Genetic Variant rs755622 Regulates Expression of the Multiple Sclerosis Severity Modifier D-Dopachrome Tautomerase in a Sex-Specific Way

Abstract

Multiple sclerosis (MS) is a sex-specific autoimmune disease involving central nervous system. Previous studies determined that macrophage migration inhibitory factor (MIF) and its homologue D-dopachrome tautomerase (DDT) sex-specifically affect MS progression. Moreover, other studies reported that rs755622 polymorphism in promoter region of MIF gene is associated with risk of MS and affects the promoter activity to regulate MIF expression in a sex-specific way. Given that MIF and DDT share a part of promoter sequence, we surmise that rs755622 can also regulate DDT expression in a sex-specific way. However, this has not yet been studied. Here, we used five large-scale expression quantitative trait loci (eQTLs) and two RNA-seq datasets from brain and blood to assess the potential influence of rs755622 variant on expression of DDT in different genders by the linear regression and differential expression analysis. The results show that the minor allele frequency of rs755622 and expression of DDT are significantly increased in males for MS subjects and this minor allele variant can significantly upregulate DDT expression for males but not females, which suggests that the regulation of DDT expression level by rs755622 can affect MS progression in males. These findings further support and expand conclusions of previous studies and may help to better understand the mechanisms of MS.

Correlation between Plasma Macrophage Migration Inhibitory Factor Levels and Long-Term Prognosis in Patients with Acute Myocardial Infarction Complicated with Diabetes

“…These results are consistent with a previous study, which reported that stress could elevate MIF levels in patients [14]. Further, these results suggest that MIF has a sex-specific effect, as was reported in a MS disease study [16, 17]. We found no difference in MIF levels between male and female patients or male and female healthy controls, but different levels of plasma MIF between the stress-induced hyperglycemia and the euglycemia groups were only found in male patients, suggesting that the pathogenetic effects of MIF in nondiabetes STEMI are sex dependent.…”

Upregulated Expression of Macrophage Migration Inhibitory Factor, Its Analogue D-Dopachrome Tautomerase, and the CD44 Receptor in Peripheral CD4 T Cells from Clinically Isolated Syndrome Patients with Rapid Conversion to Clinical Defined Multiple Sclerosis

“…It is hypothesized the inverse regulation of MIF/CD74 and CXCR4 expression in B cells in CIS patients with rapid development of CDMS may witness the existence of an immature B cell populations with senescent features, that escaped peripheral tolerance [21]. Clearly, the data of Rijvers and coworkers [21] differ from our own present analysis and the previous study indicating increased levels of MIF during CIS [20], as well as with the increasing evidence of upregulated secretion and signaling of MIF and DDT in MS and its rodent counterpart [8,9,22,23]. The reasons for these divergent findings are difficult to explain and remain to be established having in mind the possible occurrence of multiple variables, including sex and age of the patients in the different studies, along with presenting clinical characteristics, including body mass index and eventually misdiagnosed comorbidities.…”

A Polymorphism Within the MBP Gene Is Associated With a Higher Relapse Number in Male Patients of Multiple Sclerosis

“…Recent studies have pointed to other genetic polymorphisms that affect MS only in male patients (13,14) that could explain part of the difference in prevalence and course of MS between sexes. We observe a trend for a lower expression of CD69 in activated CD3 + cells in male patients carrying rs12959006 * T allele.…”