Correction to: Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits

Erratum for Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits. [BMC Med Genomics. 2019

The Role of the HLA Gene Region and Environmental Risk Factors in Follicular Non-Hodgkin Lymphoma

The first genome-wide scans searching for follicular lymphoma (FL) risk factors revealed that a section of chromosome 6 powerfully impacts risk of this disease. Common genetic variants within the human leukocyte antigen (HLA) gene region were shown to be associated with an approximate doubling of individual disease odds. This dissertation aims to concurrently improve the resolution of, expand upon, clarify, and take the first steps in explaining these findings. Chapter 1 provides a review of the broadly relevant literature, including the epidemiology of FL and related lymphomas, the molecular immunology of FL, and the HLA gene region. Chapter 2 is a study making use of the highest possible resolution HLA genotyping methodology for its time, applied to an FL case-control study. This study not only increased our knowledge of known risk factors, it also was the first study to demonstrate an association of FL with variation at HLA-DPB1. Chapter 3 describes the method which will soon be used to localize to a single locus the associations which are ambiguously assigned to several genes. Using pilot data, this study demonstrate the feasibility of performing genetic ancestry matching and HLA imputations on historically stored samples. Chapter 4 uses data from several studies to identify two amino-acid positions, which may themselves explain a substantial portion of FL risk. The fact that these amino acid positions lie in the key peptide binding groove of HLA-DRB1 gives some evidence that peptide binding is the mechanism by which these HLA associations are impacting FL development. Finally, in Chapter 5 the peptide binding properties of HLA class II alleles are computationally investigated, examining potential environmental and internal proteomes likely to be encountered by HLA proteins. This approach reveals that certain alleles which impact FL risk are predicted to be exceptionally strong or weak at binding peptides, and several candidate antigens are mined from the data. Concluding in Chapter 6, the state of HLA-FL research is summarized, and future research is recommended

Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits

Background Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene. Results We identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight. Conclusion In sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.Correction in: BMC MEDICAL GENOMICS, Volume: 12, Issue: 1, Article Number: 154, DOI: 10.1186/s12920-019-0573-9</p