Founder Mutation c.1516A>C in KLHL40 Is a Frequent Cause of Nemaline Myopathy With Hyponatremia in Ethnic Chinese.

KLHL40-related nemaline myopathy is a severe autosomal recessive muscle disorder. The current study describes 4 cases of KLHL40-related nemaline myopathy in Hong Kong ethnic Chinese presenting within 3 years, which are confirmed with clinicopathologic features and genetic studies. The incidence is estimated to be at least 1 in 45 226 livebirths (at least 1 in 41 608 among ethnic Chinese livebirths) in Hong Kong.

Genetic risk analysis of coronary artery disease in Pakistani subjects using a genetic risk score of 21 variants.

Background And Aims: Conventional coronary artery disease (CAD) risk factors like age, gender, blood lipids, hypertension and smoking have been the basis of CAD risk prediction algorithms, but provide only modest discrimination. Genetic risk score (GRS) may provide improved discrimination over and above conventional risk factors. Here we analyzed the genetic risk of CAD in subjects from Pakistan, using a GRS of 21 variants in 18 genes and examined whether the GRS is associated with blood lipid levels.

A 19-SNP coronary heart disease gene score profile in subjects with type 2 diabetes: the coronary heart disease risk in type 2 diabetes (CoRDia study) study baseline characteristics.

Background: The coronary risk in diabetes (CoRDia) trial (n = 211) compares the effectiveness of usual diabetes care with a self-management intervention (SMI), with and without personalised risk information (including genetics), on clinical and behavioural outcomes. Here we present an assessment of randomisation, the cardiac risk genotyping assay, and the genetic characteristics of the recruits.

Methods: Ten-year coronary heart disease (CHD) risk was calculated using the UKPDS score.

Angiotensin-Converting Enzyme Inhibition as an Adjunct to Pulmonary Rehabilitation in Chronic Obstructive Pulmonary Disease.

Rationale: Epidemiological studies in older individuals have found an association between the use of angiotensin-converting enzyme (ACE) inhibition (ACE-I) therapy and preserved locomotor muscle mass, strength, and walking speed. ACE-I therapy might therefore have a role in the context of pulmonary rehabilitation (PR).

Objectives: To investigate the hypothesis that enalapril, an ACE inhibitor, would augment the improvement in exercise capacity seen during PR.

Effect of SORT1, APOB and APOE polymorphisms on LDL-C and coronary heart disease in Pakistani subjects and their comparison with Northwick Park Heart Study II.

Background: Many SNPs have been identified in genes regulating LDL-C metabolism, but whether their influence is similar in subjects from different ethnicities is unclear. Effect of 4 such SNPs on LDL-C and coronary heart disease (CHD) was examined in Pakistani subjects and was compared with middle aged UK men from Northwick Park Heart Study II (NPHSII).

Methods: One thousand nine hundred sixty-five (1770 non CHD, 195 CHD) UK and 623 (219 non CHD, 404 CHD) Pakistani subjects were enrolled in the study.

PLA2G10 Gene Variants, sPLA2 Activity, and Coronary Heart Disease Risk.

Background: Observational studies report that secretory phospholipase A2 (sPLA2) activity is a marker for coronary heart disease (CHD) risk, and activity measures are thought to represent the composite activity of sPLA2-IIA, -V, and -X. The aim of this study was to use genetic variants of PLA2G10, encoding sPLA2-X, to investigate the contribution of sPLA2-X to the measure of sPLA2 activity and coronary heart disease (CHD) risk traits and outcome.

Methods And Results: Three PLA2G10 tagging single-nucleotide polymorphisms (rs72546339, rs72546340, and rs4003232) and a previously studied PLA2G10 coding single-nucleotide polymorphism rs4003228, R38C, were genotyped in a nested case: control cohort drawn from the prospective EPIC-Norfolk Study (2175 cases and 2175 controls).

Refinement of variant selection for the LDL cholesterol genetic risk score in the diagnosis of the polygenic form of clinical familial hypercholesterolemia and replication in samples from 6 countries.

Background: Familial hypercholesterolemia (FH) is an autosomal-dominant disorder caused by mutations in 1 of 3 genes. In the 60% of patients who are mutation negative, we have recently shown that the clinical phenotype can be associated with an accumulation of common small-effect LDL cholesterol (LDL-C)-raising alleles by use of a 12-single nucleotide polymorphism (12-SNP) score. The aims of the study were to improve the selection of SNPs and replicate the results in additional samples.

HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.

Background: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.

Methods: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins.

A systematic review and meta-analysis of 130,000 individuals shows smoking does not modify the association of APOE genotype on risk of coronary heart disease.

Background: Conflicting evidence exists on whether smoking acts as an effect modifier of the association between APOE genotype and risk of coronary heart disease (CHD).

Methods And Results: We searched PubMed and EMBASE to June 11, 2013 for published studies reporting APOE genotype, smoking status and CHD events and added unpublished data from population cohorts. We tested for presence of effect modification by smoking status in the relationship between APOE genotype and risk of CHD using likelihood ratio test.

Whole exome sequencing of familial hypercholesterolaemia patients negative for LDLR/APOB/PCSK9 mutations.

Background: Familial hypercholesterolaemia (FH) is an autosomal dominant disease of lipid metabolism, which leads to early coronary heart disease. Mutations in LDLR, APOB and PCSK9 can be detected in 80% of definite FH (DFH) patients. This study aimed to identify novel FH-causing genetic variants in patients with no detectable mutation.

Novel genetic approach to investigate the role of plasma secretory phospholipase A2 (sPLA2)-V isoenzyme in coronary heart disease: modified Mendelian randomization analysis using PLA2G5 expression levels.

Background: Secretory phospholipase A2 (sPLA2) enzymes are considered to play a role in atherosclerosis. sPLA2 activity encompasses several sPLA2 isoenzymes, including sPLA2-V. Although observational studies show a strong association between elevated sPLA2 activity and CHD, no assay to measure sPLA2-V levels exists, and the only evidence linking the sPLA2-V isoform to atherosclerosis progression comes from animal studies.

Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study.

Background: Familial hypercholesterolaemia is a common autosomal-dominant disorder caused by mutations in three known genes. DNA-based cascade testing is recommended by UK guidelines to identify affected relatives; however, about 60% of patients are mutation-negative. We assessed the hypothesis that familial hypercholesterolaemia can also be caused by an accumulation of common small-effect LDL-C-raising alleles.

Meta analysis of candidate gene variants outside the LPA locus with Lp(a) plasma levels in 14,500 participants of six White European cohorts.

Background: Both genome-wide association studies and candidate gene studies have reported that the major determinant of plasma levels of the Lipoprotein (a) [Lp(a)] reside within the LPA locus on chromosome 6. We have used data from the HumanCVD BeadChip to explore the contribution of other candidate genes determining Lp(a) levels.

Methods: 48,032 single nucleotide polymorphisms (SNPs) from the Illumina HumanCVD BeadChip were genotyped in 5059 participants of the Whitehall II study (WHII) of randomly ascertained healthy men and women.

Association of a sequence variant in DAB2IP with coronary heart disease.

Aims: A sequence variant, rs7025486[A], in DAB2IP on chromosome 9q33 has recently been associated with coronary heart disease (CHD). We sought to replicate this finding and to investigate associations with a panel of inflammatory and haemostatic biomarkers. We also sought to examine whether this variant, in combination with a chromosome 9p21 CHD variant (rs10757278) and the Framingham risk score (FRS), could improve the prediction of events compared with the FRS alone.

Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.

Blood lipids are important cardiovascular disease (CVD) risk factors with both genetic and environmental determinants. The Whitehall II study (n=5592) was genotyped with the gene-centric HumanCVD BeadChip (Illumina). We identified 195 SNPs in 16 genes/regions associated with 3 major lipid fractions and 2 apolipoprotein components at p<10(-5), with the associations being broadly concordant with prior genome-wide analysis.

Development of a high-resolution melting method for mutation detection in familial hypercholesterolaemia patients.

Aims: Current screening methods, such as single strand conformational polymorphism (SSCP) and denaturing high performance liquid chromatography (dHPLC) that are used for detecting mutations in familial hypercholesterolaemia (FH) subjects are time consuming, costly and only 80-90% sensitive. Here we have tested high-resolution melt (HRM) analysis for mutation detection using the Rotor-Gene(6000) realtime rotary analyser. Methods and subjects Polymerase chain reaction and melt conditions (HRM) for 23 fragments of the LDL-receptor gene, a region of exon 26 in the APOB gene (including p.

Angiotensin-converting enzyme D allele does not influence susceptibility to acute hypoxic respiratory failure in children.

Objective: The D allele of the I/D polymorphism in the angiotensin-converting enzyme (ACE) gene has been associated with an increased risk of ARDS in critically ill adults and severity of bronchopulmonary dysplasia in pre-term infants. We hypothesised that the presence of the hypoxia-associated ACE D allele would increase susceptibility to acute hypoxic respiratory failure (AHRF) in a cohort of critically ill children.

Design And Setting: Single-centre prospective observational cohort study.

A man with recurrent lower abdominal pain: Spigelian hernia.

Recurrent abdominal pain due to spigelian hernia (SH) is rare and notoriously difficult to diagnose. This is particularly true when patient present with pain only without visible or palpable mass. Ultrasonic scanning and computed tomography is valuable in diagnosing this rare condition.

Laparoscopic management of acutely incarcerated femoral hernia.

Incarcerated femoral hernia is a common surgical emergency condition. Diagnosis is always obvious and straightforward by clinical examination, and open surgical repair is the mainstay of treatment. In the era of minimally invasive surgery, laparoscopic repair of femoral hernia has been shown to be feasible and safe.

Endoscopic hemostasis by using the TriClip for peptic ulcer hemorrhage: a pilot study.

Background: The feasibility, efficacy, and safety of the TriClip in the management of peptic ulcer hemorrhage in human beings are scarcely reported in the literature.

Objective: A pilot study was conducted to assess the feasibility, efficacy, and safety of the TriClip endoscopic clipping device in the control of peptic ulcer hemorrhage.

Design: Prospective evaluation.

Non-operative management of endoscopic iatrogenic haemobilia: case report and review of literature.

Haemobilia denotes an abnormal communication between a vessel of the splanchnic circulation and the biliary system. Patients typically presents with the triad of abdominal pain, upper gastrointestinal haemorrhage, and jaundice. Common causes for haemobilia are iatrogenic causes secondary to hepatobiliary system instrumentation and trauma.