Macrophage migration inhibitory factor promoter polymorphisms are associated with disease activity in rheumatoid arthritis patients from Southern Mexico

Santoscoy‐Ascencio, Guillermo; Baños‐Hernández, Christian Johana; Navarro‐Zarza, José Eduardo; Hernández‐Bello, Jorge; Bucala, Richard; López-Quintero, Andrés; Valdés-Alvarado, Emmanuel; Parra‐Rojas, Isela; Illades‐Aguiar, Berenice; Muñoz‐Valle, José Francisco

doi:10.1002/mgg3.1037

Cited by 9 publications

(9 citation statements)

References 47 publications

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“…6 C ), which is implicated in macrophage function in host defense through the suppression of anti-inflammatory effects of glucocorticoids ( Calandra and Roger 2003 ). Variants within MIF have been recently associated to rheumatoid arthritis in southern Mexican patients ( Santoscoy-Ascencio et al 2020 ). The SNP rs2330635 (AdaptMix P value = 7.06 × 10 −8 ) is strongly associated to the expression of MIF in T-cells (eQTL P value < 8.63 × 10 −5 ) and NK cells (eQTL P value = 5.77 × 10 −9 ) and is also marginally associated to neutrophil counts (GWAS P value = 2.46 × 10 −6 ) ( fig.…”

Section: Resultsmentioning

confidence: 99%

Disentangling Signatures of Selection Before and After European Colonization in Latin Americans

Mendoza‐Revilla

Chacón-Duque

Fuentes-Guajardo

et al. 2022

Molecular Biology and Evolution

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Throughout human evolutionary history, large-scale migrations have led to intermixing (i.e., admixture) between previously separated human groups. Although classical and recent work have shown that studying admixture can yield novel historical insights, the extent to which this process contributed to adaptation remains underexplored. Here, we introduce a novel statistical model, specific to admixed populations, that identifies loci under selection while determining whether the selection likely occurred post-admixture or prior to admixture in one of the ancestral source populations. Through extensive simulations, we show that this method is able to detect selection, even in recently formed admixed populations, and to accurately differentiate between selection occurring in the ancestral or admixed population. We apply this method to genome-wide SNP data of ∼4,000 individuals in five admixed Latin American cohorts from Brazil, Chile, Colombia, Mexico, and Peru. Our approach replicates previous reports of selection in the human leukocyte antigen region that are consistent with selection post-admixture. We also report novel signals of selection in genomic regions spanning 47 genes, reinforcing many of these signals with an alternative, commonly used local-ancestry-inference approach. These signals include several genes involved in immunity, which may reflect responses to endemic pathogens of the Americas and to the challenge of infectious disease brought by European contact. In addition, some of the strongest signals inferred to be under selection in the Native American ancestral groups of modern Latin Americans overlap with genes implicated in energy metabolism phenotypes, plausibly reflecting adaptations to novel dietary sources available in the Americas.

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Section: Resultsmentioning

confidence: 99%

Disentangling Signatures of Selection Before and After European Colonization in Latin Americans

Mendoza‐Revilla

Chacón-Duque

Fuentes-Guajardo

et al. 2022

Molecular Biology and Evolution

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show abstract

“…5c), which is implicated in macrophage function in host defense through the suppression of anti-inflammatory effects of glucocorticoids (Calandra and Roger 2003). Variants within MIF have been recently associated to rheumatoid arthritis in southern Mexican patients (Santoscoy-Ascencio et al 2020). The SNP rs2330635 (AdaptMix P-value=7.06×10 -8 ) is strongly associated to the expression of MIF in T-cells (eQTL P-value<8.63×10 -5 ) and NK cells (eQTL P-value=5.77×10 -9 ) and is also marginally associated to neutrophil counts (GWAS P-value=2.46×10 -6 ) (fig.…”

Section: Signals At Immune-related Genesmentioning

confidence: 99%

Disentangling signatures of selection before and after European colonization in Latin Americans

Mendoza‐Revilla

Chacon-Duque

Fuentes-Guajardo

et al. 2021

Preprint

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Throughout human evolutionary history, large-scale migrations have led to intermixing (i.e., admixture) between previously separated human groups. While classical and recent work have shown that studying admixture can yield novel historical insights, the extent to which this process contributed to adaptation remains underexplored. Here, we introduce a novel statistical model, specific to admixed populations, that identifies loci under selection while determining whether the selection likely occurred post-admixture or prior to admixture in one of the ancestral source populations. Through extensive simulations we show that this method is able to detect selection, even in recently formed admixed populations, and to accurately differentiate between selection occurring in the ancestral or admixed population. We apply this method to genome-wide SNP data of ~4,000 individuals in five admixed Latin American cohorts from Brazil, Chile, Colombia, Mexico and Peru. Our approach replicates previous reports of selection in the HLA region that are consistent with selection post-admixture. We also report novel signals of selection in genomic regions spanning 47 genes, reinforcing many of these signals with an alternative, commonly-used local-ancestry-inference approach. These signals include several genes involved in immunity, which may reflect responses to endemic pathogens of the Americas and to the challenge of infectious disease brought by European contact. In addition, some of the strongest signals inferred to be under selection in the Native American ancestral groups of modern Latin Americans overlap with genes implicated in energy metabolism phenotypes, plausibly reflecting adaptations to novel dietary sources available in the Americas.

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“…This in turn highlights the therapeutic value of steroids in conditions where IL-8 and MIF play a central role in disease onset and progression. Of note, both IL-8 and MIF have consistently been implicated in propagating inflammatory cascades in Inflammatory Bowel Disease (IBD) [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ], Rheumatoid Arthritis (RA) [ 41 , 42 , 43 , 44 , 45 , 46 ], Systemic Lupus Erythematosus (SLE) [ 47 , 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, administering anti-MIF antibodies has been shown to reduce the degree of inflammation in experimental models of inflammatory colitis and MIF-deficient mice are resistant to developing inflammatory colitis in the first place [ 38 ]. Similarly, numerous studies demonstrate a role for IL-8 [ 39 , 40 ] and MIF [ 41 , 42 ] in propagating synovial inflammation in Rheumatoid Arthritis and MIF gene promoter polymorphisms have been shown to correlate with the 28-joint Disease Activity Score [ 43 ]. Patients with SLE tend to have higher circulating IL-8 levels and this correlates with the SLE disease activity index [ 44 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

Morning Cortisol and Circulating Inflammatory Cytokine Levels: A Mendelian Randomisation Study

Rajasundaram

Rahman

Woolf

et al. 2022

Genes

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Cortisol exerts a broad anti-inflammatory effect on the immune system. Inflammatory cytokines contribute to the molecular signalling pathways implicated in various autoimmune and inflammatory conditions. However, the mechanisms by which cortisol modulates such signalling pathways remain uncertain. Leveraging summary-level data from the CORtisol NETwork (CORNET, n = 25,314) and FINRISK (n = 8293) genome-wide association studies, we used two-sample Mendelian randomisation to investigate the causal effect of genetically proxied increased morning cortisol levels on 42 circulating cytokines. We found that increased genetically proxied morning cortisol levels were associated with reduced levels of IL-8 and increased levels of MIF. These results provide mechanistic insight into the immunomodulatory effects of endogenous cortisol and the therapeutic effects of exogenous corticosteroids. Clinically, our findings underline the therapeutic importance of steroids in inflammatory conditions where IL-8 and MIF play a central pathophysiological role in the onset and progression of disease.

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Macrophage migration inhibitory factor promoter polymorphisms are associated with disease activity in rheumatoid arthritis patients from Southern Mexico

Cited by 9 publications

References 47 publications

Disentangling Signatures of Selection Before and After European Colonization in Latin Americans

Disentangling Signatures of Selection Before and After European Colonization in Latin Americans

Disentangling signatures of selection before and after European colonization in Latin Americans

Morning Cortisol and Circulating Inflammatory Cytokine Levels: A Mendelian Randomisation Study

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