Impact of MIF Gene Promoter Variations on Risk of Rheumatic Heart Disease and Its Age of Onset in Saudi Arabian Patients

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.

Immune-Related Comorbidities in Childhood-Onset Obsessive Compulsive Disorder: Lifetime Prevalence in the Obsessive Compulsive Disorder Collaborative Genetics Association Study

“…1): RA with SLE and psoriasis (Lin et al 1998; Alarcon-Segovia et al 2005; Naldi and Mercuri 2010), MS and asthma with psoriasis (Fang et al 2015; Egeberg et al 2016), and RF with scarlet fever and throat/ear infections (Soderholm et al 2018). We also found an association between IBD and RF, consistent with preliminary evidence for shared genetic risk (Abdallah et al 2016) and data linking IBD with other immune-mediated diseases (Halling et al 2017).…”

Single-nucleotide polymorphism and haplotype analysis of macrophage migration inhibitory factor gene and its correlation with serum macrophage migration inhibitory factor levels in North Indian psoriatic patients with moderate disease severity: A cross-sectional study

“…28,29 The choice of single-nucleotide polymorphisms tested in the present study was principally based on earlier reports. [9][10][11][12]14,15,18,28 Baugh et al identified a functionally significant polymorphism in the human MIF gene, consisting of CATT repeats at position -794 of the MIF promoter. 15 The 5-CATT repeat display lowers promoter activity when compared to the 6-, 7-, or 8 repeat alleles.…”

“…[3][4][5] Polymorphisms in the promoter region of MIF gene, that is, CATT tetranucleotide repeat at -794 (rs5844572) or guanine (G) to cytosine (C) transition at -173 (-173*G/C, rs755622) have been reported to be associated with increased susceptibility to, or severity of, numerous chronic inflammatory, and autoimmune disorders in different populations. [4][5][6][7][8][9][10][11][12][13][14][15][16] Given these data, the pharmacological or immunological modulation of MIF activity might offer new therapeutic options for patients suffering from these diseases. 6 We planned this study to see whether MIF gene polymorphisms affect the susceptibility to and severity of chronic plaque psoriasis.…”

The Genetic Control of the Rheumatic Heart: Closing the Genotype-Phenotype Gap

“…A few more genes have been linked to RHD in different studies, but there are currently no meta-analyses to confirm or reject these findings. Macrophage migration inhibitory factor ( MIF ) promoter polymorphisms -173C and -794 (5-8 CATT repeats) have been associated with RHD age of onset in a Saudi Arabian population ( 53 ). The C allele at−173 was associated with higher MIF expression in T cell lines ( 54 ).…”