Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

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Integrative genomics viewer

The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.

An integrated encyclopedia of DNA elements in the human genome.

Data visualization is an essential component of genomic data analysis. However, the size and diversity of the data sets produced by today’s sequencing and array-based profiling methods present major challenges to visualization tools. The Integrative Genomics Viewer (IGV) is a high-performance viewer that efficiently handles large heterogeneous data sets, while providing a smooth and intuitive user experience at all levels of genome resolution. A key characteristic of IGV is its focus on the integrative nature of genomic studies, with support for both array-based and next-generation sequencing data, and the integration of clinical and phenotypic data. Although IGV is often used to view genomic data from public sources, its primary emphasis is to support researchers who wish to visualize and explore their own data sets or those from colleagues. To that end, IGV supports flexible loading of local and remote data sets, and is optimized to provide high-performance data visualization and exploration on standard desktop systems. IGV is freely available for download from http://www.broadinstitute.org/igv, under a GNU LGPL open-source license.

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Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration

Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution.

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A haplotype map of the human genome

We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.

/pdf/identification-and-analysis-of-functional-elements-in-1-of-2o640l8ikl.pdf

Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project

Tu1875 – Chronic Antibiotic Use and Subsequent Development of Diverticulitis

Early reports raised concern that use of non-steroidal anti-inflammatory drugs (NSAIDs) may increase risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19). Users of the COVID Symptom Study smartphone application reported use of aspirin and other NSAIDs between March 24 and May 8, 2020. Users were queried daily about symptoms, COVID-19 testing, and healthcare seeking behavior. Cox proportional hazards regression was used to determine the risk of COVID-19 among according to aspirin or non-aspirin NSAID users. Among 2,736,091 individuals in the U.S., U.K., and Sweden, we documented 8,966 incident reports of a positive COVID-19 test over 60,817,043 person-days of follow-up. Compared to non-users and after stratifying by age, sex, country, day of study entry, and race/ethnicity, non-aspirin NSAID use was associated with a modest risk for testing COVID-19 positive (HR 1.23 [1.09, 1.32]), but no significant association was observed among aspirin users (HR 1.13 [0.92, 1.38]). After adjustment for lifestyle factors, comorbidities and baseline symptoms, any NSAID use was not associated with risk (HR 1.02 [0.94, 1.10]). Results were similar for those seeking healthcare for COVID-19 and were not substantially different according to lifestyle and sociodemographic factors or after accounting for propensity to receive testing. Our results do not support an association of NSAID use, including aspirin, with COVID-19 infection. Previous reports of a potential association may be due to higher rates of comorbidities or use of NSAIDs to treat symptoms associated with COVID-19.

/pdf/aspirin-and-nsaid-use-and-the-risk-of-covid-19-qav0f8y1en.pdf

Aspirin and NSAID use and the risk of COVID-19

PURPOSE
Lower 25-hydroxyvitamin D [25(OH)D] levels have consistently been associated with higher mortality among participants with colorectal cancer (CRC). However, it is still unknown whether this association differs by vitamin-D binding protein (also known as Gc) isoforms.


METHODS
We examined the association between prediagnostic 25(OH)D levels and overall and CRC-specific mortality among participants with CRC within two prospective US cohorts. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs).


RESULTS
588 participants with CRC were observed until the date of death or last follow-up (2018), whichever came first. Deficient versus sufficient 25(OH)D concentrations (<30 vs. ≥ 50 nmol/L) were associated with higher overall mortality (HR, 2.06; 95% CI, 1.34 to 3.18) but not with CRC-specific mortality (HR, 1.51; 95% CI, 0.75 to 3.07). The HRs for overall mortality comparing deficient versus sufficient concentrations were 2.43 (95% CI, 1.26 to 4.70) for those with Gc1-1 isoform (rs4588 CC) and 1.63 (95% CI, 0.88 to 3.02) for those with Gc1-2 or Gc2-2 (rs4588 CA or AA) isoforms (P for interaction = 0.54). The HRs for CRC-specific mortality were 1.18 (95% CI, 0.27 to 5.14) for those with Gc1-1 isoform and 1.41 (95% CI, 0.62 to 3.24) for those with Gc1-2 or Gc2-2 isoforms (P for interaction = 0.94).


MAIN CONCLUSIONS
In these two US cohorts, we found that lower 25(OH)D levels were associated with higher overall mortality, but this association did not differ by Gc isoforms.

Prediagnostic vitamin D status and colorectal cancer survival by vitamin D-binding protein isoforms in the US cohorts.

https://genomemedicine.biomedcentral.com/counter/pdf/10.1186/s13073-023-01202-6

Long H. Nguyen

Papers

Tu1875 – Chronic Antibiotic Use and Subsequent Development of Diverticulitis

Aspirin and NSAID use and the risk of COVID-19

Prediagnostic vitamin D status and colorectal cancer survival by vitamin D-binding protein isoforms in the US cohorts.

Metagenomic assessment of gut microbial communities and risk of severe COVID-19

119 the sulfur microbial diet and risk of inflammatory bowel disease: results from three large prospective cohorts