Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.

Association between change of health care providers and pregnancy exposure to FDA category C, D and X drugs / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Changing health care providers frequently breaks the continuity of care, which is associated with many health care problems. The purpose of this study was to examine the association between a change of health care providers and pregnancy exposure to FDA category C, D and X drugs.</p><p><b>METHODS</b>A 50% random sample of women who gave a birth in Saskatchewan between January 1, 1997 and December 31, 2000 were chosen for this study. The association between the number of changes in health care providers and with pregnancy exposure to category C, D, and X drugs for those women with and without chronic diseases were evaluated using multiple logistical regression, with adjusted odds ratios (ORs) and its 95% confidence intervals (CIs) as the association measures.</p><p><b>RESULTS</b>A total of 18 568 women were included in this study. Rates of FDA C, D, and X drug uses were 14.35%, 17.07%, 21.72%, and 31.14%, in women with no change of provider, 1-2 changes, 3-5 changes, and more than 5 changes of health care providers. An association between the number of changes of health care providers and pregnancy exposure to FDA C, D, and X drugs existed in women without chronic diseases but not in women with chronic disease.</p><p><b>CONCLUSION</b>Change of health care providers is associated with pregnancy exposure to FDA category C, D and X drugs in women without chronic diseases.</p>

A pre-conception cohort to study preeclampsia in China: Rationale, study design, and preliminary results / 中南大学学报(医学版)

OBJECTIVE@#It is uncertain whether preeclampsia (PE) is caused by pre-existing factors or by pregnancy itself. We want to answer this important question in public health by conducting a large pre-conception cohort in China.@*METHODS@#A prospective and pre-conception cohort study with a target recruitment of 5000 couples who plan to have a baby within 6 months was performed and their conception, delivery, and postpartum were followed up in Liuyang county, Hunan Province of P. R. China.@*RESULTS@#A total of 1915 young couples have been recruited into this unique pre-conception cohort till now. In general, both systolic blood pressure and diastolic blood pressure decreased in early second trimester from pre-conception level but increased in third trimester and at delivery.@*CONCLUSION@#The proposed pre-conception cohort study will have important theoretical and practical implications on the prevention of PE and its associated cardiovascular disease risks.

Secular trends in trial of labor and associated neonatal mortality and morbidity in the United States, 1995 to 2002 / 中南大学学报(医学版)

OBJECTIVE@#A proportion of elective repeated cesarean sections where a trial of labor in a uterus with a previous scar was not attempted is on the increase. This study aimed to assess how reduced the use of trial of labor has impacted on neonatal outcomes in the United States.@*METHODS@#Pregnant women with one previous cesarean delivery and a singleton live birth of the index pregnancy were abstracted from the 1995 to 2002 birth registration data of the United States. Adjusted odds ratios for adverse neonatal outcomes of trial of labor were estimated by multiple logistic regression models, in overall study subjects and in the two periods with high and low rates of trial of labor.@*RESULTS@#A total of 1833407 eligible subjects were included in the analysis. Rate of trial of labor after one previous cesarean section dropped from 38.5% in 1995 to 15.0% in 2002. No significant change was observed in the patient population profile. Successful vaginal birth after cesarean delivery (VBAC) also declined from 76.6% in 1995 to 66.0% in 2002. A trial of labor after one previous cesarean section was correlated with increased risks of asphyxia-related neonatal death and neonatal morbidity. This risk was even more pronounced in low risk women and in the last study years with the lowest rate of trial of labor.@*CONCLUSION@#The reduced use of trial of labor after one cesarean delivery in recent years in the United States has actually resulted in increased risk of adverse neonatal outcomes associated with a trial of labor.

The association between fetal sex and preterm birth in twin pregnancies.

OBJECTIVE: To assess the association between the fetal sex and preterm birth. METHODS: We performed a retrospective population-based cohort study using the 1995-1997 registration twin data in the United States (148,234 live-birth twin pairs). The twin pairs were divided into 3 groups: male-male (male-male), female-female, and opposite sex. We used 3 different cutoff values of preterm birth: less than 28, 32, and 36 gestational weeks. The preterm birth rates among the 3 study groups were compared, and the adjusted risk ratios (relative risk) were estimated by multiple logistic regression. RESULTS: The male-male twin pairs had the highest pre-term birth rate (less than 28 weeks: 4.9%; less than 32 weeks: 12.4%; less than 36 weeks: 40.2%), the female-female twin pairs were intermediate (less than 28 weeks: 4.1%; less than 32 weeks: 10.6%; less than 36 weeks: 37.8%), and the opposite-sex twin pairs had the lowest rate (less than 28 weeks: 4.1%; less than 32 weeks: 10.1%; less than 36 weeks: 36.8%). Adjustment for important confounding factors or excluding twin pairs born to mothers who had an induction of labor or a cesarean delivery with medical complications did not change the results. The adjusted relative risks (95% confidence intervals) were 1.19 (1.11, 1.27), 1.21 (1.16, 1.26), and 1.09 (1.07, 1.11), respectively, for male-male twins compared with the opposite-sex twins under the 3 different cutoff values of preterm births. CONCLUSION: Male sex is associated with increased risk of preterm births in twin pregnancy. LEVEL OF EVIDENCE: II-2