Host factors that influence Congenital Zika Syndrome (CZS) outcome remain elusive. Interferons have been reported as the main antiviral factor in Zika and other flavivirus infections. Here, we accessed samples from 153 pregnant women (77 without and 76 with CZS) and 143 newborns (77 without and 66 with CZS) exposed to ZIKV conducted a case-control study to verify whether interferon alfa receptor 1 (IFNAR1) and interferon lambda 2 and 4 (IFNL2/4) single nucleotide polymorphisms (SNPs) contribute to CZS outcome, and characterized placenta gene expression profile at term. Newborns carrying CG/CC genotypes of rs2257167 in IFNAR1 presented higher risk of developing CZS (OR=3.41; IC=1.35-8.60; Pcorrected=0.032). No association between IFNL SNPs and CZS was observed. Placenta from CZS cases displayed lower levels of IFNL2 and ISG15 along with higher IFIT5. The rs2257167 CG/CC placentas also demonstrated high levels of IFIT5 and inflammation-related genes. We found CZS to be related with exacerbated type I IFN and insufficient type III IFN in placenta at term, forming an unbalanced response modulated by the IFNAR1 rs2257167 genotype. Despite of the low sample size se findings shed light on the host-pathogen interaction focusing on the genetically regulated type I/type III IFN axis that could lead to better management of Zika and other TORCH (Toxoplasma, Others, Rubella, Cytomegalovirus, Herpes) congenital infections.

Venous thromboembolism (VTE) is a frequent (annual incidence of 1-2 per 1000 individuals) and potentially life-threatening (case-fatality rate up to 10%) disease. VTE is associated with serious short-term and long-term complications, including a recurrence rate approaching 20% within 5 years. Anticoagulant therapy, the mainstay of VTE treatment, drastically reduces the risk of early VTE recurrence, but it exposes patients to a substantial risk of bleeding. We analyzed the genomic architecture of VTE recurrence using data from 6355 patients across 8 cohorts (including 1775 recurrences), enriched by subgroup analyses, according to sex and clinical manifestation of first VTE, which led to the identification of 28 molecular markers. Through genome-wide association studies, we identified 1 locus associated with VTE recurrence, GPR149/MME. Among all variants known to be associated with first VTE, KNG1, and FGG were associated with recurrence. Additionally, Mendelian randomization analyses identified 7 proteins as risk factors for recurrence: elevated plasma levels of coagulation factor XI, coagulation factor VIII, von Willebrand factor, histo-blood group ABO system transferase, and Golgi membrane protein 2; and decreased levels of proprotein convertase subtilisin/kexin 9 and pro–interleukin-16. Subgroup analyses revealed 18 molecular determinants associated with VTE recurrence, with notable differences between subgroups. For example, the exonic variant SLC4A1 p.Glu40Lys was significantly associated in patients who experienced pulmonary embolism but showed no effect in those with deep vein thrombosis. These findings emphasize the role of specific genetic loci and protein pathways in influencing VTE recurrence and provide valuable insights into potential therapeutic targets. Further research is needed to clarify the biological mechanisms driving these associations.

Congenital Zika syndrome (CZS) is characterized by a diverse group of congenital malformations induced by ZIKV infection during pregnancy. Type III interferons have been associated with placental immunity against ZIKV and restriction of vertical transmission in mice, and non-coding single-nucleotide polymorphisms (SNPs) on these genes are well known to influence susceptibility to other viral infections. However, their effect on ZIKV pathogenesis has not yet been explored. To investigate whether maternal non-coding SNPs at IFNL genes are associated with CZS, 52 women infected with ZIKV during pregnancy were enrolled in a case–control association study. A total of 28 women were classified as cases and 24 as controls based on the presence or absence of CZS in their infants, and seven Interferon-λ non-coding SNPs (rs12980275, rs8099917, rs4803217, rs4803219, rs8119886, rs368234815, rs12979860) were genotyped. The results of logistic regression analyses show an association between the G allele at rs8099917 and increased susceptibility to CZS under a log-additive model (_adjustedOR = 2.80; _95%CI = 1.14–6.91; p = 0.02), after adjustment for trimester of infection and genetic ancestry. These results provide evidence of an association between Interferon-λ SNPs and CZS, suggesting rs8099917 as a promising candidate for further studies on larger cohorts.

Whether to stop oral anticoagulants after a first unprovoked venous thromboembolism (VTE) is challenging, partially due to an intriguingly higher risk of VTE recurrence (rVTE) in men after therapy discontinuation. DNA methylation (DNAm) differences between men and women might underly this sex-biased rVTE risk difference. To investigate sex-specific associations between DNAm at cytosine-phosphate-guanine (CpG) sites and rVTE. In 417 unprovoked VTE patients, including 101 experiencing recurrences over 5-year follow-up (REVERSE I), we analyzed blood DNAm using the Illumina EPIC array and performed a sex-stratified epigenome-wide association study. We further examined 181 major provoked VTE patients, including 36 recurrences over 14-year follow-up (MARTHA), to investigate whether DNAm are risk factors for rVTE after anticoagulation therapy. Hypomethylated CpGs at genes TBC1D22B-cg01060850 and ZHX2-cg07808424 in men and DIP2B-ch.12.1038646R and DENND3-cg03401656 in women were associated with rVTE at genome-wide level (p<7e-8). Though not statistically significant, DENND3-cg03401656 had the same direction of effect in MARTHA women. Sensitivity analysis confirmed the robustness of the estimates including potential confounders, adaptations of the Cox model, non-Europeans, and proximal methylation quantitative trait loci (meQTLs) in the association. The associated CpGs were situated at genes for membrane trafficking, corroborating the participation of Rab regulatory proteins in rVTE, and transcription factors. We identified DNAm marks as potential risk factors for sex-biased recurrence in unprovoked VTE. Further replication and experimental validation could refine our understanding on the regulation of the identified DNAm sites and help optimize personalized decision-making for long-term anticoagulation after first VTE.