Abstract
Although macrophage migration inhibitory factor (MIF) has consistently been shown to be an important immune modulator, data on the association between MIF promoter variations and the risk of developing rheumatic heart disease (RHD) remain inconclusive. RHD is an important complication of streptococcal infections in the Middle East, not least in Saudi Arabia, and identifying risk markers is an important priority. Therefore, we investigated the association between two functional MIF promoter variations and RHD susceptibility and severity in Saudi patients: the MIF-173G > C substitution (rs755622) and the MIF-794 CATT5–8 tetranucleotide repeat (rs5844572). Three hundred twenty-six individuals (124 RHD patients and 202 age-, sex-, and ethnically matched healthy controls) were genotyped using allelic discrimination and fragment analysis. Data were analyzed with respect to disease susceptibility, severity, sex, and age of onset. There was a significantly lower frequency of 173C allele carriage in RHD patients compared to controls [odds ratio (OR) = 0.47; 95% confidence intervals (CIs) = 0.28–0.77; p = 0.003]. Interestingly, the 173C allele was associated with late disease onset (p = 0.001). The 794 5-repeat allele was associated with decreased RHD risk (OR = 0.56; 95% CIs = 0.38–0.82; p = 0.003). In contrast, the 794 6-repeat allele was associated with increased risk of RHD (OR = 1.7; 95% CIs = 1.2–2.5; p = 0.002). MIF promoter variations appear to have a dual role in RHD, with 173C allele non-carriers at higher risk of developing RHD at a younger age. These results require further validation in larger multi-ethnic cohorts, and functional studies are necessary to understand the underlying molecular mechanisms driving the at-risk phenotype.
Highlights
Rheumatic heart disease (RHD) is an autoimmune disease that can develop following throat infections with one of the group A beta-hemolytic streptococci (GAS)
We report that the pleiotropic inflammatory cytokine migration inhibitory factor (MIF) exerts dual effects in RHD patients
The 173C allele was associated with reduced RHD risk and, interestingly, this genotype was associated with later disease onset
Summary
Rheumatic heart disease (RHD) is an autoimmune disease that can develop following throat infections with one of the group A beta-hemolytic streptococci (GAS). Standard antibiotic treatments are effective and help to prevent the disease, RHD is a common source of acquired pediatric heart disease in many developing nations [1], to the extent that the World Health. RHD is an important and ongoing cause of cardiac disease in indigenous populations in developed countries [5, 6]. In a hospital-based study of children admitted with rheumatic fever (RF), the precursor of RHD, in Saudi Arabia, carditis was reported in 53% and severe carditis in 32% of cases [7]. Molecular mimicry is thought to trigger RHD [9]; the exact mechanisms underlying autoimmunity and cardiac tissue damage remain unknown
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