Impact of the MIF -173G/C variant on cardiovascular disease risk: a meta-analysis of 9,047 participants.

Introduction: Many factors contribute to the risk of cardiovascular disease (CVD), an umbrella term for several different heart diseases, including inflammation. Macrophage migration inhibitory factor (MIF) is an important immune modulator that has been shown to be involved in the pathogenesis of different heart diseases, so understanding pathogenic variants of the MIF gene is important for risk stratification. We therefore conducted a meta-analysis to investigate whether the MIF -173G/C (rs755622) polymorphism is associated with CVD. Methods: The PubMed, Science Direct, and Embase databases were searched from inception to June 2023 for case-control studies of the MIF -173G/C polymorphism and its relationship to any type of CVD. Correlations between the MIF -173G/C polymorphism and CVD were estimated by pooling the odds ratios (ORs) with 95% confidence intervals in allelic, dominant, and recessive models using random-effects meta-analysis. Results: A total of 9,047 participants (4141 CVD cases and 4906 healthy controls) from 11 relevant studies were included. In the total population, there was no significant association between the MIF -173G/C (rs755622) polymorphism and the risk of developing CVD in the three different models. In a stratified analysis by ethnicity, the allelic model (C vs G) was significantly associated with CVD in the Arab and Asian populations (OR = 0.56, CI 0.42 -0.75 and OR = 1.28, CI 1.12 -1.46, respectively); the dominant model (CC+CG vs GG) was significantly associated with CVD in the Arab population (OR = 0.42, CI 0.30 -0.61); while the recessive model (GG+GC vs CC) was associated with CVD susceptibility in the Arab population (OR = 3.84, CI 1.57 -9.41). There were no significant associations between the MIF -173 G/C polymorphism and CVD risk in the European population. Conclusion, the MIF -173G/C polymorphism is associated with CVD in some populations. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, PROSPERO (CRD42023441139).

Awareness and Management of Knee Pain and Osteoarthritis in Saudi Arabia: A Cross-Sectional Analysis.

OBJECTIVE:  The study sought to assess the level of awareness regarding osteoarthritis and its management. METHODS:  This study was cross-sectional, using data from a sample of 389 individuals from the central region of Saudi Arabia. The participants completed an online questionnaire and ensured anonymity.  Results: A total of 389 participants made up the sample for this study, which had a predominance of females (56.6%, n=220), a majority aged <50 years (66.6%, n=259), and most of them (51.7%, n=201) weighing 60-80 kg, substantial proportion lived in the Riyadh region (27.5%, n=107), with more than half (59.4%, n=231) having a university education and working in offices (28.3%, n=110). The majority (73.3%, n=285) of participants were married, and a vast majority (87.9%, n=342) were not smokers. The findings revealed that only 32.9% (n=128) of the participants had good knowledge about osteoarthritis. The study found that stiffness (80.2%, n=312) and swelling (97.9%, n = 381) are the most common signs and symptoms of osteoarthritis; the risk factors for osteoarthritis were genetic factors (79.7%, n=310) and age (91.3%, n=355). The treatment of osteoarthritis identified in the study included exercises such as swimming (85.1%, n=331), physical therapy (86.6%, n=337), and joint replacement surgery (92.0%, n=358). The study established a statistically significant association between age, education level, previous diagnosis of osteoarthritis, family history of osteoarthritis (p = 0.004, 0.001, 0.002, and 0.001, respectively), and level of knowledge about osteoarthritis. However, there was no statistically significant association between gender, marital status, smoking status, previous knee injuries, physical activity level, and the level of knowledge about osteoarthritis (p > 0.05).  Conclusion: Overall, the study revealed that 32.9% (n=128) of the participants had good knowledge about osteoarthritis. Participants aged 50-60 years, those with a university and post-graduate level of education, as well as those who had a previous diagnosis of osteoarthritis and those with a family history of osteoarthritis, had greater and better knowledge and awareness about osteoarthritis. Joint stiffness and swelling were identified, as the most common signs and symptoms of osteoarthritis. The risk factors identified in the study were genetic factors and age, while the treatment options noted by the study were exercise, such as swimming, physical therapy, and joint replacement surgery. The study notes the need for enhanced public awareness of the problems associated with osteoarthritis among the Saudi Arabian population.

Digenic Inheritance of LAMA4 and MYH7 Mutations in Patient with Infantile Dilated Cardiomyopathy.

Background and objectives: Dilated cardiomyopathy (DCM) is a rare cardiac disease characterised by left ventricular enlargement, reduced left ventricular contractility, and impaired systolic function. Childhood DCM is clinically and genetically heterogenous and associated with mutations in over 100 genes. The aim of this study was to identify novel variations associated with infantile DCM. Materials and Methods: Targeted next generation sequencing (NGS) of 181 cardiomyopathy-related genes was performed in three unrelated consanguineous families from Saudi Arabia. Variants were confirmed and their frequency established in 50 known DCM cases and 80 clinically annotated healthy controls. Results: The three index cases presented between 7 and 10 months of age with severe DCM. In Family A, there was digenic inheritance of two heterozygous variants: a novel variant in LAMA4 (c.3925G > A, p.Asp1309Asn) and a known DCM mutation in MYH7 (c.2770G > A; p.Glu924Lys). The LAMA4 p.Asp1309Asn variant was predicted to be likely pathogenic according to international guidelines. The other two families had no identifiable potentially deleterious variants. Conclusions: Inheritance of two genetic variants may have a synergistic or dose effect to cause severe DCM. We report of a novel p.Asp1309Asn variation associated with DCM. Targeted NGS is useful in the molecular diagnosis of DCM and to guide whole-family management and counselling.

Targeted Next-Generation Sequencing of 406 Genes Identified Genetic Defects Underlying Congenital Heart Disease in Down Syndrome Patients.

Down syndrome (DS) is the most common autosomal chromosome anomaly. DS is frequently associated with congenital heart disease (CHD). Patients with DS have 40-60% chance of having CHD. It means that CHD in DS is not only due to trisomy 21 and there are some other genetic factors underlying CHD in DS children. In this study, a total of 240 DNA samples from patients were analyzed including 100 patients with CHD only, 110 patients having CHD along with DS and 30 patients with isolated DS. A cardiovascular gene panel consisting of probes for 406 genes was used to screen DNA samples of all 240 patients for mutation identification. All variants were annotated and common variants were obtained. Briefly, 28 common variants (variants common in two or more than two individuals) were obtained in a group of samples containing DNA from DS patients having CHD as well, 63 variants were found to be unique to DS group of samples and 73 variants have been identified in patients with CHD only. In order to identify genomic variations determining the risk for CHD in DS, only those variants present in DS-CHD group and absent in isolated CHD and/or isolated DS group were considered for further analysis. Variants specific to DS-CHD group were further evaluated based on expression and function data and pathogenicity of the variant of interest. We have implicated mutations in GATA3, KCNH2, ENG, FLNA, and GUSB genes as an underlying risk factor for CHD in DS patients.

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

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.

IL10 Promoter Polymorphisms are Associated with Rheumatic Heart Disease in Saudi Arabian Patients.

Rheumatic heart disease (RHD) is an inflammatory disease that develops following streptococcal infections. IL10 helps to balance immune responses to pathogens. IL10 polymorphisms have been associated with RHD, although results remain inconclusive. Our aim was to investigate the association between IL10 polymorphisms and RHD in Saudi Arabian patients. IL10 promoter polymorphisms (-1082A/G, -829C/T, and -592C/A) were genotyped in 118 RHD patients and 200 matched controls using the TaqMan allelic discrimination assay. There was a significant difference in IL10-1082 genotype frequency between patients and controls (p = 0.01). -1082G allele carriage (GG+GA vs AA) and the (-1082, -819, -592) GCC haplotype carriage were associated with an increased risk of RHD (p = 0.004, OR 2.1, 95% CIs 1.7-3.4 and p = 0.004, OR 2, 95% CIs 1.3-3.4, respectively). The ACC haplotype was associated with a decrease in RHD risk (p = 0.015, OR 0.6, 95% CIs 0.4-0.9). IL10 promoter polymorphisms may play an important role in the development of RHD and provide an opportunity for therapeutic stratification.