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Familial hypercholesterolemia (FH) is a monogenic lipid disorder which promotes atherosclerosis and cardiovascular diseases. Owing to the lack of sufficient published information, this study aims to identify the potential genetic biomarkers for FH by studying the global gene expression profile of blood cells. The microarray expression data of FH patients and controls was analyzed by different computational biology methods like differential expression analysis, protein network mapping, hub gene identification, functional enrichment of biological pathways, and immune cell restriction analysis. Our results showed the dysregulated expression of 115 genes connected to lipid homeostasis, immune responses, cell adhesion molecules, canonical Wnt signaling, mucin type O-glycan biosynthesis pathways in FH patients. The findings from expanded protein interaction network construction with known FH genes and subsequent Gene Ontology (GO) annotations have also supported the above findings, in addition to identifying the involvement of dysregulated thyroid hormone and ErbB signaling pathways in FH patients. The genes like CSNK1A1, JAK3, PLCG2, RALA, and ZEB2 were found to be enriched under all GO annotation categories. The subsequent phenotype ontology results have revealed JAK3I , PLCG2, and ZEB2 as key hub genes contributing to the inflammation underlying cardiovascular and immune response related phenotypes. Immune cell restriction findings show that above three genes are highly expressed by T-follicular helper CD4+ T cells, naïve B cells, and monocytes, respectively. These findings not only provide a theoretical basis to understand the role of immune dysregulations underlying the atherosclerosis among FH patients but may also pave the way to develop genomic medicine for cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) is a gastrointestinal disorder whose genetic basis is not fully understood. Therefore, we studied a Saudi family with two CD affected siblings to discover the causal genetic defect. Through whole exome sequencing (WES), we identified that both siblings have inherited an extremely rare and deleterious CPED1 genetic variant (c.241 A > G; p.Thr81Ala) segregating as autosomal recessive mutation, suggesting its putative causal role in the CD. Saudi population specific minor allele frequency (MAF) analysis has confirmed its extremely rare prevalence in homozygous condition (MAF is 0.0004). The Sanger sequencing analysis confirmed the absence of this homozygous variant in 100 sporadic Saudi CD cases. Genotype-Tissue Expression (GTEx) data has revealed that CPED1 is abundantly expressed in gastrointestinal mucosa. By using a combination of systems biology approaches like protein 3D modeling, stability analysis and nucleotide sequence conservation analysis, we have further established that this variant is deleterious to the structural and functional aspects of CPED1 protein. To the best of our knowledge, this variant has not been previously reported in CD or any other gastrointestinal disease. The cell culture and animal model studies could provide further insight into the exact role of CPED1 p.Thr81Ala variant in the pathophysiology of CD. In conclusion, by using WES and systems biology analysis, present study for the first-time reports CPED1 as a potential causative gene for CD in a Saudi family with potential implications to both disease diagnosis and genetic counseling. [ABSTRACT FROM AUTHOR]