Susceptibility gene identification and risk evaluation model construction by transcriptome-wide association analysis for salt sensitivity of blood pressure.

BACKGROUND: Salt sensitivity of blood pressure (SSBP) is an intermediate phenotype of hypertension and is a predictor of long-term cardiovascular events and death. However, the genetic structures of SSBP are uncertain, and it is difficult to precisely diagnose SSBP in population. So, we aimed to identify genes related to susceptibility to the SSBP, construct a risk evaluation model, and explore the potential functions of these genes. METHODS AND RESULTS: A genome-wide association study of the systemic epidemiology of salt sensitivity (EpiSS) cohort was performed to obtain summary statistics for SSBP. Then, we conducted a transcriptome-wide association study (TWAS) of 12 tissues using FUSION software to predict the genes associated with SSBP and verified the genes with an mRNA microarray. The potential roles of the genes were explored. Risk evaluation models of SSBP were constructed based on the serial P value thresholds of polygenetic risk scores (PRSs), polygenic transcriptome risk scores (PTRSs) and their combinations of the identified genes and genetic variants from the TWAS. The TWAS revealed that 2605 genes were significantly associated with SSBP. Among these genes, 69 were differentially expressed according to the microarray analysis. The functional analysis showed that the genes identified in the TWAS were enriched in metabolic process pathways. The PRSs were correlated with PTRSs in the heart atrial appendage, adrenal gland, EBV-transformed lymphocytes, pituitary, artery coronary, artery tibial and whole blood. Multiple logistic regression models revealed that a PRS of P < 0.05 had the best predictive ability compared with other PRSs and PTRSs. The combinations of PRSs and PTRSs did not significantly increase the prediction accuracy of SSBP in the training and validation datasets. CONCLUSIONS: Several known and novel susceptibility genes for SSBP were identified via multitissue TWAS analysis. The risk evaluation model constructed with the PRS of susceptibility genes showed better diagnostic performance than the transcript levels, which could be applied to screen for SSBP high-risk individuals.

Difluoromethylsulfonyl Imidazolium Salt for Difluoromethylation of Alkenes.

Herein, we describe the design and synthesis of a difluoromethylsulfonyl imidazolium salt, which can act as a radical difluoromethylation reagent to achieve the challenging amino- and oxy-difluoromethylation of alkenes. Notably, the three steps for the synthesis of the imidazolium salt do not require any tedious distillation or column chromatography purification process, and the amino- and oxy-difluoromethylation paths are simply determined by the selection of reaction solvents.

Synthesis and 18F Labeling of Alkenyl Sulfonyl Fluorides via an Unconventional Elimination Pathway.

A successful Cu-catalyzed addition of both Cl and SO2OCF2H groups into alkenes allows us to discover the unusual reactivity of the SO2OCF2H group. As opposed to common sulfonic esters (RSO2-O-R'), in which the R' group is highly electrophilic, the SO2 moiety demonstrates higher electrophilicity in RSO2-OCF2H. The unexpected reactivity is further developed not only as a synthetic tool for well-functionalized alkenyl sulfonyl fluorides but also for the first 18F labeling of alkenyl sulfonyl fluorides.

Palladium-Catalyzed Enantioselective C-H Olefination of Diaryl Sulfoxides through Parallel Kinetic Resolution and Desymmetrization.

The first example of PdII -catalyzed enantioselective C-H olefination with non-chiral or racemic sulfoxides as directing groups was developed. A variety of chiral diaryl sulfoxides were synthesized with high enantioselectivity (up to 99 %) through both desymmetrization and parallel kinetic resolution (PKR). This is the first report of PdII -catalyzed enantioselective C(sp2 )-H functionalization through PKR, and it represents a novel strategy to construct sulfur chiral centers.