Variants in the TNFA, IL6 and IFNG genes are associated with the dengue severity in a sample from Colombian population

Abstract

Introducción. La composición genética del huésped determina, entre otros aspectos, el perfil clínico del dengue, lo cual se debería al efecto de variantes en los genes que codifican citocinas proinflamatorias.Objetivo. Evaluar la asociación entre las variantes de tres polimorfismos en los genes candidatos TNFA, IL6 e IFNG con la gravedad del dengue en una población colombiana.Materiales y métodos. Se evaluaron los polimorfismos rs1800750, rs2069843 y rs2069705 de los genes TNFA, IL6 e IFNG, respectivamente, en 226 pacientes con dengue. Los genotipos se tipificaron usando la reacción en cadena de la polimerasa (PCR) y los polimorfismos de la longitud de los fragmentos de restricción (Restriction Fragment Length Polymorphism, RFLP). Para determinar el riesgo de diferentes fenotipos del dengue, se compararon las frecuencias alélicas con la prueba de ji al cuadrado, y los genotipos y los haplotipos, con regresión logística. Por último, los análisis se ajustaron utilizando datos de autoidentificación o del componente genético ancestral.Resultados. El alelo A del rs2069843, ajustado por autoidentificación, se asoció con casos de dengue hemorrágico en afrocolombianos. En la muestra completa, dicho polimorfismo, ajustado por componente genético ancestral, fue reproducible. Además, hubo asociaciones significativas entre las combinaciones alélicas GGT y GAC de los rs1800750, rs2069843 y rs2069705 en pacientes con dengue hemorrágico, con ajuste por componente genético ancestral y sin él. Además, la combinación alélica AGC produjo 58,03 pg/ml más de interleucina 6 que la GGC, independientemente de los componentes genéticos europeo, amerindio y africano.Conclusión. Las variantes de los polimorfismos GGT y GAC de los rs1800750, rs2069843 y rs2069705 en los genes TNFA, IL6 e IFNG, respectivamente, se correlacionaron con la gravedad del dengue en esta muestra de población colombiana.

Dengue, Severity Paradox, and Socioeconomic Distribution Among Afro-Colombians

“…Although our analyses allow the consideration of the dengue severity paradox as the result of the intersectionality described above, the nature of the data used in this study does not allow one to definitively refute or confirm the proposed apparent protective effect of African ancestry on dengue severity. First, despite a described strong correlation between self-reported ethnicity and ancestry in Colombia, 21,22 the degree of correlation changes according to the setting, the degree of admixture, and the socioenvironmental conditions. [16][17][18][19]22 Therefore, any assessment on the reported ethnicity presented here should be interpreted as a sociodemographic construct and not simply as a biologic characteristic.…”

“…First, despite a described strong correlation between self-reported ethnicity and ancestry in Colombia, 21,22 the degree of correlation changes according to the setting, the degree of admixture, and the socioenvironmental conditions. [16][17][18][19]22 Therefore, any assessment on the reported ethnicity presented here should be interpreted as a sociodemographic construct and not simply as a biologic characteristic. 29,43 Second, the ascertainment of biologic effects of ancestry would likely require the assessment of biomarkers or immunologic analyses that were out of the scope of this study.…”

“…However, such factors are only potential candidates to explain the paradox if considered to behave differentially by ethnicity or ancestry, which has not yet to our knowledge been reported in the literature. 4,[16][17][18][20][21][22] The analysis of neighborhood SES and dengue rates showed a non-monotonic association, with larger presence of dengue cases among low and medium-SES neighborhoods. These findings are consistent with other analyses in Latin America, where increased dengue among low-SES settings is attributed to socio-environmental factors such as limited water supply and overcrowding that facilitate Aedes presence.…”

“…[7][8][9][10][11][12] Self-declared Black ethnicity and African ancestry are considered "protective" for severe forms of dengue. 5,[13][14][15][16][17][18][19][20][21][22][23] The rarity of severe dengue in Haiti and West Africa and ancestry studies on dengue from Cuba, Brazil, and Colombia have been used to support the hypothesis of a decreased likelihood of severe dengue among these populations; postulating that the protective mechanism of ancestry is via a differential presence of cytokines/biomarkers across populations. [13][14][15][16][17][20][21][22] Brazilian and Cuban studies, including genome-wide association studies, reported reductions up to 60% in the odds of dengue severity for self-reported Black ethnicity and increasing African ancestry, [15][16][17] even after adjusting for socioeconomic factors.…”

“…5,13–23 The rarity of severe dengue in Haiti and West Africa and ancestry studies on dengue from Cuba, Brazil, and Colombia have been used to support the hypothesis of a decreased likelihood of severe dengue among these populations; postulating that the protective mechanism of ancestry is via a differential presence of cytokines/biomarkers across populations. 13–17,20–22 Brazilian and Cuban studies, including genome-wide association studies, reported reductions up to 60% in the odds of dengue severity for self-reported Black ethnicity and increasing African ancestry, 15–17 even after adjusting for socioeconomic factors. 18,19 However, the literature on ethnicity and socioeconomic status (SES) as drivers of dengue infection remains limited, paradoxical, and imprecise.…”