Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

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Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Background: The genetic basis of left ventricular (LV) image-derived phenotypes, which play a vital role in the diagnosis, management, and risk stratification of cardiovascular diseases, is unclear...

Genome-Wide Analysis of Left Ventricular Image-Derived Phenotypes Identifies Fourteen Loci Associated With Cardiac Morphogenesis and Heart Failure Development.

The biomedical research sector in Saudi Arabia has recently received special attention from the government, which is currently supporting research aimed at improving the understanding and treatment of common diseases afflicting Saudi Arabian society. To build capacity for research and training, a number of centres of excellence were established in different areas of the country. Among these, is the Centre of Excellence in Genomic Medicine Research (CEGMR) at King Abdulaziz University, Jeddah, with its internationally ranked and highly productive team performing translational research in the area of individualized medicine. Here, we present a panorama of the recent trends in different areas of biomedical research in Saudi Arabia drawing from our vision of where genomics will have maximal impact in the Kingdom of Saudi Arabia. We describe advances in a number of research areas including; congenital malformations, infertility, consanguinity and pre-implantation genetic diagnosis, cancer and genomic classifications in Saudi Arabia, epigenetic explanations of idiopathic disease, and pharmacogenomics and personalized medicine. We conclude that CEGMR will continue to play a pivotal role in advances in the field of genomics and research in this area is facing a number of challenges including generating high quality control data from Saudi population and policies for using these data need to comply with the international set up.

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Individualized medicine enabled by genomics in Saudi Arabia

Background: Truncating variants in the TTN gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers. Methods...

Clinical Phenotypes and Prognosis of Dilated Cardiomyopathy Caused by Truncating Variants in the TTN Gene.

Precision Medicine in the Management of Dilated Cardiomyopathy: JACC State-of-the-Art Review

Background: Both genetic and environmental factors play major roles in the development of inflammatory bowel disease (IBD). Recent studies have identified a number of genetic susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC). Objectives: The present study aimed at examining the association of nine polymorphisms in four different genes with the development of CD and UC in a sample of Saudi patients with IBD. Materials and Methods: All gene polymorphisms were identified by polymerase chain reaction and by direct sequencing. Allele and genotype frequencies of polymorphisms of NOD2/CARD15 (R702W, G908R, L1007finsC), Toll-like receptor 4 (TLR4) (D299G, T399I), OCTN promoter (C1672, G207C) and DLG5 (G113A, C4136A) genes were determined in Saudi subjects with CD (51), UC (26) and in 75 normal controls. Results: Out of the nine polymorphisms studied in four loci, only two polymorphisms in two different loci were found to have increased in patients compared with the control subjects. The CT genotype of TLR4 T3991 was over represented in patients with CD or UC compared to that in controls (odds ratios [OR], 5.63:95% confident interval [CI], 1.19-26.69; P = 0.03). In addition, the GA genotype of DLG5 G113A was over represented in patients with CD or UC compared with that in controls (OR, 4.72:95% CI 2.30-9.66; P = 0.0001). However, there were no significant associations found between all other polymorphisms studied and the susceptibility of CD or UC found in the Saudi population. Conclusion: Our finding indicates that association of IBD with nine gene polymorphisms was only significant in two of these polymorphic variants.

Association of NOD2/CARD15, DLG5, OCTN1 and toll-like receptor 4 gene polymorphisms with inflammatory bowel disease: A university hospital experience

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miRNA Expression Associated with HbF in Saudi Sickle Cell Anemia

Abstract Ischemic stroke represents a significant societal burden across the globe. Rare high penetrant monogenic variants and less pathogenic common single nucleotide polymorphisms (SNPs) have been described as being associated with risk of diseases. Genetic studies in Saudi Arabian patients offer a greater opportunity to detect rare high penetrant mutations enriched in these consanguineous populations. We performed whole exome sequencing on 387 ischemic stroke subjects from Saudi Arabian hospital networks with up to 20,230 controls from the Saudi Human Genome Project and performed gene burden analyses of variants in 177 a priori loci derived from knowledge-driven curation of monogenic and genome-wide association studies of stroke. Using gene-burden analyses, we observed significant associations in numerous loci under autosomal dominant and/or recessive modelling. Stroke subjects with modified Rankin Scale (mRSs) above 3 were found to carry greater cumulative polygenic risk score (PRS) from rare variants in stroke genes (standardized PRS mean &gt; 0) compared to the population average (standardized PRS mean = 0). However, patients with mRS of 3 or lower had lower cumulative genetic risk from rare variants in stroke genes (OR (95%CI) = 1.79 (1.29–2.49), p = 0.0005), with the means of standardized PRS at or lower than 0. In conclusion, gene burden testing in Saudi stroke populations reveals a number of statistically significant signals under different disease inheritance models. However, interestingly, stroke subjects with mRS of 3 or lower had lower cumulative genetic risk from rare variants in stroke genes and therefore, determining the potential mRS cutoffs to use for clinical significance may allow risk stratification of this population. 

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Whole‐exome sequencing analyses in a Saudi Ischemic Stroke Cohort reveal association signals, and shows polygenic risk scores are related to Modified Rankin Scale Risk

Mohammed Shakil Akhtar

Papers

Association of NOD2/CARD15, DLG5, OCTN1 and toll-like receptor 4 gene polymorphisms with inflammatory bowel disease: A university hospital experience

miRNA Expression Associated with HbF in Saudi Sickle Cell Anemia

Whole‐exome sequencing analyses in a Saudi Ischemic Stroke Cohort reveal association signals, and shows polygenic risk scores are related to Modified Rankin Scale Risk