Analysis of ileal sodium/bile acid cotransporter and related nuclear receptor genes in a family with multiple cases of idiopathic bile acid malabsorption

INTRODUCTION Bile acids are synthesized from cholesterol in the liver and secreted into the small intestine, where they facilitate absorption of fat, fat-soluble vitamins and cholesterol[1]. The bile acids are then reabsorbed from the intestine and return…     

Association between A218C polymorphism of the tryptophan-hydroxylase-1 gene,harm avoidance and binge eating behavior in bulimia nervosa

Genes involved in serotonin transmission are likely involved in the biological predisposition to bulimia nervosa. We investigated whether the A218C polymorphism of the tryptophan-hydroxylase-1 gene was associated to bulimia nervosa and/or to some phenotypic aspects of the disorder. One hundred eighty Caucasian women (91 patients with bulimia nervosa and 89 healthy controls) were enrolled into the study. They underwent a blood sample collection for A218C polymorphism of the tryptophan-hydroxylase-1 genotyping and a clinical evaluation assessing comorbidity for Axis I and II psychiatric disorders, harm avoidance personality dimension and bulimic symptoms. The distribution of both tryptophan-hydroxylase-1 A218C genotypes and alleles did not significantly differ between patients and controls. Bulimic women with the AA genotype exhibited a more severe binge eating behavior and higher harm avoidance scores than those with CC genotype. These findings support the idea that tryptophan-hydroxylase-1 A218C polymorphism does not play a part in the genetic susceptibility to bulimia nervosa, but it seems to be involved in predisposing bulimic patients to a more disturbed eating behavior and higher harm avoidance.     

Genetic causes of monogenic familial hypercholesterolemia in the Greek population: Lessons,mistakes, and the way forward

Familial hypercholesterolemia (FH) is a leading cause of premature atherosclerosis. Genetic defects in the LDLR, APOB and PCSK9 genes cause FH, and confirmation of a gene defect is essential for an indisputable diagnosis of the disease. FH is underdiagnosed and we aimed to revise the genetic defects that have been characterized in FH patients of Greek origin and define an effective, future strategy for genetic studies. A literature search was performed in MEDLINE and EMBASE on genetic studies with FH patients of Greek origin. To date, no APOB and PCSK9 mutations have been found in the Greek population. It must be noted however, that only a small number of patients has been screened for PCSK9 mutations. In total, 41 LDLR defects have been characterized, with 6 common mutations c.1646G>A (p.Gly546Asp), c.858C>A (p.Ser286Arg), c.81C>G (p.Cys27Trp), c.1285G>A (p.Val429Met), c.517T>C (p.Cys173Arg), and c.1775G>A (p.Gly592Glu) that account for >80% of all mutations. Due to geographic isolation, ​founder mutations exist in a subpopulation in North West Greece and the Greek Cypriot population but not in the general population. Genetic testing should focus primarily on LDLR, and subsequently on PCSK9 and APOB. The Greek population is genetically homogeneous, which allows for a quick molecular diagnosis of the disease. Cascade screening is feasible and will certainly facilitate the identification of additional patients.     

QT interval prolongation and risk for cardiac events in genotyped LQTS-index children

Congenital long-QT syndrome (LQTS) is an inherited cardiac disorder with a disturbance in repolarization characterized by a prolonged QT interval on the surface electrocardiogram and life-threatening ventricular tachycardia. Publications from the International LQTS Registry have provided information that the cardiac risk may be influenced by gender, genotype, exposure to arrhythmia triggers, and previous cardiac events. In children, early-onset of disease, changes in life style, and medical treatment is a sensitive issue and significant, gender-related differences of a first life-threatening event were reported. Thus, we investigated the clinical features of a large genotyped population of LQTS-index children (age ≤16 years) upon a single-center experience and determined risk factors for symptoms. Of 83 children [mean corrected QT interval (QTc) 510 ± 74 ms], 89% had LQT1, -2, or -3. Nine patients (11%) were identified as having Jervell and Lange-Nielsen syndrome. Among symptomatic children (n = 51, 61%), syncope was the most prevalent symptom at initial presentation (49%); however, aborted cardiac arrest (ACA) occurred in 33% and sudden cardiac death (SCD) in 18%, respectively, as the initial manifestation. During a mean follow-up period of 5.9 ± 4.7 years, 31% of the children developed symptoms while on therapy (86% syncope, 9% ACA, 5% SCD). Statistical analyses of risk factors for cardiac events showed that the QTc >500 ms was a strong and significant predictor for cardiac events during follow-up (p = 0.02). Furthermore, a prior syncope [hazard ratio (HR), 4.05; 95% confidence interval (CI), 1.1 to 15.0; p = 0.03] or an ACA (HR, 11.7; 95% CI, 3.1 to 43.4; p = <0.001) identified children with an increased risk for recurrent cardiac events compared to asymptomatic LQT children. LQTS-index children manifest with a high percentage of severe symptoms. Among presently validated risk factors for LQTS, a QTc interval >500 ms and a history of prior syncope or ACA were strong predictors for recurrent cardiac events.     

Prevention of type 1 diabetes

Prevention of loss of b cells in type 1 diabetes is a major goal of current research. Knowledge of the genetic susceptibility, increasing ability to predict who may be at risk, recognition of the potential clinical impact of residual insulin secretion after diagnosis, and development of new immunomodulatory agents have supported an increasing number of clinical trials to prevent b-cell loss. Interventions can be targeted at 3 stages: before the development of autoimmunity (primary prevention), after autoimmunity is recognized (secondary prevention), or after diagnosis when significant numbers of b cells remain (tertiary prevention). Thus far, several agents show promise when given shortly after diagnosis, but no interventions before diagnosis have shown benefit. Knowledge in this area has grown quickly in recent years and will continue to grow rapidly with several international collaborative efforts underway.     

实验性变态反应性脑脊髓炎大鼠模型的复制

目的：观察不同的遗传背景（远交系和近交系）和饲养环境对Wistar大鼠实验性变态反应性脑脊髓炎（EAE）发病率的影响，摸索EAE模型制作的实验方法与技术。方法： 采用动物行为学、常规HE和LFB染色方法，观察不同的遗传背景和饲养环境下豚鼠全脊髓匀浆诱导大鼠EAE的发病情况与中枢神经系统（CNS）的病理变化。结果： （1）动物行为学的改变：各组大鼠EAE发病率、潜伏期和症状评分无显著差异，但近交系组发病大鼠可出现四肢瘫痪。（2）病理学改变：每组发病大鼠CNS内可见不同程度的炎性细胞浸润；髓鞘染色可见广泛的神经髓鞘变性、脱失；而其中近交系组的5只EAE大鼠髓鞘脱失部位大多局限在炎症改变明显的血管套周围的白质区。结论： 远交系与近交系，或清洁级与普通级的Wistar大鼠的EAE的发病率无明显差异，而远交系与近交系的不同遗传背景可能会影响大鼠EAE的体征和病理表现。     

Genetic regulation of thymic involution

In this review, we have summarized our work using combined complex statistical genetics, bioinformatics, and functional genomics to determine the genetic basis of the age-related thymic involution in C57BL/6J X DBA/2J recombinant inbred mice and the parental B6 and D2 mice. We have shown that these mice provided a valuable genetic model that can permit resampling of thymuses from different aged but genetically identical animals and determination of the relative significance of age-associated changes in the thymus. Our results suggest that the quantitative trait loci (QTL) regulating the Con A-induced thymocyte proliferative response were mapped to mouse chromosome Chr 11 (D11Mit51 at 18 cM), a region that harbors the IL-12b gene. The importance of IL-12b in maintaining thymic integrity and function during the aging process was confirmed by a more rapid involution of the thymus in IL-12b knockout (IL-12b-/-) mice compared to wild-type (WT) mice. Functionally, IL-12 provided a strong synergistic effect to augment the IL-7 or IL-2 induced thymocyte proliferative response, especially in both aged WT and IL-12b-/- mice, but not in normal young mice. In contract to the proliferative response, the age-related decline in the total number of thymocytes was determined at different age, and mapped to loci on Chr 9, 62 cM and Chr 10, 32 cM. Using matrix-assisted laser desorption/ionisation-time of flight-mass spectrometry (MALDI-TOF-MS), increased expression of peroxiredoxin was found to be correlated with thymic involution. Our results suggest the possibility to identify the complex molecular network that can be associated with the regulation of thymic involution in aged mice using a high-dimensional functional genomics approach.     

Continuity and Change in Preschool ADHD Symptoms: Longitudinal Genetic Analysis with Contrast Effects

The genetic and environmental mediation of continuity and change in parent-reported ADHD symptoms were investigated in a cohort of over 6000 twin pairs at 2, 3 and 4 years of age. Genetic analyses of the cross-sectional data yielded heritability estimates of 0.78–0.81 at each age, with contrast effects. A common pathway model provided the best fit to the longitudinal data, indicating that genetic influences underlie 91% of the stable variance in ADHD symptomatology. In other words, what is stable for ADHD symptoms is largely genetic. Contrast effects acting in the same direction at different ages contributed to the observed continuity:longitudinal correlations were greater for dizygotic than monozygotic twins.The Twins Early Development Study is funded by the Medical Research Council.     

The methionine allele of the COMT polymorphism impairs prefrontal cognition in children and adolescents with ADHD

ADHD is a highly heritable psychiatric disorder of childhood. A functional polymorphism (Val158Met) of the catechol-O-methyltransferase (COMT) gene has attracted interest as a candidate gene for ADHD. The high-activity valine variant of this polymorphism degrades prefrontal dopamine three to four times more quickly than the low-activity methionine variant and could therefore contribute to the proposed hypodopaminergic state in ADHD. Here we tested for association of this polymorphism with ADHD and examined its influence on prefrontal cognition in ADHD. We have previously reported no association of the Val158Met COMT gene polymorphism in 94 Irish ADHD families (Hawi et al. (2000) Am J Med Genet 96:282–284). Here we re-examined this finding with an extended sample of 179 ADHD cases using a family control design. We also examined the performance of children and adolescents with ADHD (n=61) on a standardised test of sustained attention. Analysis confirmed the absence of an association between the Val158Met COMT gene polymorphism and the clinical phenotype of ADHD. COMT genotype, however, affected prefrontal cognition in ADHD: ADHD children who were homozygous for the valine variant had significantly better sustained attention than those ADHD children possessing at least one copy of the methionine variant. Children possessing the methionine variant performed significantly below age-related norms on tests of sustained attention. Contrary to expectations, the methionine variant of the Val158Met COMT gene polymorphism impaired prefrontally-mediated cognition in ADHD. This effect may be understood by positing a hyper-functioning of prefrontal dopaminergic systems. Against this background, the slower clearance of dopamine associated with the methionine variant of the COMT gene polymorphism may be disadvantageous to cognition in ADHD.Mark Bellgrove and Katharina Domschke contributed equally to this work and should therefore both be considered first authors. The work reported herein was supported by a grant from the Irish Health Research Board.     

Gene expression and genotyping studies implicate the interleukin 7 receptor in the pathogenesis of primary progressive multiple sclerosis

Multiple sclerosis (MS) is an enigmatic disease of the central nervous system resulting in sclerotic plaques with the pathological hallmarks of demyelination and axonal damage, which can be directly or indirectly orchestrated by cells from the peripheral circulation. The majority of patients with MS follow a relapsing–remitting course in the early stages of the disease (RRMS) but most ultimately enter a secondary progressive phase (SPMS). About 10% of patients follow a primary progressive course from the onset (PPMS). We measured gene expression in whole blood of people with and without chronic progressive MS (CPMS), PPMS and SPMS, to discover genes which may be differentially expressed in peripheral blood in active disease, and so identify pathologically significant genes and pathways; and we investigated genetic differences in the promoters of dysregulated genes encoded in genomic regions associated with MS. If SPMS and PPMS were independently compared to the controls, there was little overlap in the set of most dysregulated genes. Ribosomal protein genes, whose expression is usually associated with cell proliferation and activation, were dramatically over-represented in the set of most down-regulated genes in PPMS compared to SPMS (P<10^–4, ²). The T cell proliferation gene IL7R (CD127) was also underexpressed in PPMS, but was up-regulated in SPMS compared to the controls. One interleukin 7 receptor (IL7R) promoter single nucleotide polymorphism (SNP), –504 C, was undertransmitted in PPMS trios (P=0.05, TDT), and carriers of this allele were under-represented in PPMS cases from two independent patient cohorts (combined P=0.006, FE). The four known IL7R promoter haplotypes were shown to have similar expression levels in healthy controls, but not in CPMS (P<0.01, t test). These data support the hypothesis that PPMS has significant pathogenetic differences from SPMS, and that IL7R may be a useful therapeutic target in PPMS.Members of the Southern MS Genetics Consortium: Justin Rubio, Trevor Kilpatrick, Helmut Butzkueven, Niall Tubridy, Mark Mariott, Caron Chapman, John Carey, Jo Baker, Laura Johnson, Rachel Tan, Simon Foote, Stewart Huxtable, Melanie Bahlo, Jim Stankovich, Terry Speed