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MIF (macrophage migration inhibitory factor) promoter polymorphisms and susceptibility to severe malarial anemia
Gordon A Awandare1, Jeremy J Martinson, Tom Were
1Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Background:
Severe malarial anemia (SMA) resulting from Plasmodium falciparum infection is one of the leading causes of childhood mortality in sub-Saharan Africa. The innate immune mediator macrophage migration inhibitory factor (MIF) plays a critical role in the pathogenesis of SMA.
Methods:
To investigate the influence of MIF genetic variation on susceptibility to SMA, haplotypes of the MIF -173G/C and -794CATT5-8 polymorphisms were examined in a cohort of Kenyan children.
Results:
A statistically significant relationship between increasing frequencies of longer CATT repeats at -794 and increasing severity of malarial anemia was observed. In addition, there was a strong association between lower MIF concentrations and longer CATT repeats. Multivariate logistic regression analyses demonstrated that the 6G haplotype (ie, MIF -794CATT6/-173G) was associated with protection against SMA, whereas carriers of the 7C or 8C haplotype had increased risk of developing SMA. Furthermore, carriers of the 7C or 8C haplotype had reduced plasma MIF levels during acute disease.
Conclusions:
The findings demonstrate that variation in the MIF promoter influences susceptibility to SMA and peripheral MIF production. However, the MIF -173 and -794 polymorphisms appear to have both independent and interactive effects on different measures of disease severity, suggesting that MIF plays a complex role in malarial pathogenesis.
Insights
Genetic variations in macrophage migration inhibitory factor (MIF) influence susceptibility to severe malarial anemia (SMA). Specific MIF haplotypes offer protection, while others increase SMA risk and reduce MIF levels in children.
Area of Science:
- Immunogenetics
- Infectious Disease Pathogenesis
- Human Genetics
Background:
- Severe malarial anemia (SMA) is a major cause of child mortality in sub-Saharan Africa.
- Macrophage migration inhibitory factor (MIF) is an innate immune mediator critical in SMA pathogenesis.
Purpose of the Study:
- To investigate the impact of genetic variations in the MIF gene promoter on susceptibility to SMA.
- To analyze the relationship between MIF polymorphisms and MIF production in children.
Main Methods:
- Examined haplotypes of MIF -173G/C and -794CATT5-8 polymorphisms in Kenyan children.
- Utilized multivariate logistic regression to assess associations with SMA severity and plasma MIF levels.
Main Results:
- Longer CATT repeats at the -794 locus correlated with increased SMA severity.
- The 6G haplotype provided protection against SMA, while 7C and 8C haplotypes increased risk.
- Longer CATT repeats and 7C/8C haplotypes were associated with lower plasma MIF levels.
Conclusions:
- MIF promoter variations significantly influence SMA susceptibility and peripheral MIF production.
- MIF polymorphisms exhibit complex, interactive effects on SMA pathogenesis and disease severity.
- Genetic variation in MIF plays a crucial role in the host response to Plasmodium falciparum infection.
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