Somatic loss of function mutations in cohesin genes are frequently associated with various cancer types, while cohesin disruption in the germline causes cohesinopathies such as Cornelia-de-Lange syndrome (CdLS). Here, we present the discovery of a recurrent heterozygous RAD21 germline aberration at amino acid position 298 (p.P298S/A) identified in three children with lymphoblastic leukemia or lymphoma in a total dataset of 482 pediatric cancer patients. While RAD21 p.P298S/A did not disrupt the formation of the cohesin complex, it altered RAD21 gene expression, DNA damage response and primary patient fibroblasts showed increased G2/M arrest after irradiation and Mitomycin-C treatment. Subsequent single-cell RNA-sequencing analysis of healthy human bone marrow confirmed the upregulation of distinct cohesin gene patterns during hematopoiesis, highlighting the importance of RAD21 expression within proliferating B- and T-cells. Our clinical and functional data therefore suggest that RAD21 germline variants can predispose to childhood lymphoblastic leukemia or lymphoma without displaying a CdLS phenotype. Full article

Resistin and soluble suppression of tumorigenicity 2 (sST2) are useful predictors in patients with coronary artery disease (CAD). Their serum levels are significantly attributed to variations in RETN and IL1RL1 loci. We investigated candidate variants in the RETN locus for resistin levels and those in the IL1RL1 locus for sST2 levels and evaluated the prognostication of these two biomarkers and the corresponding variants for long-term outcomes in the patients with CAD. We included 4652, 557, and 512 Chinese participants from the Taiwan Biobank (TWB), cardiovascular health examination (CH), and CAD cohorts, respectively. Candidate variants in RETN and IL1RL1 were investigated using whole-genome sequence (WGS) and genome-wide association study (GWAS) data in the TWB cohort. The weighted genetic risk scores (WGRS) of RETN and IL1RL1 with resistin and sST2 levels were calculated. Kaplan–Meier curves were used to analyze the prognostication of resistin and sST2 levels, WGRS of RETN and IL1RL1, and their combinations. Three RETN variants (rs3219175, rs370006313, and rs3745368) and two IL1RL1 variants (rs10183388 and rs4142132) were independently associated with resistin and sST2 levels as per the WGS and GWAS data in the TWB cohort and were further validated in the CH and CAD cohorts. In combination, these variants explained 53.7% and 28.0% of the variation in resistin and sST2 levels, respectively. In the CAD cohort, higher resistin and sST2 levels predicted higher rates of all-cause mortality and major adverse cardiac events (MACEs) during long-term follow-up, but WGRS of RETN and IL1RL1 variants had no impact on these outcomes. A synergistic effect of certain combinations of biomarkers with RETN and IL1RL1 variants was found on the prognostication of long-term outcomes: Patients with high resistin levels/low RETN WGRS and those with high sST2 levels/low IL1RL1 WGRS had significantly higher all-cause mortality and MACEs rates, and those with both these combinations had the poorest outcomes. Both higher resistin and sST2 levels, but not RETN and IL1RL1 variants, predict poor long-term outcomes in patients with CAD. Furthermore, combining resistin and sST2 levels with the WGRS of RETN and IL1RL1 genotyping exerts a synergistic effect on the prognostication of CAD outcomes. Future studies including a large sample size of participants with different ethnic populations are needed to verify this finding. Full article

The KLF14 gene is a key metabolic transcriptional transregulator with monoallelic maternal expression. KLF14 variants are only associated with adipose tissue gene expression, and KLF14 promoter methylation is strongly associated with age. This study investigated whether age, sex, and obesity mediate the effects of KLF14 variants and DNA methylation status on body shape indices and metabolic traits. In total, the data of 78,742 and 1636 participants from the Taiwan Biobank were included in the regional plot association analysis for KLF14 variants and KLF14 methylation, respectively. Regional plot association studies revealed that the KLF14 rs4731702 variant and the nearby strong linkage disequilibrium polymorphisms were the lead variants for lipid profiles, blood pressure status, insulin resistance surrogate markers, and metabolic syndrome mainly in female participants and for body shape indices mainly in obese women. Significant age-dependent associations between KLF14 promoter methylation levels and body shape indices, and metabolic traits were also noted predominantly in female participants. KLF14 variants and KLF14 hypermethylation status were associated with metabolically healthy and unhealthy phenotypes, respectively, in obese individuals, and only the KLF14 variants demonstrated a significant association with both higher adiposity and lower cardiometabolic risk in the same allele, revealing uncoupled excessive adiposity from its cardiometabolic comorbidities, especially in obese women. Variations of KLF14 are associated with body shape indices, metabolic traits, insulin resistance, and metabolically healthy status. Differential genetic and epigenetic effects of KLF14 are age-, sex- and obesity-dependent. These results provided a personalized reference for the management of cardiometabolic diseases in precision medicine. Full article

The CD33 gene encodes for a member of the sialic-acid-binding immunoglobulin-type lectin (Siglec) family, and is one of the top-ranked Alzheimer’s disease (AD) risk genes identified by genome-wide association studies (GWAS). Many CD33 polymorphisms are associated with an increased risk of AD, but the function and potential mechanism of many CD33 single-nucleotide polymorphisms (SNPs) in promoting AD have yet to be elucidated. We recently identified the CD33 SNP rs2455069-A>G (R69G) in a familial form of dementia. Here, we demonstrate an association between the G allele of the rs2455069 gene variant and the presence of AD in a cohort of 195 patients from southern Italy. We carried out in silico analysis of the 3D structures of CD33 carrying the identified SNP to provide insights into its functional effect. Structural models of the CD33 variant carrying the R69G amino acid change were compared to the CD33 wild type, and used for the docking analysis using sialic acid as the ligand. Our analysis demonstrated that the CD33-R69G variant may bind sialic acid at additional binding sites compared to the wild type, thus potentially increasing its affinity/specificity for this molecule. Our results led to a new hypothesis of rs2455069-A>G SNP as a risk factor for AD, suggesting that a long-term cumulative effect of the CD33-R69G variant results from the binding of sialic acid, acting as an enhancer of the CD33 inhibitory effects on amyloid plaque degradation. Full article

The SKP1, CUL1, F-box protein (SCF) complex represents a family of 69 E3 ubiquitin ligases that poly-ubiquitinate protein substrates marking them for proteolytic degradation via the 26S proteasome. Established SCF complex targets include transcription factors, oncoproteins and tumor suppressors that modulate cell cycle activity and mitotic fidelity. Accordingly, genetic and epigenetic alterations involving SCF complex member genes are expected to adversely impact target regulation and contribute to disease etiology. To gain novel insight into cancer pathogenesis, we determined the prevalence of genetic and epigenetic alterations in six prototypic SCF complex member genes (SKP1, CUL1, RBX1, SKP2, FBXW7 and FBXO5) from patient datasets extracted from The Cancer Genome Atlas (TCGA). Collectively, ~45% of observed SCF complex member mutations are predicted to impact complex structure and/or function in 10 solid tumor types. In addition, the distribution of encoded alterations suggest SCF complex members may exhibit either tumor suppressor or oncogenic mutational profiles in a cancer type dependent manner. Further bioinformatic analyses reveal the potential functional implications of encoded alterations arising from missense mutations by examining predicted deleterious mutations with available crystal structures. The SCF complex also exhibits frequent copy number alterations in a variety of cancer types that generally correspond with mRNA expression levels. Finally, we note that SCF complex member genes are differentially methylated across cancer types, which may effectively phenocopy gene copy number alterations. Collectively, these data show that SCF complex member genes are frequently altered at the genetic and epigenetic levels in many cancer types, which will adversely impact the normal targeting and timely destruction of protein substrates, which may contribute to the development and progression of an extensive array of cancer types. Full article

While the shelterin complex guards and coordinates the mechanism of telomere regulation, deregulation of this process is tightly linked to malignant transformation and cancer. Here, we present the novel finding of a germline stop-gain variant (p.Q199*) in the shelterin complex gene POT1, which was identified in a child with acute myeloid leukemia. We show that the cells overexpressing the mutated POT1 display increased DNA damage and chromosomal instabilities compared to the wildtype counterpart. Protein and mRNA expression analyses in the primary patient cells further confirm that, physiologically, the variant leads to a nonfunctional POT1 allele in the patient. Subsequent telomere length measurements in the primary cells carrying heterozygous POT1 p.Q199* as well as POT1 knockdown AML cells revealed telomeric elongation as the main functional effect. These results show a connection between POT1 p.Q199* and telomeric dysregulation and highlight POT1 germline deficiency as a predisposition to myeloid malignancies in childhood. Full article

Mutations in splicing factor genes have a severe impact on the survival of cancer patients. Splicing factor 3b subunit 1 (SF3B1) is one of the most frequently mutated genes in chronic lymphocytic leukemia (CLL); patients carrying these mutations have a poor prognosis. Since the splicing machinery and the epigenome are closely interconnected, we investigated whether these alterations may affect the epigenomes of CLL patients. While an overall hypomethylation during CLL carcinogenesis has been observed, the interplay between the epigenetic stage of the originating B cells and SF3B1 mutations, and the subsequent effect of the mutations on methylation alterations in CLL, have not been investigated. We profiled the genome-wide DNA methylation patterns of 27 CLL patients with and without SF3B1 mutations and identified local decreases in methylation levels in SF3B1^mut CLL patients at 67 genomic regions, mostly in proximity to telomeric regions. These differentially methylated regions (DMRs) were enriched in gene bodies of cancer-related signaling genes, e.g., NOTCH1, HTRA3, and BCL9L. In our study, SF3B1 mutations exclusively emerged in two out of three epigenetic stages of the originating B cells. However, not all the DMRs could be associated with the methylation programming of B cells during development, suggesting that mutations in SF3B1 cause additional epigenetic aberrations during carcinogenesis. Full article

The purpose of the study was to investigate the role of vitamin D binding protein (VDBP, DBP) and its polymorphism in the vitamin D pathway and human health. This narrative review shows the latest literature on the most popular diseases that have previously been linked to VDBP. Vitamin D plays a crucial role in human metabolism, controlling phosphorus and calcium homeostasis. Vitamin D binding protein bonds vitamin D and its metabolites and transports them to target tissues. The most common polymorphisms in the VDBP gene are rs4588 and rs7041, which are located in exon 11 in domain III of the VDBP gene. rs4588 and rs7041 may be correlated with differences not only in vitamin D status in serum but also with vitamin D metabolites. This review supports the role of single nucleotide polymorphisms (SNPs) in the VDBP gene and presents the latest data showing correlations between VDBP variants with important human diseases such as obesity, diabetes mellitus, tuberculosis, chronic obstructive pulmonary disease, and others. In this review, we aim to systematize the knowledge regarding the occurrence of diseases and their relationship with vitamin D deficiencies, which may be caused by polymorphisms in the VDBP gene. Further research is required on the possible influence of SNPs, modifications in the structure of the binding protein, and their influence on the organism. It is also important to mention that most studies do not have a specific time of year to measure accurate vitamin D metabolite levels, which can be misleading in conclusions due to the seasonal nature of vitamin D. Full article

Psoriasis is a multifactorial genetic disease for which the genetic factors explain about 70% of disease susceptibility. Up to 30–40% of psoriasis patients develop psoriatic arthritis (PsA). However, PsA can be considered as a “disease within a disease”, since in most cases psoriasis is already present when joint complaints begin. This has made studies that attempt to unravel the genetic basis for both components of psoriatic disease enormously difficult. Psoriatic disease is also accompanied by a high burden of comorbid conditions, mainly of the cardiometabolic type. It is currently unclear whether these comorbidities and psoriatic disease have a shared genetic basis or not. The nuclear factor of kappa light chain enhancer of activated B cells (NF-κB) is a transcription factor that regulates a plethora of genes in response to infection, inflammation, and a wide variety of stimuli on several cell types. This mini-review is focused on recent findings that highlight the importance of this pathway both in the susceptibility and in the determinism of some features of psoriatic disease. We also briefly review the importance of genetic variants of this pathway as biomarkers of pharmacological response. All the above may help to better understand the etiopathogenesis of this complex entity. Full article

Syncope, defined as a transient loss of consciousness caused by transient global cerebral hypoperfusion, affects 30–40% of humans during their lifetime. Vasovagal syncope (VVS) is the most common cause of syncope, the etiology of which is still unclear. This review summarizes data on the genetics of VVS, describing the inheritance pattern of the disorder, candidate gene association studies and genome-wide studies. According to this evidence, VVS is a complex disorder, which can be caused by the interplay between genetic factors, whose contribution varies from monogenic Mendelian inheritance to polygenic inherited predisposition, and external factors affecting the monogenic (resulting in incomplete penetrance) and polygenic syncope types. Full article

The tumor viruses human T-lymphotropic virus 1 (HTLV-1), hepatitis C virus (HCV), Merkel cell polyomavirus (MCPyV), high-risk human papillomaviruses (HR-HPVs), Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpes virus (KSHV) and hepatitis B virus (HBV) account for approximately 15% of all human cancers. Although the oncoproteins of these tumor viruses display no sequence similarity to one another, they use the same mechanisms to convey cancer hallmarks on the infected cell. Perturbed gene expression is one of the underlying mechanisms to induce cancer hallmarks. Epigenetic processes, including DNA methylation, histone modification and chromatin remodeling, microRNA, long noncoding RNA, and circular RNA affect gene expression without introducing changes in the DNA sequence. Increasing evidence demonstrates that oncoviruses cause epigenetic modifications, which play a pivotal role in carcinogenesis. In this review, recent advances in the role of host cell epigenetic changes in virus-induced cancers are summarized. Full article