Is the Association of the Rare rs35667974 IFIH1 Gene Polymorphism With Autoimmune Diseases a Case of RNA Epigenetics?

Interferon induced with helicase C domain-containing protein 1 (IFIH1) gene encodes a cytoplasmic RNA helicase otherwise known as melanoma differentiation-associated 5 (MDA5), a RIG-1-like RNA helicase that recognizes viral RNA and is involved in innate immunity through recognition of viral RNA. Upon binding to double-stranded (ds) RNA, MDA5 forms a filamentous assembly along the length of dsRNA and utilizes molecular signatures to discriminate self, versus non-self on the basis of dsRNA length and methylation. Its missense variant rs35667974 is protective for type 1 diabetes, psoriasis, and psoriatic arthritis, but is also found to be associated with an increased risk for ankylosing spondylitis, Crohn's disease, and ulcerative colitis. To gain insight into the complex role of this variant we performed a structural analysis of MDA5 in complex with dsRNA using molecular dynamics simulations. Our data suggest that while the Ile923Val mutation of the rs35667974 variant does not affect binding to native dsRNA significantly, it displays a destabilizing effect in the presence of 2'-O uridine methylation. Thus, the presence of 2'-O-methylation at the dsRNA introduces a sensing signature that leads to selective reduction of the overall MDA catalytic activity. This study represents an evaluation of the role of the shared rs35667974 variant of autoimmune locus IFIH1, reported to lead to selectively reduced catalytic activity of the modified MDA5 phenotype and, as a consequence, reduced negative feedback on cytokine and chemokine signaling and selectively protection against autoimmunity.

Increased risk of rheumatoid arthritis in patients with endometriosis: genetic aspects.

RA is an inflammatory joint disease of an autoimmune nature, with a complex mode of inheritance characterized by chronic and destructive inflammation in the peripheral joints of the hands and feet and irreversible disability. This disorder occurs more often in women, and reproductive and hormonal factors have been shown to be related to increased risk. Endometriosis is a chronic, complex, oestrogen-dependent and progressive gynaecological disorder characterized by the growth of endometrial tissue outside the uterine cavity. Thus far, substantial abnormalities in the immune system of women with endometriosis have been demonstrated. Epidemiological data have suggested a link between endometriosis and the risk of incident RA. The similarities between molecular and cellular pathways of endometriosis and RA may implicate a partially shared genetic background. In this review we present an overview of the shared genetic factors known thus far that are associated with the development of both disorders.

C1q Gene Polymorphism Is Associated with Asymptomatic Bacteriuria in Patients with Type 2 Diabetes Mellitus.

Background and Objectives: Asymptomatic bacteriuria (ASB) appears to have a higher prevalence in diabetics and has been associated with various genetic polymorphisms of the innate immune system. Single nucleotide polymorphisms (SNPs) of the C1q gene that encodes for the trigger molecule of the classical complement pathway increase the risk of bacterial infections as well as other diseases. In the present study, we sought to investigate the association of C1q rs292001 (G > A) SNP with ASB in patients with type 2 diabetes (T2D). Materials and Methods: In this case-control study, performed at the University and the Venizeleion General Hospital of Heraklion, Crete, Greece, 75 adult male and female Cretan patients with T2D and ASB and 75 adult male and female Cretan patients with T2D but without ASB were enrolled and genotyped for rs292001 SNP of C1q gene. Genetic analysis was based on the polymerase chain reaction (PCR) and restriction fragment length polymorphisms (RLFPs) methods. Results: Τhe frequency of homozygotes for the G/G genotype of C1q rs292001 was significantly higher in patients with T2D and ASB than in the control group (p-value = 0.0480, OR = 2.952, 95% CI: 1.052−7.542). Conclusions: Τhe present study provides the first evidence of an association between the C1q rs292001 SNP and an increased susceptibility for ASB in an adult Cretan population with T2D, thus suggesting that this SNP can be encountered as a risk factor for the presence of ASB in patients with T2D.

Coexistence of cervical endometriosis with premalignant and malignant gynecological pathologies: report on a series of 27 cases.

Although cervical endometriosis represents a rare condition, there is evidence that implicates a complex interaction with other gynecological pathologies. This study aims to highlight this entity and further to explore the impact of oncological pathology of female genital tract on patients with cervical endometriosis. We retrospectively investigated the medical and pathological reports of 27 cases with cervical endometriosis, which were diagnosed by tissue biopsy. The results of the study show a relationship between CIN (cervical intraepithelial neoplasia) cases 19/27 (70percent) and cervical endometriosis. CIN I was more frequently found compared to patients with CIN II and CIN III. Furthermore, a high prevalence of HPV (human papilloma virus) was confirmed. Out of 27 patients, 2 cases with cervical (7.4percent), 2 with endometrial (7.4percent) and 3 with ovarian cancer (11.1percent) were detected. We confirmed the coexistence of more than one malignant gynecological pathology with cervical endometriosis in four cases (14.8percent). To conclude, cervical endometriosis is a rare disease co-existing considerably with premalignant and malignant gynecological conditions according to our data. Although the pathophysiology and genetics of cervical dysplasia is well delineated, further research is needed to establish the association between cervical endometriosis and gynecological premalignant and malignant pathology.

Identification and characterization of a rare variant in apolipoprotein A-IV, p.(V336M), and evaluation of HDL functionality in a Greek cohort with extreme HDL cholesterol levels.

High-Density Lipoprotein cholesterol (HDL-C) levels do not correlate well with Coronary Artery Disease (CAD) risk, while HDL functionality affects atherogenesis and is a better prognostic marker for CAD. Often, the extreme HDL-C levels have a multigenic origin. Here, we searched for single-nucleotide polymorphisms (SNPs) in ten genes of HDL metabolism in a Greek cohort with very low (<10th percentile, n = 13) or very high (>90th percentile, n = 21) HDL-C. We also evaluated the association between HDL-C levels, HDL functionality (anti-oxidant capacity) and CAD in the subjects of this cohort. Individuals with low HDL-C levels had higher triglyceride levels, lower apoA-I levels, decreased HDL anti-oxidant capacity and higher incidence of CAD compared with individuals with control or high HDL-C levels. With next generation sequencing we identified 18 exonic SNPs in 6 genes of HDL metabolism and for selected amino acid changes we performed computer-aided structural analysis and modeling. A previously uncharacterized rare apolipoprotein A-IV variant, apoA-IV [V336M], present in a subject with low HDL-C (14 mg/dL) and CAD, was expressed in recombinant form and structurally and functionally characterized. ApoA-IV [V336M] had similar α-helical content to WT apoA-IV but displayed a small thermodynamic stabilization by chemical unfolding analysis. ApoA-IV [V336M] was able to associate with phospholipids but presented reduced kinetics compared to WT apoA-IV. Overall, we identified a rare apoA-IV variant in a subject with low HDL levels and CAD with altered biophysical and phospholipid binding properties and showed that subjects with very low HDL-C presented with HDL dysfunction and higher incidence of CAD in a Greek cohort.

Immunoglobulin and B-cell disturbances in patients with chronic idiopathic neutropenia.

Chronic idiopathic neutropenia (CIN) is a granulocytic disorder associated with presence of activated, myelosuppressive T-lymphocytes. In the present study we have evaluated constituents of humoral immunity in CIN patients (n=48) compared to healthy controls (n=52). CIN patients displayed lower serum IgG levels due to a reduction in IgG1, IgG3, IgG4 but not IgG2, lower IgA and increased IgM levels compared to controls. The proportion of CD19+ cells did not differ between patients and controls; however the proportion of the naïve IgD+/CD27- B-cells was increased and the proportion of class-switched memory IgD-/CD27+ B-cells was decreased in the patients. The percentage of CD40+ B-cells did not differ between patients and controls and no aberrations in the CD40-meadiated signal transduction pathway or in CD40-gene polymorphisms were identified. These data provide further evidence that immune disturbances are associated with the pathophysiology of CIN and point out for the first time the implication of the B-cell system.