👤 Dervis Salih

Recent trials in Alzheimer's disease (AD) demonstrate encouraging outcomes. These trials target risk mechanisms identified through genetic analysis whilst directly aiming to reduce progression rates. Evidence from other neurodegenerative diseases suggests the genetics of progression is distinct from risk of disease. To expand these initial successes and improve clinical outcomes further we need to understand genetics of progression of disease. These can be deduced through rigorous analysis of meticulously phenotyped longitudinal cohorts. In this study we first looked at known genetic drivers of risk, namely polygenic risk scores for AD and A total of 387 individuals with, genetic data, amyloid positivity and in active decline (ADNI (n=222) and AIBL(n=165)) were used to perform generalised mixed effects linear model genome wide association studies of longitudinal cognitive decline as measured by mini mental state examination. The resulting summary statistics were subjected z, and colocalization analyses. Established AD risk factors, including These findings enhance our understanding of the biological underpinnings of AD progression, opening new avenues for therapeutic intervention. Show less

Alzheimer's disease is a neurodegenerative disorder that causes significant cognitive impairment and memory loss. It is the leading cause of dementia on a global scale and is distinguished by the pathological build-up of amyloid-beta peptides and tau protein. This study presents the development of E-pharmacophore modeling, which utilizes reported co-crystal structure involving beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) to screen the eMolecules database. The present study comprehensively dealt with the virtual screening and structure-based prediction of thiazole compounds against BACE1 protein. To investigate the binding mode of virtual-screened hits (VS-hits), top 100 VS-hits were docked into BACE1 followed by in silico ADMET prediction. Top two VS-hits (CP1 and CP2) with highest docking scores along with co-crystalized ligand (CPZ) were further subjected to MESP, HOMO, LUMO, MD simulation, and MMGBSA analysis to inspect the dynamic stability of inhibitor-BACE1 complexes and the key molecular interaction responsible for their improved binding affinity toward BACE1. This research identified CP1 and CP2 as top two potential novel BACE1 inhibitors from the library of natural products, whose Glide docking scores range from -8.87 to -7.89 kcal/mol-1. Interestingly, both ligands were able to establish interactions with a set of conserved residues F108, I110, I118, L30, Q12, G13, G11, A335, S229, D228, G230, D32, G34, S35, and Y71. ADMET assessment of the selected compounds was also noted to be within acceptable ranges. The preliminary in-silico ADMET evaluation revealed encouraging results for all the modeled and in-house library compounds. The RMSD and RMSF analysis revealed that both ligands remained stable and maintained their interaction throughout the simulation time (100 nanoseconds). The MM/GBSA (ranging from -36.734 to -27.431 kcal/mol) predicted binding affinities are in strong correlation with that of the docking score, which not only supports the docking results but also suggests that CP1 exhibits superior binding affinity towards BACE1. Keeping in view these findings, CP1 might be a promising candidate for drug discovery against BACE1 inhibitors. The findings of this research have the potential to offer valuable recommendations for the advancement of novel, potent, and efficacious BACE1 inhibitors. Show less

Background Polymorphisms in the low-density lipoprotein receptor (LDLR) and apolipoprotein B 100 (APOB-100) genes have been linked to severe hypercholesterolemia in several populations. This study investigated the frequency of LDLR-Ava II and APOB-Xba I polymorphisms among Kurdish patients with severe hypercholesterolemia. Methodology We investigated LDLR-Ava II and APOB-Xba I gene polymorphisms in Kurdish patients attending the Duhok Specialized Laboratory Center in Duhok, Kurdistan Region, Iraq. We included a total of 80 subjects in this study, of which 40 (20 males and 20 females) had severe hypercholesterolemia, and 40 apparently healthy volunteers (21 males and 19 females) had normocholesterolemia, served as a control group. We used the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique to determine the polymorphisms of the LDLR-Ava II and APOB-Xba I genes. Results In those with severe hypercholesterolemia, the observed allele frequencies were AA LDLR-Ava II polymorphism (eight, 20%) followed by TT APOB-Xba I polymorphisms (six, 15%), whereas these frequencies were five (12.5%) and one (2.5%) in those with normocholesterolemia, respectively. The AA genotype group had considerably higher cholesterol and LDL-C levels compared with the GG genotype group. A similar pattern was observed when comparing the TT and CC genotype groups. Conclusions Our results showed a high frequency of AA LDLR-Ava II polymorphism in conjunction with TT APOB-Xba I polymorphism which may be strongly associated with hypercholesterolemia in the Kurdish population. Show less

Prediabetes is defined as a hyperglycemic state between normal glucose metabolism and diabetes mellitus. It is also recognized as a predisposing factor for cardiovascular disease. Apolipoprotein is a constituent of lipoproteins, and its ratio levels (ApoB/ApoA1 ratio) are considered an independent risk factor for cardiovascular diseases. This study aimed to evaluate the apolipoprotein ratio (ApoB/ApoA1 ratio) and lipoprotein ratio (low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio) in prediabetes in relation to glycemic levels and establish the association between apolipoprotein and lipoprotein ratios in prediabetic individuals and their glycemic levels. A case-control study was conducted among 150 participants, 75 with prediabetes and 75 apparently healthy individuals (with no prediabetes or diabetes), from January 1, 2023 to December 30, 2023. The parameters involved are fasting serum glucose, insulin, blood HbA1c%, HDL-C, LDL-C, apolipoprotein A, apolipoprotein B, and lipoprotein(a) (Lp(a)), measured using different principles. Prediabetes was more predominant in males (58.7%), particularly those aged over 40 years (74.7%). The mean Lp(a) (46.18±11.66 mg/dl), LDL-C/HDL-C ratio (1.74±0.96), and ApoB/ApoA ratio (1.10±0.62) were significantly higher among prediabetic individuals. Moreover, these ratios were insignificantly higher in prediabetic individuals with HbA1c level (5.8-6.4%) and fasting glucose level (100-125 mg/dl) than those with lower levels. Prediabetic individuals exhibited a notably elevated average level of Lp(a), as well as increased mean ApoB/ApoA1 ratio and mean LDL-C/HDL-C ratio compared to individuals who were apparently healthy. Show less

In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016-December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1, VAMP1, MCTP2, and TBP). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most "negative" clinical exome tests are unsolved due to interpretation rather than technical limitations. Show less

Dysmorphology syndromes are among the most common referrals to clinical genetics specialists. Inability to match the dysmorphology pattern to a known syndrome can pose a major diagnostic challenge. With an aim to accelerate the establishment of new syndromes and their genetic etiology, we describe our experience with multiplex consanguineous families that appeared to represent novel autosomal recessive dysmorphology syndromes at the time of evaluation. Combined autozygome/exome analysis of multiplex consanguineous families with apparently novel dysmorphology syndromes. Consistent with the apparent novelty of the phenotypes, our analysis revealed a strong candidate variant in genes that were novel at the time of the analysis in the majority of cases, and 10 of these genes are published here for the first time as novel candidates (CDK9, NEK9, ZNF668, TTC28, MBL2, CADPS, CACNA1H, HYAL2, CTU2, and C3ORF17). A significant minority of the phenotypes (6/31, 19%), however, were caused by genes known to cause Mendelian phenotypes, thus expanding the phenotypic spectrum of the diseases linked to these genes. The conspicuous inheritance pattern and the highly specific phenotypes appear to have contributed to the high yield (90%) of plausible molecular diagnoses in our study cohort. Reporting detailed clinical and genomic analysis of a large series of apparently novel dysmorphology syndromes will likely lead to a trend to accelerate the establishment of novel syndromes and their underlying genes through open exchange of data for the benefit of patients, their families, health-care providers, and the research community.Genet Med 18 7, 686-695. Show less