Association of F11 polymorphism rs2289252 with deep vein thrombosis and related phenotypes in population of Latvia

Introduction

Deep vein thrombosis (DVT) has a strong inherited predisposition that is partly explained by the strong genetic risk factors such as mutations in factor V, prothrombin, antithrombin III, protein C and S genes. Only recently the first GWAS have been performed on DVT resulting in discovery of novel genetic variants, however, the information on the common polymorphisms predisposing to the risk of DVT is still scarce.

Materials and Methods

Here we selected six SNPs (rs5361 in SELE, rs2066865 in FGG, rs2227589 in SERPINC1, rs1613662 in GP6, rs13146272 in CYP4V2, rs2289252 in F11) reported to be associated with venous thrombosis conditions and studied the association of these common variants in selected case (n = 177) and control (n = 235) groups from population of Latvia. Genotyping was performed using TaqMan hybridization probe SNP genotyping assay.

Results

Patients with DVT had a significantly higher frequency of F11 rs2289252 polymorphism (p = 0.001; OR [95%CI] = 1.61 [1.20-2.14]). When stratified by recurrence of DVT the tendency was observed that the same SNP had higher OR value in group of DVT patients with repeated episodes of DVT compared to patients with single DVT episode (p = 0.009; OR [95%CI] = 2.27[1.22-4.21] and p = 0.009; OR [95%CI] = 1.52[1.11-2.08] respectively), but due to limited group of cases this finding should be replicated.

Conclusion

We conclude that F11 gene variant rs2289252 contribute to inherited forms of DVT incidence and correlation of other analysed SNPs should be explored in populations with greater sample size and associated with various thrombosis related traits.     

Novel LDLR Variants in Patients with Familial Hypercholesterolemia: In Silico Analysis as a Tool to Predict Pathogenic Variants in Children and Their Families

Familial hypercholesterolemia (FH) is an autosomal dominant disease with a frequency of 1:500 in its heterozygous form. To date, mutations in the low‐density lipoprotein receptor gene (LDLR) are the only identified causes of FH in the Greek population, causing high levels of low‐density lipoprotein (LDL) and total cholesterol and premature atherosclerosis. The Greek FH population is genetically homogeneous, but most previous studies screened for the most common mutations only. The study aimed to characterize and assess novel LDLR variants. LDLR was examined by whole‐gene DNA sequencing in 561 FH patients from 262 families of Greek origin. Novel LDLR variants were analyzed in silico using various software predicting pathogenicity and changes in protein stability. Twelve novel LDLR variants were identified, six of which are putative disease‐causing variants: c.977C>G in exon 7, c.1124A>C in exon 8, c.1381G>T in exon 10, c.628_643dup{636del}, c.661–673dup in exon 4, and 13 c.1987+1_+33del in intron 13. All six putative variants were confirmed in the hypercholesterolemic members of the family. The results show that in silico analysis is a valuable tool to predict potential pathogenicity of novel variants, especially for populations that have not been extensively studied. The identification of novel pathogenic variants will facilitate the molecular diagnosis of FH from early childhood.     

Suppression of epithelial restitution using an inhibitor against Rho-associated coiled-coil containing protein kinase aggravates colitis through reduced epithelial expression of A-kinase anchor protein 13

In the gastrointestinal tract, the immediate healing response to mucosal damage is critical to sustain mucosal homeostasis. The migration of surrounding epithelial cells to cover the denuded area without proliferation is termed restitution, followed by early reparation of the damage. In this study, we determined the role of A-kinase anchor protein 13 (AKAP13) in mice with dextran sulphate sodium (DSS)-induced colitis upon mucosal injury and restitution, and investigated whether inhibition of Rho-associated coiled-coil containing protein kinase (ROCK), downstream effector of AKAP13, affects these mucosal responses. BALB/c mice were challenged with 4% or 2% DSS in their drinking water for up to 8 or 16 days, respectively. During this period, mice received subcutaneous injections of fasudil hydrochloride hydrate (FH, 10 mg/kg, twice per day), an inhibitor of phosphorylation of ROCK. In immunohistochemistry, AKAP13 was highly expressed in the mucosal epithelium prior to DSS-induced mucosal injury, and also expressed in ulcer-covering non-proliferative epithelium, which corresponded to restituted epithelial cells. Coadministration of FH increased serum amyloid A levels and histopathological scores for mucosal injury, as compared with the DSS group. The effects were associated with a decrease in gene expression of Akap13 in the mucosal tissue and the inhibition of restitution rata (the length of restituted epithelial cells per ulcer). These results suggested that AKAP13 and ROCK are involved in mucosal response at early injury and restitution during healing in DSS-induced colitis in mice.     

直肠黏膜渗液FH检测在非手术直肠癌局部疗效评价中的临床意义

目的探讨直肠黏膜渗液FH检测在非手术直肠癌患者局部疗效诊断的临床意义。 方法选取2016年12月至2017年12月36例非手术直肠癌患者，在治疗前、治疗中、治疗后分别进行直肠黏膜渗液FH检测和肠镜检查，以肠镜病理结果为标准，采用SPSS17.0软件进行分析，肠镜和FH两种检测方法对比结果采用卡方检验；Kappa一致性系数检验考察两种检测方法检验结果的相关性和一致性，P<0.05差异具有统计学意义。 结果在治疗前、治疗中、治疗后行直肠黏膜渗液FH检测及肠镜检查的检出率分别为97.2%、100%；55.6%、66.7%；27.8%、33.3%，P均>0.05，差异无统计学意义；在治疗前、治疗中、治疗后FH检测的阳性预测值为91.8%、93.0%和94.7%；治疗中、治疗后两种检测方法的相关性检测Kappa一致性系数分别为0.769和0.870，且P均<0.0001。 结论直肠黏膜渗液FH检测在评估非手术直肠癌局部疗效中的作用和肠镜检查效果基本一致，有望为非手术直肠癌疗效评价提供更加简便、快捷的指标。     

Oncometabolites‐driven tumorigenesis: From genetics to targeted therapy

Although the alteration of cellular metabolism in cancer was reported by Warburg in the early 1930s, a regain of interest in cancer metabolism has more recently followed the discovery of germline or somatic mutations in genes coding for metabolic enzymes (succinate dehydrogenase, fumarate hydratase and isocitrate dehydrogenase) that are associated with tumor susceptibility. Mutations in these genes are found in numerous tumor types including paragangliomas, kidney cancers, leiomyomas, glioblastomas and acute myeloid leukemia. They lead to the accumulation of so‐called oncometabolites that behave as competitors of 2‐oxoglutarate‐dependent dioxygenases, involved in a broad spectrum of pathways such as hypoxic response and epigenetic reprogramming. Here, we review the diverse pathways affected by oncometabolites, their potential role in cancer formation, maintenance, metastasis and sensitivity to chemotherapies, as well as emerging new therapeutic strategies.     

Proton MR spectroscopy of the femoral head--evaluation of patients at risk for avascular necrosis

PURPOSE: To detect alteration of the fatty component by measuring the in vivo lipid and water content of normal-looking femoral heads of patients with and without risk for avascular necrosis (AVN) by using proton MR spectroscopy (MRS). MATERIALS AND METHODS: Marrow composition was measured by proton MRS (TR/TE = 5000/20 msec) in a sample volume placed in the epiphysis of the intact femoral heads of patients with unilateral osteonecrosis of the hip (group 1, N = 61, then excluding the post-traumatic or steroid user, final N = 45) and age-matched controls (group 2, N = 49). Three response variables were derived from MRS: the lipid linewidth (LW), water LW, and lipid/water ratio. RESULTS: Of the three variables, the lipid and water LWs differed significantly between groups (P < 0.001 and P = 0.05, respectively; t-test). The lipid/water ratio had borderline significance (P = 0.06). The three variables differed significantly between groups when multivariate regression (P < 0.0001) was analyzed; and age and sex had no significant effect on the three dependent variables. CONCLUSION: Proton MRS can depict alteration in the lipid and water composition of normal-looking femoral heads with and without AVN on the contralateral hip. Proton MRS may be a potential tool for investigating of the femoral head component in vivo and predicting the risk for development of AVN.     

Biogenesis and function of the autotransporter adhesins YadA,intimin and invasin

Bacteria often express numerous virulence factors. These virulence factors make them successful pathogens, by e.g. mediating attachment to host cells and thereby facilitating persistence or invasion, or by contributing to the evasion of the host immune system to allow proliferation and spread within the host and in the environment. The site of first contact of Gram negative bacteria with the host is the bacterial outer membrane (OM). Consisting of an asymmetrical lipid bilayer with phospholipids forming the inner, and lipopolysaccharides forming the outer leaflet, the OM harbors numerous integral membrane proteins that are almost exclusively β-barrel proteins. One distinct family of OM β-barrel proteins strongly linked to bacterial virulence are the autotransporter (AT) proteins. During the last years huge progress has been made to better understand the mechanisms underlying the insertion of AT proteins into the OM and also AT function for interaction with the host. This review shortly summarizes our current knowledge about outer membrane protein (OMP) and more specifically AT biogenesis and function. We focused on the AT proteins that we haved studied in most detail: i.e. the Yersinia adhesin A (YadA) and invasin of Yersinia enterocolitica (Ye) as well as its homolog intimin (Int) expressed by enteropathogenic Escherichia coli. In addition, this review provides a short outlook about how we could possibly use this knowledge to fight infection.     

Effects of plant stanol and sterol esters on serum phytosterols in a family with familial hypercholesterolemia including a homozygous subject

We studied the concentrations and ratios to cholesterol of noncholesterol sterols reflecting absorption (eg, campesterol) or synthesis (eg, lathosterol) of cholesterol off and on plant sterol and stanol ester spreads in serum and in different lipoproteins of a family with familial hypercholesterolemia, including heterozygous parents receiving no treatment and their homozygous offspring undergoing long-term treatment with statins and apheresis. Serum cholesterol levels were similar in the homozygous and heterozygous individuals, but the concentrations of sterols reflecting cholesterol absorption were as much as 10 times greater in the homozygous child than in the heterozygous parents, whereas the respective markers of cholesterol synthesis only tended to be higher. About 70% of squalene in the homozygous individual (60% in the heterozygous family members) and 85% to 90% of noncholesterol sterols (60%-80% in the heterozygous subjects) were transported by low-density lipoprotein. The ratios of absorption sterols to cholesterol were higher in high-density lipoprotein (HDL) than in very low-density lipoprotein (VLDL), whereas those of synthesis markers and plant stanols were highest in VLDL. The ratios of absorption sterols in serum were mostly lower than those in HDL but higher than in VLDL, whereas the ratios of synthesis sterols in serum were lower than they were in VLDL. Both spreads reduced serum total cholesterol by about 14% in the heterozygous family members and 9% in the homozygous individual. The sterol ester spread increased serum plant sterol concentrations (eg, campesterol in the homozygous family member increased from 5 to 9 mg/dL) and the ratios to cholesterol, but the stanol ester spread decreased them. Plant sterol esters seemed to similarly decrease serum cholesterol in this family with familial hypercholesterolemia, but the clinical role of increased plant sterol concentrations, almost doubled in the LDL of homozygous individuals, is not known.     

Rare variant in the fumarate hydratase gene found in patients with clinical features of hereditary leiomyomatosis and renal cell cancer (HLRCC): A case series

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an inherited cancer predisposition syndrome caused by autosomal dominant heterozygous pathogenic variants in the fumarate hydratase (FH) gene. FH pathogenic variant carriers are at an increased risk for cutaneous leiomyomas, renal cell cancer, and uterine fibroids. We present a case series of patients identified at two different medical institutions with clinically diagnostic features of HLRCC and a shared rare variant in the FH gene.