RESUMO
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.
Assuntos
Miosinas Cardíacas/genética , Cardiomiopatia Dilatada/genética , Laminina/genética , Mutação de Sentido Incorreto , Cadeias Pesadas de Miosina/genética , Doenças Raras/genética , Estudos de Coortes , Ecocardiografia , Feminino , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Saúde do Lactente , Masculino , Linhagem , Arábia SauditaRESUMO
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.
Assuntos
Interleucina-10/genética , Polimorfismo de Nucleotídeo Único , Cardiopatia Reumática/genética , Adulto , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Masculino , Regiões Promotoras Genéticas , Cardiopatia Reumática/epidemiologia , Arábia Saudita/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Rheumatic Heart Disease (RHD) remains a major cause of cardiovascular diseases and the most devastating effects are shown on children and young adults. RHD is caused due to the interaction between microbial, environmental, immunologic, and genetic factors. The Renin- Angiotensin Aldosterone System (RAAS) has been strongly implicated as the susceptibility pathway in the pathogenesis of the cardiovascular disease. OBJECTIVE: The present study investigated the modulating effect of Angiotensin II type 1 receptor (AGTR1) 1166A>C polymorphism on the RHD and its clinical features in Saudi Arabia. METHODS: AGTR1 1166A>C polymorphism was genotyped in 96 echocardiographically confirmed RHD patients and 142 ethnically matched controls by the TaqMan allelic discrimination method. RESULTS: Genotype distribution of the AGTR1 1166A>C polymorphism was not significantly different between RHD and control groups. Furthermore, AGTR1 1166A>C genotypes are not associated with the clinical features of RHD. These data support that there was no evidence for an association between AGTR1 1166A>C polymorphism and RHD in Saudi Arabia. CONCLUSION: To the best of our knowledge, this is the first study that has investigated the possible association between AGTR1 1166A>C polymorphism and susceptibility to RHD and its clinical features. Even though the AGTR1 gene, 1166A>C (rs5186), was reported to be associated with hypertension, left ventricular hypertrophy and coronary heart disease. The present study did not find any association between AGTR1 1166A>C polymorphism and RHD in Saudi Arabia. Further studies are needed to confirm our findings.
Assuntos
Predisposição Genética para Doença/genética , MicroRNAs/genética , Receptor Tipo 1 de Angiotensina/genética , Cardiopatia Reumática/genética , Sítios de Ligação/genética , Doenças Cardiovasculares/genética , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Sistema Renina-Angiotensina/genética , Arábia Saudita , Adulto JovemRESUMO
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.