COPD-TS group had elevated IL-4, IL-5, and IFN-γ compared with carriers of AG or GG.

Conclusion: The rs4986790 common allele and the A-C haplotype (rs4986790-rs4986791) were associated with a higher COPD risk in smokers; COPD patients carrying the AA genotype showed increased pro-inflammatory cytokines.

Keywords: COPD; SNPs; biomass-burning smoke; cytokines; tobacco smoke.

MeSH terms

Adult
Aged
Biomass
Female
Genetic Predisposition to Disease
Genotype*
Humans
Interferon-gamma* / blood
Interferon-gamma* / genetics
Interleukin-4 / blood
Interleukin-4 / genetics
Interleukin-5 / blood
Interleukin-5 / genetics
Male
Mexico
Middle Aged
Polymorphism, Single Nucleotide*
Pulmonary Disease, Chronic Obstructive* / etiology
Pulmonary Disease, Chronic Obstructive* / genetics
Smoke / adverse effects
Smokers
Smoking / adverse effects
Toll-Like Receptor 4* / genetics

Substances

Toll-Like Receptor 4
Interferon-gamma
TLR4 protein, human
Interleukin-4
Interleukin-5
Smoke
IL4 protein, human
IL5 protein, human
IFNG protein, human

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the allocated budget to research (HLA Laboratory) from the Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas (INER).