Summary Background Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no ...genetic markers of treatment response have been reproducibly identified. Methods Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. Findings A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10−8 ; rs78015114, p=1·31 × 10−8 ; rs74795342, p=3·31 × 10−9 ; and rs75222709, p=3·50 × 10−9 ). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1–13·0). Interpretation The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4 . LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. Funding Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.
Background Recent studies reported a gain-of-function mutation in the gene encoding coagulation Factor XII (F12) among 5 German and French families with estrogen-associated angioedema who share a ...common ancestor. The role of this factor, additional pathways that might contribute to increased bradykinin levels, or both remain to be determined in other families with estrogen-dependent or estrogen-associated inherited angioedema. Objective The purpose of this study was to determine whether mutations in F12 and polymorphisms in the genes encoding aminopeptidase P (APP) and angiotensin I–converting enzyme (ACE), which have been associated with increased bradykinin levels, contribute to estrogen-dependent inherited angioedema in a large family of Italian origin. Methods We screened the coding regions of F12 and the gene encoding membrane-bound APP ( XPNPEP2 ), for genetic variants in the 3 affected female subjects. In addition, we genotyped this family for the insertion/deletion polymorphism in the ACE gene, which accounts for variable ACE levels. Results The 3 affected female subjects all have the threonine-to-lysine (Thre328Lys) mutation, which is associated with higher Factor XII activity. In addition, they have at least one A allele of rs3788853 at the XPNPEP2 locus, which is associated with lower APP activity, and at least one I allele in ACE , which is associated with reduced ACE activity. Conclusion A missense mutation in F12 is present in the 3 affected female subjects of this family with estrogen-dependent inherited angioedema. In addition, these affected females have polymorphisms associated with lower levels of both APP and ACE, the major enzymes responsible for bradykinin degradation. Thus, our study suggests that multiple genes might contribute to estrogen-dependent or estrogen-associated inherited angioedema and explain some of the observed heterogeneity.
Abstract Background Congenital insensitivity to pain is a rare autosomal recessive disease. Individuals who are diagnosed with congenital insensitivity to pain usually present severely impaired pain ...perception, and in some cases, they also manifest a decreased sense of smell (anosmia). This disease is caused by loss of function mutations affecting the SCN9A gene, which encodes the voltage-gated sodium channel Nav1.7. It is noteworthy that nearly every mutation linking this particular channel to congenital insensitivity to pain has been demonstrated to underlie the translation of a truncated protein. Methods Complete sequencing of the SCN9A gene in a Moroccan 3-year-old child with congenital insensitivity to pain. Result We identified a homozygous nonsense mutation (c.4795C>T) in exon 27, that results in codon stop in the amino acid (p.R1599X). Conclusion In this report we present a previously unreported homozygous nonsense mutation present in a consanguineous Moroccan congenital insensitivity to pain patient with anosmia. The identification of this mutation extends the spectrum of mutations affecting the Nav1.7 channel, and it confirms earlier studies that established Nav1.7 roles in nociception and the sense of smell.
Abstract The current study aimed to examine whether the APOE ε4 allele, associated with dementia with Lewy bodies (DLB), and possibly with dementia in Parkinson’s disease (PD), is also associated ...with idiopathic REM sleep behavior disorder (RBD). Two SNPs, rs429358 and rs7412, were genotyped in RBD patients (n=480) and in controls (n=823). APOE ε4 allele frequency was 0.14 among RBD patients and 0.13 among controls (OR=1.11, 95% CI 0.88-1.40, p =0.41). APOE ε4 allele frequencies were similar in those who converted to DLB (0.14) and those who converted to PD (0.12) or multiple system atrophy (0.14, p =1.0). The APOE ε4 allele is neither a risk factor for RBD nor it is associated with conversion from RBD to DLB or other synucleinopathies.
Abstract Background Very few data exist on the long-term follow-up of patients with intermediate nonobstructive saphenous vein graft (SVG) lesions. The purpose of this study was to evaluate the ...5-year clinical outcomes of the patients enrolled in the Moderate Vein Graft Lesion Stenting With the Taxus Stent and Intravascular Ultrasound (VELETI) and the factors associated with SVG disease progression and outcomes. Methods Patients with ≥ 1 intermediate SVG lesion (30%-60% diameter stenosis) were randomized to either stenting the SVG lesion with a paclitaxel-eluting stent (PES group, n = 30) or to medical treatment alone (MT group, n = 27). All patients were followed yearly up to 5 years. Results Major adverse cardiac events (MACEs) (cardiac death, myocardial infarction MI, revascularization) related to the target SVG lesion tended to be lower in the PES group (17% vs 33%; P = 0.146) due to a lower lesion revascularization rate (13% vs 33%; P = 0.072), with no difference in cardiac death or MI between groups. MACEs related to the target SVG and global MACEs were similar between groups ( P > 0.20 for both). A higher cholesterol level at baseline was the only independent predictive factor of MACEs related to the target SVG ( P = 0.016). Conclusions Over a 5-year period, one third of intermediate lesions in old SVGs progressed, leading to a cardiac event. Stenting these lesions with PESs tended to improve clinical outcomes by reducing lesion progression but not SVG failure. Higher cholesterol levels were associated with SVG disease progression and clinical events. This pilot study provides the basis for a larger trial to determine the efficacy of intermediate SVG lesion plaque sealing.
Abstract Background Vanishing white matter disease is an autosomal recessive leukodystrophy caused by mutations in any of the five genes encoding the subunits of the eukaryotic translation initiation ...factor 2B. Most of the reported patients are of North American and European ancestry. Objective The objective of the study was to review the clinical, radiological, and molecular characteristics of vanishing white matter disease in a cohort of French-Canadian patients. Methods Between 2004 and March 2012, five French-Canadian (non-Cree) patients from Quebec were clinically and genetically diagnosed with vanishing white matter disease within three Montreal Neurogenetics and Leukodystrophy clinics. Their clinical presentation and evolution, demographic characteristics, genetic mutations, and imaging were reviewed and compared with what is known in the literature. Results Sequencing of the exons and intronic boundaries of the EIF2B1-5 genes revealed a rare 260C>T (A87V) missense mutation in EIF2B3 in two homozygous patients and one compound heterozygous patient. This mutation was previously reported in only one patient in the literature. The carrier frequency is unknown. Also, three of five Quebec patients had an extremely rare vanishing white matter disease presentation of migraines with transient neurological abnormalities. Conclusion The 260C>T (A87V) mutation in exon 3 of the EIF2B3 gene is likely a founder mutation for vanishing white matter disease in Quebec. Transient hemiparesthesia and hemiparesis episodes accompanied by headaches as presenting abnormalities of vanishing white matter disease are usually rare but seemed to be more frequent among the French-Canadian Quebec patients. They seemed to be preceded by periods of stress.
Methods Genomic DNA of the patient and two affected sons was extracted from peripheral blood and exon 9, intron 9 and exon 10 of F12 was sequenced using Sanger sequencing.
Objectives The aim of this study was to determine whether a very early imaging strategy improves the prediction of late systolic dysfunction and poor outcomes in ST-segment elevation myocardial ...infarction (STEMI) compared with traditional predictors. Background Earlier prediction of poor outcomes after STEMI is desirable, because it will allow tailored therapy at the earliest possible time, when benefits might be greatest. Methods One hundred and three patients with acute STEMI were studied by contrast-enhanced cardiovascular magnetic resonance within 12 h of primary angioplasty and at 6 months and followed >2 years. The primary end point was left ventricular (LV) dysfunction, whereas poor outcomes were a key secondary end point. Results Traditional risk factors were only modest predictors of late LV dysfunction. Late gadolinium enhancement (LGE) volume maintained a stronger association to LV ejection fraction change than infarct transmurality, microvascular obstruction, or myocardial salvage during STEMI (p = 0.02). Multivariable logistic regression identified LGE volume during STEMI as the best predictor of late LV dysfunction (odds ratio: 1.36, p = 0.03). An LGE ≥23% of LV during STEMI accurately predicted late LV dysfunction (sensitivity 89%, specificity 74%). The LGE volume provided important incremental benefit for predicting late dysfunction (area under the curve = 0.92, p ≤ 0.03 vs. traditional risk factors). Twenty-three patients developed poor outcomes (1 death, 2 myocardial infarctions, 5 malignant arrhythmias, 4 severe LV dysfunction <35%, 11 hospital stays for heart failure) over 2.6 ± 0.9 years; LGE volume remained a strong independent predictor of poor outcomes, whereas LGE ≥23% carried a hazard ratio of 6.1 for adverse events (p < 0.0001). Conclusions During the hyperacute phase of STEMI, LGE volume provides the strongest association and incremental predictive value for late systolic dysfunction and discerns poor late outcomes.
Objective Brain-derived neurotrophic factor (BDNF) is a key factor in neuroplasticity and has been implicated in the affective disorders; studies have demonstrated elevated BDNF in patients taking ...lithium and other mood stabilizers. The objective of our study was to analyze BDNF in lithium-responsive patients with bipolar disorder (BD) to further understand the role of BDNF in the pathophysiology of BD. Methods Using enzyme-linked immunosorbent assay, we measured transformed B lymphocytes for BDNF protein. Results BDNF levels were 36% lower in lymphoblasts from patients with BD ( n = 12), compared with matched control participants ( n = 13), and 55% lower when compared with their unaffected relatives ( n = 14). Lithium significantly decreased BDNF levels in patients with BD and healthy control participants, although BDNF levels remained lower (33%) in the BD group posttreatment. Conclusion Decreased BDNF may constitute part of the pathophysiologic process of BD in a lithium-responsive subgroup of individuals with this disease. A compensatory mechanism protecting the genetically predisposed unaffected relatives from phenotypic expression of BD is suggested.
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