Prothrombotic gene polymorphisms: possible contributors to hepatic artery thrombosis after orthotopic liver transplantation.

Background: Gene polymorphisms involved in hemostasis have been associated with an increased risk of thromboembolic events. The aim of this study was to assess whether prothrombotic gene polymorphism is a risk factor for hepatic vascular thrombosis after orthotopic liver transplantation (OLT).

Methods: In a series of 421 transplant procedures, genomic DNA was available for genotyping in 381 donors (91%) and 382 recipients (91%).

Lack of association of C-C chemokine receptor 5 Δ32 deletion status with rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, and disease severity.

Objective: C-C chemokine receptor 5 (CCR5) plays an important role in inflammation. A 32 base-pair (Δ32) deletion in the CCR5 gene leads to a nonfunctional receptor. This deletion has been reported to have a protective effect on the development and progression of several autoimmune diseases.

Influence of common variants near INSIG2, in FTO, and near MC4R genes on overweight and the metabolic profile in adolescence: the TRAILS (TRacking Adolescents' Individual Lives Survey) Study.

Background: Overweight is a complex trait in which both environmental and genetic factors play a role.

Objective: We aimed to evaluate the influence of common genetic variants identified by genome-wide association studies on overweight and the metabolic profile in adolescence.

Design: In a population-based cohort of 663 girls and 612 boys aged 16 y, weight, height, skinfold thicknesses, percentage body fat, waist circumference, blood pressure, glucose, insulin, lipid profile, and DNA were obtained.

CD14 polymorphisms in mother and infant, soluble CD14 in breast milk and atopy development in the infant (KOALA Study).

Different CD14 polymorphisms have been associated with atopic phenotypes in infants. In addition, CD14 genotypes of breastfeeding mothers have been associated with soluble CD14 (sCD14) levels in breast milk. The role of CD14 genotypes of infant and mother and their interaction with sCD14 levels in breast milk in atopy development remain to be established.

Level and course of FEV1 in relation to polymorphisms in NFE2L2 and KEAP1 in the general population.

Background: The metabolism of xenobiotics plays an essential role in smoking related lung function loss and development of Chronic Obstructive Pulmonary Disease. Nuclear Factor Erythroid 2-Like 2 (NFE2L2 or NRF2) and its cytosolic repressor Kelch-like ECH-associated protein-1 (KEAP1) regulate transcription of enzymes involved in cellular detoxification processes and Nfe2l2-deficient mice develop tobacco-induced emphysema. We assessed the impact of Single Nucleotide Polymorphisms (SNPs) in both genes on the level and longitudinal course of Forced Expiratory Volume in 1 second (FEV1) in the general population.

Association between donor MBL promoter haplotype and graft survival and the development of BOS after lung transplantation.

Background: Lung transplantation is a well accepted therapy for end-stage lung disease, despite high mortality rates. Mortality after transplantation is mainly caused by allograft failure in the first years after transplantation. Mannose binding lectin (MBL), a recognition molecule of innate immunity, has been associated with transplant outcome in other solid organ transplantation.

Runt-related transcription factor 3 is associated with ulcerative colitis and shows epistasis with solute carrier family 22, members 4 and 5.

Background: Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), are intestinal inflammatory disorders with a complex genetic background. Mice deficient for the runt-domain-transcription-factor3 (Runx3) develop spontaneous colitis. Human RUNX3 resides in an IBD-susceptibility locus.

Possible association between telomere length and renal dysfunction in patients with chronic heart failure.

Renal function impairment relates to poor outcome in patients with chronic heart failure (HF). Differences in biological aging could affect the susceptibility to develop renal dysfunction in chronic HF. In the present study, we explored the association of leukocyte telomere length with renal function in patients with chronic HF.

PROS1 analysis in 87 pedigrees with hereditary protein S deficiency demonstrates striking genotype-phenotype associations.

Hereditary protein S (PS) deficiency predisposes to venous thrombosis. Previously, we demonstrated a difference in risk of venous thrombosis between PS deficiency type I and type III. We used direct sequencing, multiplex ligation-dependent probe amplification (MLPA), and linkage analysis to study whether this difference could be explained by molecular heterogeneity.

Variation in bleomycin hydrolase gene is associated with reduced survival after chemotherapy for testicular germ cell cancer.

Purpose: Response to chemotherapy may be determined by gene polymorphisms involved in metabolism of cytotoxic drugs. A plausible candidate is the gene for bleomycin hydrolase (BLMH), an enzyme that inactivates bleomycin, an essential component of chemotherapy regimens for disseminated testicular germ-cell cancer (TC). We investigated whether the single nucleotide polymorphism (SNP) A1450G of the BLMH gene (rs1050565) is associated with survival.

Serum chemokine levels in Hodgkin lymphoma patients: highly increased levels of CCL17 and CCL22.

Hodgkin lymphoma (HL) is characterized by a minority of neoplastic Hodgkin-Reed Sternberg (HRS) cells surrounded by a non-neoplastic reactive infiltrate. As immunological mechanisms appear to be crucial in classical HL pathogenesis, altered serum chemokine levels might be related to disease activity. Serum levels of nine chemokines were examined in 163 untreated HL patients and 334 controls.

Glucocorticoid replacement is associated with hypertriglyceridaemia, elevated glucose and higher non-HDL cholesterol and may diminish the association of HDL cholesterol with the -629C>A CETP promoter polymorphism in GH-receiving hypopituitary patients.

Objectives: The effect of glucocorticoid substitution on the prevalence of metabolic syndrome components (NCEP ATP III criteria) and serum lipid levels was determined in GH-replaced hypopituitary patients. As glucocorticoid replacement is associated with a pronounced decrease in plasma cholesteryl ester transfer protein (CETP) activity, we also tested associations of HDL cholesterol with the -629C>A CETP promoter polymorphism in subjects with and without ACTH deficiency.

Design And Patients: In a university setting, we retrieved protocolized clinical and laboratory data from 165 adult hypopituitary patients, who had received GH for 1 year.

Novel association in chromosome 4q27 region with rheumatoid arthritis and confirmation of type 1 diabetes point to a general risk locus for autoimmune diseases.

Recently, association of celiac disease with common single-nucleotide polymorphism (SNP) variants in an extensive linkage-disequilibrium block of 480 kb containing the KIAA1109, Tenr, IL2, and IL21 genes has been demonstrated in three independent populations (rs6822844P combined=1.3 x 10(-14)). The KIAA1109/Tenr/IL2/IL21 block corresponds to the Idd3 locus in the nonobese diabetic mouse model of type 1 diabetes (T1D).

Renal function dependent association of AGTR1 polymorphism (A1166C) and electrocardiographic left-ventricular hypertrophy.

Background: The association of renin-angiotensin system (RAS) polymorphisms and left-ventricular hypertrophy (LVH) may depend on the presence of risk factors for LVH, such as renal dysfunction. We studied whether renal function modulates the association between RAS polymorphisms and LVH in a cross-sectional study of 8592 inhabitants of Groningen.

Methods: Left-ventricular hypertrophy was determined with electrocardiograms, using the Cornell voltage-duration product.

Association of interleukin-1 receptor-associated kinase M (IRAK-M) and inflammatory bowel diseases.

Objective: Inflammatory bowel diseases (IBD) have a complex genetic background. The interleukin receptor associated kinase-M (IRAK-M) is a NF-kappaB-mediated, negative regulator of Toll-like receptor (TLR) signaling. A functional mutation in a negative regulator might induce impaired endotoxin tolerance and increased inflammatory responses.

Genetic susceptibility has a more important role in pediatric-onset Crohn's disease than in adult-onset Crohn's disease.

Background: Genetic susceptibility may play a more important role in the etiology of early-onset inflammatory bowel disease (IBD) than in late-onset IBD, and therefore pediatric-onset IBD patients can be expected to have a higher frequency of gene mutations. We aimed to determine genotypes and phenotypes of patients with pediatric-onset IBD, to compare them with those of patients with adult-onset IBD and with controls, and to identify genotype-phenotype associations.

Methods: Polymorphisms R702W, G908R, and 3020insC of CARD15 (caspase activating recruitment domain 15); Asp299Gly and Thr399Ile of TLR4; -207G-->C, 1672C-->T (L503F), rs3792876, rs274551, rs272893, and rs273900 of SLC22A4/5; and 113G-->A as well as rs2289311, rs1270912, and rs2165047 of DLG5 (Drosophila discs large homologue 5) were assessed in 103 pediatric-onset and 696 adult-onset IBD patients.

Telomere length of circulating leukocytes is decreased in patients with chronic heart failure.

Objectives: This study sought to test the hypothesis that patients with chronic heart failure (CHF) have shorter telomeres compared with age-balanced and gender-balanced healthy individuals.

Background: Telomere length is considered to be a marker of biological aging. Chronic heart failure might be viewed as a condition associated with accelerated biological aging.

The human leukocyte antigen class I region is associated with EBV-positive Hodgkin's lymphoma: HLA-A and HLA complex group 9 are putative candidate genes.

Various studies have indicated that the human leukocyte antigen (HLA) region is associated with Hodgkin's lymphoma. We recently showed a specific association of the HLA class I region with EBV-positive Hodgkin's lymphoma cases. One haplotype of two consecutive microsatellite markers (D6S265 and D6S510) was overrepresented in the patient group, whereas another haplotype was underrepresented.

Absence of association between the multidrug resistance (MDR1) gene and inflammatory bowel disease.

Objective: The multidrug resistance (MDR1) gene encodes for P-glycoprotein, a drug efflux pump. Mice deficient for the MDR1a gene spontaneously develop colitis. In humans, a polymorphism in exon 26 (C3435T) is associated with reduced expression levels and function of MDR1.

Identification of a novel PROS1 c.1113T-->GG frameshift mutation in a family with mixed type I/type III protein S deficiency.

We report a family with type I and type III protein S (PS) deficiency, which showed to be phenotypic variants of the same genetic disease. Direct sequencing analysis of the PROS1 gene was performed to establish the genotype. The ratio of protein C antigen and total PS antigen levels (protein C/S ratio) was used to classify subjects at risk of venous thromboembolism.

An increased coronary risk is paradoxically associated with common cholesteryl ester transfer protein gene variations that relate to higher high-density lipoprotein cholesterol: a population-based study.

Background: Several cholesteryl ester transfer protein (CETP) polymorphisms affect high-density lipoprotein (HDL) cholesterol, but the impact of CETP gene variants on incident coronary disease in the general population is uncertain after correction for their effect on HDL cholesterol.

Design: We determined relationships between the CETP -629C-->A promoter (n = 8141), the TaqIB (n = 8289), and the I405V (n = 8265) polymorphisms, serum lipids, C-reactive protein, and clinical factors with incident coronary heart disease (defined as death from or hospitalization for myocardial infarction, ischemic heart disease, or coronary intervention) during a median of 4.94 yr follow-up.

Restenosis after percutaneous coronary intervention is associated with the angiotensin-II type-1 receptor 1166A/C polymorphism but not with polymorphisms of angiotensin-converting enzyme, angiotensin-II receptor, angiotensinogen or heme oxygenase-1.

Objectives: The renin-angiotensin system (RAS) is thought to play a major role in the pathophysiology of de-novo restenotic lesions and in-stent restenosis after percutaneous coronary intervention (PCI). Heme oxygenase-1 (HO-1), is thought to beneficially influence these processes. We examined the effect of pharmacologic as well as genetic RAS interactions on restenosis in a large population of consecutive patients undergoing PCI, and evaluated possible gene-gene interactions in both systems.

Use of sequence variation in three highly variable regions of the mitochondrial DNA for the discrimination of allogeneic platelets.

Background: Human mitochondrial DNA (mtDNA) polymorphisms can be used to detect allogeneic transfused platelets. To increase the number of informative polymorphisms we investigated three hypervariable regions (HVR1, HVR2, and HVR3) within the displacement loop (D-loop) region of the mtDNA.

Study Design And Methods: mtDNA was obtained from 119 unrelated blood donors.

No increased susceptibility to breast cancer from combined CHEK2 1100delC genotype and the HLA class III region risk factors.

CHEK2 is low-penetrance breast cancer susceptibility gene. The 1100delC mutation may interact with variants/mutations in other breast cancer susceptibility loci. We identified a risk haplotype in the HLA class III region in breast cancer patients [de Jong MM, Nolte IM, de Vries EGE, et al.