👤 Fares Barakat

Depression is prevalent among colorectal cancer (CRC) survivors. Although various physical activity intensities are differentially associated with depressive symptoms, the underlying mediator and moderator involving interoception and mindfulness, remain unclear. This study aims to examine whether interoceptive accuracy differentially mediates the relationship between various physical activity intensities and depressive symptoms and whether mindfulness moderates these pathways. In this multicenter cross-sectional study, 395 CRC survivors completed validated questionnaires assessing depressive symptoms, physical activity participation, interoceptive accuracy, and mindfulness. Mediation and moderated mediation analyses via PROCESS version 4.1 for SPSS tested whether interoceptive accuracy mediated associations between light and moderate-to-vigorous physical activity (LPA vs. MVPA) and depressive symptoms, and whether mindfulness moderated these pathways. Both LPA and MVPA are negatively associated with depressive symptoms (p < 0.001). Interoceptive accuracy significantly mediated these associations, accounting for 49.09% of the total effect for LPA and 20.56% for MVPA. Mindfulness moderated the LPA-interoceptive accuracy (B = -0.004, p = 0.031), interoceptive accuracy-depression (B = -0.022, p = 0.004), and MVPA-depression pathways (B = -0.001, p = 0.034), suggesting differential, intensity-dependent associations. LPA showed negative associations with depressive symptoms, with interoceptive accuracy fully mediating this association. In contrast, MVPA demonstrated both direct and indirect associations with depressive symptoms, partially mediated by interoceptive accuracy. Mindfulness strengthened these relationships through complementary and synergistic moderation, highlighting the dynamic interaction between bodily awareness and physical activity in psychological recovery. Tailoring gentle, mindful movement to enhance interoception may offer a feasible, integrative rehabilitation strategy to reduce depression among CRC survivors. Show less

Microtubule-actin cross-linking factor 1 (MACF1) is a large protein of the spectraplakin family, which is essential for brain development. MACF1 interacts with microtubules through the growth arrest-specific 2 (Gas2)-related (GAR) domain. Heterozygous MACF1 missense variants affecting the zinc-binding residues in this domain result in a distinctive cortical and brain stem malformation. Evidence for other MACF1-associated disorders is still limited. Here, we present a cohort of 45 individuals with heterozygous or bi-allelic MACF1 variants to explore the phenotypic spectrum and assess possible pathogenic relevance. We observe that de novo heterozygous missense variants in the EF-hand domains also result in distinctive brain malformation and provide experimental evidence that variants in the EF-hand/GAR module increase microtubule binding, suggestive of a toxic gain of function. Notably, no phenotype-genotype correlation was possible for the remaining heterozygous variants in other domains. A clinical review of eight families with bi-allelic variants reveals a possible complex neurodevelopmental syndrome of the central and peripheral nervous systems. In these individuals, bi-allelic variants mostly affect the Plakin domain. Furthermore, RNA sequencing and chromatin immunoprecipitation (ChIP) analyses of human fetal brain tissue reveal five MACF1 isoforms with region-specific expression, differing in their exon 1 transcription start sites but splicing to a common exon 2. This differential expression explains the frontal-predominant lissencephaly in an individual with a homozygous stop-gain in exon 1 (MACF1-204: c.70C>T [p.Arg24∗]), as this isoform is preferentially expressed in the frontal cortex. We conclude that MACF1-related disorders are strictly linked to domain function and the level of transcript expression, explaining the observed wide clinical heterogeneity. Show less

Refractive error (RE) and myopia are complex polygenic conditions with the majority of genome-wide associated genetic variants in non-exonic regions. Given this, and the onset during childhood, gene-regulation is expected to play an important role in its pathogenesis. This prompted us to explore beyond traditional gene finding approaches. We performed a genetic association study between variants in non-coding RNAs and enhancers, and RE and myopia. We obtained single-nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes, miRNA-binding sites, long non-coding RNAs genes (lncRNAs) and enhancers from publicly available databases: miRNASNPv2, PolymiRTS, VISTA Enhancer Browser, FANTOM5 and lncRNASNP2. We investigated whether SNPs overlapping these elements were associated with RE and myopia leveraged from a large GWAS meta-analysis (N = 160,420). With genetic risk scores (GRSs) per element, we investigated the joint effect of associated variants on RE, axial length (AL)/corneal radius (CR), and AL progression in an independent child cohort, the Generation R Study (N = 3638 children). We constructed a score for biological plausibility per SNP in highly confident miRNA-binding sites and enhancers in chromatin accessible regions. We found that SNPs in two miRNA genes, 14 enhancers and 81 lncRNA genes in chromatin accessible regions and 54 highly confident miRNA-binding sites, were in RE and myopia-associated loci. GRSs from SNPs in enhancers were significantly associated with RE, AL/CR and AL progression. GRSs from lncRNAs were significantly associated with all AL/CR and AL progression. GRSs from miRNAs were not associated with any ocular biometric measurement. GRSs from miRNA-binding sites showed suggestive but inconsistent significance. We prioritized candidate miRNA binding sites and candidate enhancers for future functional validation. Pathways of target and host genes of highly ranked variants included eye development (BMP4, MPPED2), neurogenesis (DDIT4, NTM), extracellular matrix (ANTXR2, BMP3), photoreceptor metabolism (DNAJB12), photoreceptor morphogenesis (CHDR1), neural signaling (VIPR2) and TGF-beta signaling (ANAPC16). This is the first large-scale study of non-coding RNAs and enhancers for RE and myopia. Enhancers and lncRNAs could be of large importance as they are associated with childhood myopia. We provide a confident blueprint for future functional validation by prioritizing candidate miRNA binding sites and candidate enhancers. Show less

Coronary artery diseases (CAD) are clinical cardiovascular events associated with dyslipidemia in common. The interaction between environmental and genetic factors can be responsible for CAD. The present paper aimed to examine the association between c.56C > G (rs3135506) APOA5 gene polymorphism and CAD in Moroccan individuals and to perform an association update meta-analysis. The c.56C > G variant was genotyped in 122 patients with CAD and 134 unrelated controls. Genetic association analysis and comparison of biochemical parameters were performed using The case-control study data showed that the c.56C > G polymorphism was associated with CAD susceptibility under codominant ( Our case-control study revealed a significant association between c.56C > G polymorphism and CAD in the Moroccan population. In addition, meta-analysis data supported the implication of this polymorphism in CAD susceptibility. Show less

Apolipoprotein A5 (APOA5) has been linked to metabolic syndrome (MetS) in several populations. In North Africa, only the Tunisian and Moroccan populations were investigated. Our aim is to assess the association between APOA5 gene variant (rs662799) and haplotypes with MetS in Tunisian population and to perform a meta-analysis in North Africa. A total of 594 Tunisian participants were genotyped for polymorphism rs662799 using KASPar technology. Two polymorphisms rs3135506 and rs651821 in APOA5 gene genotyped in our previous study, were used in addition to rs662799 to assess the haplotype association with MetS. The genotype of 875 participants was used for the meta-analysis. Statistical analyses were performed with R software. The rs662799 increases the risk of MetS under the dominant (P=0.018) and the additive models (P=0.028) in the Tunisian population. After stratification of the cohort following the sex and the geographic origin, a positive association of rs662799 with MetS was found for participant from the Northern region and for the women group. Only the haplotype AGT showed a significant association with MetS by decreasing the risk of the disease. The meta-analysis reported a significant association of rs662799 and rs3135506 with MetS. Our results showed a significant association between the APOA5 gene variants rs662799 and haplotypes with MetS and its traits in Tunisia. An impact of the sex and the geographic origin on the genotype distribution was highlighted. Our funding emphasizes the role of APOA5 in the development of MetS in North Africa. Show less

This study aimed to analyze the association between UBE2E2, G6PC2, PROX1, DUSP9, ADCY5 and APOC3 polymorphisms and the risk of metabolic syndrome (MetS) in Moroccan patients. The study was applied on 316 unrelated individuals from Morocco, 177 MetS patients and 139 controls. The metabolic syndrome was diagnosed according to the International Diabetes Federation (IDF) criteria. All subjects were genotyped for the following polymorphisms: rs7612463 (UBE2E2), rs560887 (G6PC2), rs340874 (PROX1), rs5945326 (DUSP9), rs11708067 (ADCY5) and rs5128 (APOC3) using TaqMan allelic discrimination assay and PCR-RFLP. The rs5128 (APOC3) and rs340874 (PROX1) polymorphisms were found to be significantly associated with susceptibility to MetS (P=0.003 and P=0.033, respectively), with odds ratios (ORs) of 4.39 (95% CI=1.66-11.56) and 2.81 (95% CI=1.09-7.27), respectively. Two variants presented a tendency to be protector factors against MetS risk: rs5945326 in DUSP9 gene (OR=0.32; 95% CI=0.17-0.62; =0.001) and rs11708067 in ADCY5 gene (OR=0.51; 95% CI=0.28-0.95; P=0.034). No association was detected between rs7612463 (UBE2E2) and rs560887 (G6PC2) SNPs and MetS increased risk. This study suggests a potential role of rs5128, rs340874, rs5945326 and rs11708067 variants in MetS susceptibility in the Moroccan population. Show less

The aim of the present study is to explore the association between the APOA5 polymorphisms and haplotypes with obesity in Moroccan patients. The study was performed in 459 subjects, Obese (n=164) and non-obese (n=295). All subjects were genotyped for the APOA5 -1131T>C (rs662799) and c.56C>G (rs3135506) polymorphisms. The contribution of APOA5 polymorphisms and haplotypes in the increased risk of obesity were explored using logistic regression analyses. The -1131T>C and c.56C>G polymorphisms were significantly associated with obesity. Both polymorphisms were strongly associated with increased BMI. Analysis of constructed haplotypes showed a significant association between CG haplotype and susceptibility to obesity (OR [95%CI]=3.09 [1.93-4.97]; P<0.001). These results support a potential role for APOA5 common variants and related haplotypes as risk factors for obesity. Show less

In this case-control study we investigated the relative contribution of commons APOA5 polymorphisms and haplotypes to the risk of metabolic syndrome in Moroccan patients. Using the International Diabetes Federation (IDF) criteria for metabolic syndrome, the study included 176 patients and 105 controls. We genotyped APOA5 polymorphisms (-1131 T > C, c.56C > G, c.553G > T and c.1259 T > C) by PCR-RFLP analysis. The effects of APOA5 polymorphisms and constructed haplotypes on metabolic syndrome were estimated using logistic regression analyses. The statistical analysis showed a significant association between APOA5 -1131 T > C and APOA5 c.56C > G polymorphisms with metabolic syndrome in both Codominant and Dominant models. The APOA5 -1131 T > C polymorphism was associated with increased fasting glucose (p = 0.0295) and reduced HDL levels (p = 0.0091). Carriers of the APOA5 c.56G allele had increased triglyceride levels (p = 0.0435) and waist circumference (p = 0.0122). Similarly the APOA5 1259 T > C variant was associated with increased waist circumference (p = 0.0463). The haplotypes CCGT (OR = 3.223; p = 0.00278) and CGGT (OR = 8.234; p = 0.00534) were significantly associated with susceptibility to metabolic syndrome. Our results confirms the association of APOA5 -1131 T > C and c.56C > G variants with the predisposition to metabolic syndrome complications. Show less

The goal of the study is to investigate the association between the APOA5 polymorphisms and haplotypes with Arterial Hypertension (AHT) in Moroccan patients. The study was performed in 283 subjects, 149 patients with AHT and 134 controls. All subjects were genotyped for the APOA5 -1131 T > C (rs662799), 56C > G (rs3135506) and c.553G > T (rs2075291) polymorphisms. There was a strong association between -1131 T > C and 56C > G polymorphisms with AHT. The -1131 T > C and 56C > G polymorphisms were significantly associated with increased systolic blood pressure (SBP) and triglycerides (TG) levels. There were 4 haplotypes with a frequency higher than 5%, constructed from APOA5 polymorphisms, with the following order: -1131 T > C, 56C > G and c.553G > T. Haplotype H1 (TCG) was associated with decreased risk of AHT, whereas the haplotypes H2 (CCG) and H4 (CGG) were significantly associated with an increased risk of AHT. Carriers of H1 haplotype had a lower SBP and DBP and TG. In contrast, significant elevated SBP, DBP and TG were found in H4 haplotypes carriers. Our data demonstrate for the first time that several common SNPs in the APOA5 gene and their haplotypes are closely associated with modifications of blood pressure and serum lipid parameters in the AHT patient. Show less