Cardiovascular disease (CVD) is the most common cause of death in the U.S. Its risk factors include smoking, hypertension, obesity, and dyslipidemia. High low-density lipoprotein cholesterol (LDL-C) is one of the well-established treatable risk factors for CVD. However, many individuals remain underdiagnosed and current medications do not serve all patients well, mainly due to the side-effects of statins. There are several successful examples of hypercholesterolemia treatments that are developed based on original discoveries in genetic studies, both from dyslipidemic families and population-based association studies. Identification of genes for low LDL-C in individuals with extremely low LDL-C levels is especially attractive as it can help reveal biologically safe mechanisms to lower LDL-C in humans. Chapter 3 describes the exome sequencing analysis we performed in two small Mexican families with familial hypobetalipoproteinemia, characterized by very low levels of LDL-C. We identified a region on chromosome 2p16, segregating with FHBL in the affected family members. In chapter 2, we studied an extended multigenerational Austrian family with familial hypercholesterolemia (FH), characterized by high LDL-C and premature cardiovascular events. We comprehensively analyzed this family using linkage analysis followed by whole exome sequencing; evaluated their weighted genetic risk scores relative to the general population; and systematically analyzed all previously known FH genes in all family members. We identified a family-specific 10-SNP combination, distinguishing the affected family members from the unaffected ones. In addition, we observed that a subset of family members have rare, previously identified less severe, FH mutation combinations in the LDLR and APOB genes, likely also contributing to their high levels of LDL-C.
Almost 800,000 individuals suffer a stroke yearly in the United States, and stroke is the leading cause of serious long-term disability. Therefore, it is crucial to develop therapeutic interventions improving outcomes of stroke. One attractive putative treatment option is the limp remote ischemic conditioning (RIC) that is shown to provide neuro-protective effects in previous animal studies, and a trend in human studies. However, mechanisms of RIC are not well understood in humans. In chapter 4, we identified cell cycle and inflammatory changes in our transcriptome and DNA methylation analyses associated with RIC. In summary, this dissertation employs a variety of state-of-the-art massive parallel sequencing methods combined with different study designs to search for genetic risk factors for low and high LDL-C as well as genomic changes associated with the RIC treatment. We identified a region on chromosome 2p16 for FHBL; a family-specific combination of 10 GWAS lipid SNPs for FH; and specific cell cycle and inflammatory changes associated with RIC, a potential new treatment of stroke.