Epidemiology of Acute Myocarditis/Pericarditis in Hong Kong Adolescents Following Comirnaty Vaccination.

BACKGROUND: Age-specific incidence of acute myocarditis/pericarditis in adolescents following Comirnaty vaccination in Asia is lacking. This study aimed to study the clinical characteristics and incidence of acute myocarditis/pericarditis among Hong Kong adolescents following Comirnaty vaccination. METHODS: This is a population cohort study in Hong Kong that monitored adverse events following immunization through a pharmacovigilance system for coronavirus disease 2019 (COVID-19) vaccines. All adolescents aged between 12 and 17 years following Comirnaty vaccination were monitored under the COVID-19 vaccine adverse event response and evaluation program. The clinical characteristics and overall incidence of acute myocarditis/pericarditis in adolescents following Comirnaty vaccination were analyzed. RESULTS: Between 14 June 2021 and 4 September 2021, 33 Chinese adolescents who developed acute myocarditis/pericarditis following Comirnaty vaccination were identified. In total, 29 (87.88%) were male and 4 (12.12%) were female, with a median age of 15.25 years. And 27 (81.82%) and 6 (18.18%) cases developed acute myocarditis/pericarditis after receiving the second and first dose, respectively. All cases are mild and required only conservative management. The overall incidence of acute myocarditis/pericarditis was 18.52 (95% confidence interval [CI], 11.67-29.01) per 100 000 persons vaccinated. The incidence after the first and second doses were 3.37 (95% CI, 1.12-9.51) and 21.22 (95% CI, 13.78-32.28 per 100 000 persons vaccinated, respectively. Among male adolescents, the incidence after the first and second doses were 5.57 (95% CI, 2.38-12.53) and 37.32 (95% CI, 26.98-51.25) per 100 000 persons vaccinated. CONCLUSIONS: There is a significant increase in the risk of acute myocarditis/pericarditis following Comirnaty vaccination among Chinese male adolescents, especially after the second dose.

Multicystic encephalomalacia and gastrointestinal injury following single fetal death in first trimester and subsequent fetofetal transfusion syndrome in a monochorionic triplet pregnancy: a case report.

BACKGROUND: Monochorionic multifetal pregnancies are at increased risk of adverse perinatal outcome because of placental vascular anastomoses. We present a case of multicystic encephalomalacia and gastrointestinal injury in two surviving fetuses following single fetal death in first trimester and subsequent fetofetal transfusion syndrome in a monochorionic triplet pregnancy. CASE PRESENTATION: A 31-year-old nulliparous woman had a spontaneous monochorionic triamniotic triplet pregnancy. Three live fetuses with single placenta were seen at 8-week ultrasound scan. One fetus demised at 11 weeks and 3 days of gestation. Dilated echogenic bowel and ascites were found in one surviving fetus at 23 weeks of gestation. At 28 weeks of gestation, the pregnancy was complicated by fetofetal transfusion syndrome in which discordant amniotic fluid volumes were found. Two days later, emergency Caesarean section was performed because of worsening of fetal Doppler and biophysical profile. One baby was found to have jejunal atresia requiring surgery at 4 days old. He had periventricular leukomalacia and intracranial haemorrhage, but subsequent normal neurological development. Another baby had gastric perforation requiring surgery at 2 days old. He was confirmed to have multicystic encephalomalacia by cranial ultrasound and magnetic resonance imaging. He suffered from developmental delay, epilepsy and cerebral palsy. CONCLUSION: This case alerts the obstetricians the possible hypoxic-ischemic injury to the survivors of monochorionic triplet pregnancy after the co-triplet death in the first trimester and fetofetal transfusion syndrome. Antenatal assessment and postnatal follow-up are important for these high-risk multiple pregnancies.

The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.

BACKGROUND: A high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular inflammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown. METHODS: Applying the mendelian randomisation principle, we used single nucleotide polymorphisms (SNPs) in the gene IL6R to evaluate the likely efficacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic findings with the effects of tocilizumab reported in randomised trials in patients with rheumatoid arthritis. FINDINGS: In 40 studies including up to 133,449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log interleukin-6 concentration (increase per allele 9·45%, 95% CI 8·34-10·57) as well as reduced C-reactive protein (decrease per allele 8·35%, 95% CI 7·31-9·38) and fibrinogen concentrations (decrease per allele 0·85%, 95% CI 0·60-1·10). This pattern of effects was consistent with IL6R blockade from infusions of tocilizumab (4-8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials. In 25,458 coronary heart disease cases and 100,740 controls, the IL6R rs7529229 SNP was associated with a decreased odds of coronary heart disease events (per allele odds ratio 0·95, 95% CI 0·93-0·97, p=1·53×10(-5)). INTERPRETATION: On the basis of genetic evidence in human beings, IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials. Genetic studies in populations could be used more widely to help to validate and prioritise novel drug targets or to repurpose existing agents and targets for new therapeutic uses. FUNDING: UK Medical Research Council; British Heart Foundation; Rosetrees Trust; US National Heart, Lung, and Blood Institute; Du Pont Pharma; Chest, Heart and Stroke Scotland; Wellcome Trust; Coronary Thrombosis Trust; Northwick Park Institute for Medical Research; UCLH/UCL Comprehensive Medical Research Centre; US National Institute on Aging; Academy of Finland; Netherlands Organisation for Health Research and Development; SANCO; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Agentschap NL; European Commission; Swedish Heart-Lung Foundation; Swedish Research Council; Strategic Cardiovascular Programme of the Karolinska Institutet; Stockholm County Council; US National Institute of Neurological Disorders and Stroke; MedStar Health Research Institute; GlaxoSmithKline; Dutch Kidney Foundation; US National Institutes of Health; Netherlands Interuniversity Cardiology Institute of the Netherlands; Diabetes UK; European Union Seventh Framework Programme; National Institute for Healthy Ageing; Cancer Research UK; MacArthur Foundation.

Outcome of hepatobiliary scanning: preterm versus full-term cholestatic infants.

OBJECTIVES: The aims of this study were to evaluate the specificity of a non-draining hepatobiliary scintigraphy (HBS) for biliary atresia (BA) in preterm and full-term babies, to verify the relationship between non-draining scan and higher levels of direct bilirubin and to find an objective criterion to guide the time in performing HBS. METHODS: A total of 175 infants (113 males and 62 females, median age of 45 days) with 181 HBS performed in Tuen Mun Hospital between January 1998 and May 2010 were retrospectively analysed. A 'non-draining' scan was defined as one showing no excretion of radiolabelled tracer into the small bowel 24 h after injection. The disease category, epidemiological and laboratory data were compared between infants having non-draining and draining scans. In addition, the predictive value of a negative scan for BA was compared between preterm and full-term infants. RESULTS: Twenty infants (11.4%) were surgically confirmed to have BA. A non-draining scan was found to be 100% sensitive for BA, and the specificity was 96% and 78% among full-term infants and preterm infants, respectively. The mean direct bilirubin values of infants with BA and intrahepatic cholestasis were 141.9 and 111.3 µmol/L, respectively, which were significantly higher than 67.2 µmol/L seen in infants with draining scans. This analysis shows that using direct bilirubin ≥63 µmol/L as an objective criterion in guiding the time to perform HBS is most cost-effective. CONCLUSION: Our data supported that using direct bilirubin ≥63 µmol/L as an objective criterion in guiding the time to perform HBS will avoid unnecessary scans.

The effects of a single nucleotide polymorphism in SLCO1B1 on the pharmacodynamics of pravastatin.

AIM: To determine whether the SNP rs4149056 in SLCO1B1 alters the pharmacodynamics of pravastatin. METHODS: rs4149056 was genotyped in 626 pravastatin-treated participants in the WOSCOPS trial and the response after 1 year of treatment was compared between the different genotypes. RESULTS: Pravastatin reduced serum LDL cholesterol by 22.2% in TT homozygotes, by 22.2% in TC heterozygotes and by 17.7% in CC homozygotes (TT + TC vs. CC P value 0.33). There were no significant differences in the response of total cholesterol, LDL, HDL, triglycerides or CRP to pravastatin between the genotypes. CONCLUSION: The rs4149056 SNP did not significantly affect the pharmacodynamics of pravastatin.

Medium-term outcomes of myocarditis and pericarditis following BNT162b2 vaccination among adolescents in Hong Kong.

In this study, we examined the clinical and electrophysiological outcomes of adolescents in Hong Kong who developed myocarditis or pericarditis following BNT162b2 vaccination for COVID-19, and followed-up for 60-180 days after their initial diagnosis. Clinical assessments included electrocardiogram (ECG) and echocardiogram at the initial admission and follow-up were compared. Treadmill testing was also performed in some cases. Between 14 June 2021 and 16 February 2022, 53 subjects were approached to participate in this follow-up study, of which 28 patients were followed up for >60 days with a median follow-up period of 100 days (range, 61-178 days) and were included in this study. On admission, 23 patients had ECG abnormalities but no high-grade atrioventricular block. Six patients had echocardiogram abnormalities, including reduced contractility, small rim pericardial effusions, and hyperechoic ventricular walls. All patients achieved complete recovery on follow-up. After discharge, 10 patients (35.7%) reported symptoms, including occasional chest pain, shortness of breath, reduced exercise tolerance, and recurrent vasovagal near-syncope. At follow-up, assessments, including ECGs, were almost all normal. Among the three patients with possible ECG abnormalities, all their echocardiograms or treadmill testings were normal. Sixteen patients (57.1%) underwent treadmill testing at a median of 117 days post-admission, which were also normal. However, at follow-up, there was a significant mean bodyweight increase of 1.81 kg (95%CI 0.47-3.1 kg, p = 0.01), possibly due to exercise restriction. In conclusion, most adolescents experiencing myocarditis and pericarditis following BNT162b2 vaccination achieved complete recovery. Some patients developed non-specific persistent symptoms, and bodyweight changes shall be monitored.

Healthy individuals carrying the PCSK9 p.R46L variant and familial hypercholesterolemia patients carrying PCSK9 p.D374Y exhibit lower plasma concentrations of PCSK9.

BACKGROUND: We measured plasma PCSK9 concentrations in healthy men with a PCSK9 (proprotein convertase subtilisin/kexin type 9) loss-of-function variant (p.R46L), in statin-treated patients with a clinical diagnosis of familial hypercholesterolemia (FH) and carrying a PCSK9 gain-of-function mutation (p.D374Y), and in statin-treated patients with FH due to different genetic causes. METHODS: PCSK9 was measured with a previously described ELISA. RESULTS: In 81 healthy middle-aged Caucasian men, the PCSK9 concentration was significantly associated with the concentrations of total cholesterol (r = 0.42; P < 0.0001), LDL cholesterol (r = 0.34; P = 0.01), and triglycerides (r = 0.25; P = 0.02). In p.R46L carriers, mean (SD) concentrations of PCSK9 were 15% lower than in RR individuals [65.5 microg/L (21.6 microg/L) vs 77.5 microg/L (18.2 microg/L); P = 0.03]. In patients with the p.D374Y variant (n = 7), the mean PCSK9 concentration was significantly lower than in the combined group of patients with an LDLR (low density lipoprotein receptor) mutation (n = 25), an APOB [apolipoprotein B (including Ag(x) antigen)] variant encoding p.R3527Q (n = 6), or no detectable mutation (n = 14) [96.4 microg/L (42.5 microg/L) vs 151.6 microg/L (69.6 microg/L); P = 0.02]. Two of the 14 patients with no mutation had PCSK9 concentrations below the mean for p.D374Y carriers; sequencing of the PCSK9 gene and promoter revealed no mutations. Among 409 FH patients, we identified 6 carriers of the promoter variant -287G>A (1.5%), a frequency similar to that (1.0%) previously reported for 2772 healthy men in the UK. In neither group was the -287G>A variant associated with differences in lipid traits. CONCLUSIONS: The loss-of-function p.R46L variant is associated with the expected lower concentrations of circulating PCSK9; the gain-of-function p.D374Y mutation is also associated with lower concentrations, presumably because of the higher affinity of this variant for the LDL receptor and its more rapid clearance. In treated FH patients, a low plasma PCSK9 concentration does not appear to be a useful screening tool for identifying novel PCSK9 mutations.

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. Hyponatremia appears to be another common feature in these patients. Salient histological features include nemaline bodies ranging from 200 to 500 nm in diameters on ultrastructural examination as well as negative KLHL40 immunohistochemistry; type II fiber predominance is obvious in 2 cases. We demonstrate the founder effect associated with genetic variant c.1516A>C (p.Thr506Pro) by polymorphic marker analysis, which revealed a 0.56-0.75-Mb or 0.41-0.78-cM shared haplotype encompassing the disease allele. The mutation is believed to have occurred around 412 generations ago or 6220 BCE, as estimated using DMLE+ and a formula described by Boehnke. We believe the founder variant might possibly underlie a sizable portion of nemaline myopathy in ethnic Chinese. Analysis of the KLHL40 gene may be considered as the first-tier testing of congenital myopathy in this ethnic group.

Vitamin D receptor genotypes influence quadriceps strength in chronic obstructive pulmonary disease.

BACKGROUND: Quadriceps weakness is an important complication of chronic obstructive pulmonary disease (COPD) and is associated with impaired exercise capacity and greater mortality. Its etiology is multifactorial, and evidence is growing that it is partly determined by genetic susceptibility. OBJECTIVE: Using an established cohort, we tested whether quadriceps weakness in patients with COPD is influenced by common variations in the gene for the vitamin D receptor. DESIGN: Vitamin D receptor FokI and BsmI genotypes and the (I/D) angiotensin-converting enzyme (ACE) and bradykinin receptor (+9/-9) genotypes were identified in 107 patients with stable COPD [x +/- SD forced expiratory volume in 1 s (FEV(1)): 34.5 +/- 16.5] and 104 healthy, age-matched control subjects. Quadriceps maximum voluntary contraction force and fat-free mass assessed by bioelectrical impedance analysis were measured. RESULTS: After adjustment for covariables, both patients and control subjects who were homozygous for the C allele of the FokI polymorphism had less quadriceps strength than did those with > or =1 T allele [41.0 +/- 11.8 compared with 46.0 +/- 13.2 kg (P = 0.01) and 32.5 +/- 11.2 compared with 36.2 +/- 13.1 kg (P = 0.005), respectively]. The b allele of the BsmI polymorphism was associated with greater quadriceps strength in patients-37.0 +/- 13.3, 33.8 +/- 11.6, and 33.8 +/- 11.6 kg for bb, bB, and BB, respectively (P = 0.0005)-but had no effect in healthy control subjects. The effect of BsmI on quadriceps strength was least apparent in patients with the ACE II genotype (P = 0.003). CONCLUSIONS: The FokI common variants in the VDR gene are associated with skeletal muscle strength in both patients and control subjects, whereas the BsmI polymorphism is associated with strength only in patients.

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. However, for a small hernia with its content reduced spontaneously during examination, even computed tomography will miss the diagnosis. In the era of laparoscopic surgery, the role of laparoscopy in the management of recurrent abdominal pain of unknown origin has become more and more important. It is especially true in the management of SH as it is both diagnostic and therapeutic. We report a case of SH presented as recurrent lower abdominal pain of unknown origin and its successful diagnosis and treatment by laparoscopic approach.

Common variants in the TCF7L2 gene and predisposition to type 2 diabetes in UK European Whites, Indian Asians and Afro-Caribbean men and women.

Common variants of TCF7L2, encoding a beta-cell-expressed transcription factor, are strongly associated with increased risk of type 2 diabetes (T2D). We examined this association using both prospective and case-control designs. A total of 2,676 healthy European white middle-aged men from the prospective NPHSII (158 developed T2D over 15 years surveillance) were genotyped for two intronic SNPs [rs 7903146 (IVS3C>T) and rs12255372 (IVS4G>T)] which showed strong linkage disequilibrium (D' = 0.88, p<0.001; R(2)=0.76, p<0.001). The IVS5T allele frequency was 0.28 (95% CI 0.27-0.29) and 0.33 (0.28-0.39) in healthy and T2D, respectively (p=0.04). Compared to CC men, CT and TT men had an adjusted [for age, body mass index, systolic blood pressure, triglyceride and C-reactive protein levels] hazard ratio for T2D of 1.65 (1.13-2.41) and 1.87 (0.99-3.53), respectively, p<0.01. The population attributable fraction for diabetes risk was 17%. In 1459, European white T2D men and women (60% male), T allele frequency was 0.36 (0.34-0.38), and compared to NPHSII healthy men the OR for T2D for the CT and TT subjects was 1.43 (1.24-1.65) and 2.11 (1.69-2.63), respectively p=<0.0001. A similar effect was observed in 919 T2D Indian Asians [OR=1.50 (1.14-1.99) and 1.64 (1.03-2.63) p=0.003] and 385 Afro-Caribbean subjects [OR=1.25 (0.90-1.75) and 1.32 (0.74-2.33) p=0.17] compared to non-diabetic ethnically matched subjects from South London. Weaker associations were found for the IVS4G>T in all studies. Linkage disequilibrium between the two SNPs was high in Indian Asians (D'=0.94), but much weaker in Afro-Caribbeans (D'=0.17) and haplotype frequencies differed markedly in this group. These results extend previous observations to other ethnic groups, and strongly confirm that TCF7L2 genotype is a major risk factor for development of T2D.

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. However, laparoscopic repair of acutely incarcerated femoral hernia has gained little discussion in the past. In this paper, we report the results of 8 consecutive cases of strangulated femoral hernia that was successfully managed by the laparoscopic approach.

Greater preclinical atherosclerosis in treated monogenic familial hypercholesterolemia vs. polygenic hypercholesterolemia.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a common inherited disorder of low density lipoprotein-cholesterol (LDL-C) metabolism. It is associated with higher risk of premature coronary heart disease. Around 60% of patients with a clinical diagnosis of FH do not have a detectable mutation in the genes causing FH and are most likely to have a polygenic cause for their raised LDL-C. We assessed the degree of preclinical atherosclerosis in treated patients with monogenic FH versus polygenic hypercholesterolemia. METHODS: FH mutation testing and genotypes of six LDL-C-associated single nucleotide polymorphisms (SNPs) were determined using routine methods. Those with a detected mutation (monogenic) and mutation-negative patients with LDL-C SNP score in the top two quartiles (polygenic) were recruited. Carotid intima media thickness (IMT) was measured by B-mode ultrasound and the coronary artery calcium (CAC) score was performed in three lipid clinics in the UK and the Netherlands. RESULTS: 86 patients (56 monogenic FH, 30 polygenic) with carotid IMT measurement, and 166 patients (124 monogenic, 42 polygenic) with CAC score measurement were examined. After adjustment for age and gender, the mean of all the carotid IMT measurements and CAC scores were significantly greater in the monogenic than the polygenic patients [carotid IMT mean (95% CI): 0.74 mm (0.7-0.79) vs. 0.66 mm (0.61-0.72), p = 0.038 and CAC score mean (95%): 24.5 (14.4-41.8) vs. 2.65 (0.94-7.44), p = 0.0004]. CONCLUSIONS: In patients with a diagnosis of FH, those with a monogenic cause have a higher severity of carotid and coronary preclinical atherosclerosis than those with a polygenic aetiology.

The genetic spectrum of familial hypercholesterolemia in south-eastern Poland.

BACKGROUND: Familial hypercholesterolemia (FH) is a common autosomal dominant disorder with a frequency of 1 in 200 to 500 in most European populations. Mutations in LDLR, APOB and PCSK9 genes are known to cause FH. In this study, we analyzed the genetic spectrum of the disease in the understudied Polish population. MATERIALS AND METHODS: 161 unrelated subjects with a clinical diagnosis of FH from the south-eastern region of Poland were recruited. High resolution melt and direct sequencing of PCR products were used to screen 18 exons of LDLR, a region of exon 26 in the APOB gene and exon 7 of PCSK9. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect gross deletions and insertions in LDLR. Genotypes of six LDL-C raising SNPs were used for a polygenic gene score calculation. RESULTS: We found 39 different pathogenic mutations in the LDLR gene with 10 of them being novel. 13 (8%) individuals carried the p.Arg3527Gln mutation in APOB, and overall the detection rate was 43.4%. Of the patients where no mutation could be found, 53 (84.1%) had a gene score in the top three quartiles of the healthy comparison group suggesting that they have a polygenic cause for their high cholesterol. CONCLUSIONS: These results confirm the genetic heterogeneity of FH in Poland, which should be considered when designing a diagnostic strategy in the country. As in the UK, in the majority of patients where no mutation can be found, there is likely to be a polygenic cause of their high cholesterol level.

Association of TLL1 gene polymorphism (rs1503298, T > C) with coronary heart disease in PREDICT, UDACS and ED cohorts.

OBJECTIVE: To determine the sequence variant of TLL1 gene (rs1503298, T > C) in three British cohorts (PREDICT, UDACS and ED) of patients with type-2 Diabetes mellitus (T2DM) in order to assess its association with coronary heart disease (CHD). STUDY DESIGN: Analytical study. PLACE AND DURATION OF STUDY: UCL, London, UK. Participants were genotyped in 2011-2012 for TLL1 SNP. Samples and related information were previously collected in 2001-2003 for PREDICT, and in 2001-2002 for UDACS and ED groups. METHODOLOGY: Patients included in PREDICT (n=600), UDACS (n=1020) and ED (n=1240) had Diabetes. TLL1 SNP (rs1503298, T > C) was genotyped using TaqMan technology. Allele frequencies were compared using c2 test, and tested for Hardy-Weinberg equilibrium. The risk of disease was assessed from Odds ratios (OR) with 95% Confidence Intervals (95% CI). Moreover, for the PREDICT cohort, the SNP association was tested with Coronary Artery Calcification (CAC) scores. RESULTS: No significant association was found for this SNP with CHD or CAC scores in these cohorts. CONCLUSION: This SNP could not be confirmed as a risk factor for CHD in T2DM patients. However, the low power of thesmall sample size available is a limitation to the modest effect on risk. Further studies in larger samples would be useful.

Genome-wide association study identifies variants in casein kinase II (CSNK2A2) to be associated with leukocyte telomere length in a Punjabi Sikh diabetic cohort.

BACKGROUND: Telomere length is a heritable trait, and short telomere length has been associated with multiple chronic diseases. We investigated the relationship of relative leukocyte telomere length with cardiometabolic risk and performed the first genome-wide association study and meta-analysis to identify variants influencing relative telomere length in a population of Sikhs from South Asia. METHODS AND RESULTS: Our results revealed a significant independent association of shorter relative telomere length with type 2 diabetes mellitus and heart disease. Our discovery genome-wide association study (n=1616) was followed by stage 1 replication of 25 top signals (P<10(-6)) in an additional Sikhs (n=2397). On combined discovery and stage 1 meta-analysis (n= 4013), we identified a novel relative telomere length locus at chromosome 16q21 represented by an intronic variant (rs74019828) in the CSNK2A2 gene (ß=-0.38; P=4.5×10(-8)). We further tested 3 top variants by genotyping in UK cardiovascular disease (UKCVD) (whites n=2952) for stage 2. Next, we performed in silico replication of 139 top signals (P<10(-5)) in UK Twin, Nurses Heart Study, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, and MD Anderson Cancer Controls (n=10 033) and joint meta-analysis (n=16 998). The observed signal in CSNK2A2 was confined to South Asians and could not be replicated in whites because of significant difference in allele frequencies (P<0.001). CSNK2A2 phosphorylates telomeric repeat binding factor 1 and plays an important role for regulation of telomere length homoeostasis. CONCLUSIONS: By identification of a novel signal in telomere pathway genes, our study provides new molecular insight into the underlying mechanism that may regulate telomere length and its association with human aging and cardiometabolic pathophysiology.

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. In the absence of an assay that directly quantifies sPLA2-V levels, we used PLA2G5 mRNA levels in a novel, modified Mendelian randomization approach to investigate the hypothesized causal role of sPLA2-V in coronary heart disease (CHD) pathogenesis. METHODS AND RESULTS: Using data from the Advanced Study of Aortic Pathology, we identified the single-nucleotide polymorphism in PLA2G5 showing the strongest association with PLA2G5 mRNA expression levels as a proxy for sPLA2-V levels. We tested the association of this SNP with sPLA2 activity and CHD events in 4 prospective and 14 case-control studies with 27 230 events and 70 500 controls. rs525380C>A showed the strongest association with PLA2G5 mRNA expression (P=5.1×10(-6)). There was no association of rs525380C>A with plasma sPLA2 activity (difference in geometric mean of sPLA2 activity per rs525380 A-allele 0.4% (95% confidence intervals [-0.9%, 1.6%]; P=0.56). In meta-analyses, the odds ratio for CHD per A-allele was 1.02 (95% confidence intervals [0.99, 1.04]; P=0.20). CONCLUSIONS: This novel approach for single-nucleotide polymorphism selection for this modified Mendelian randomization analysis showed no association between rs525380 (the lead single-nucleotide polymorphism for PLA2G5 expression, a surrogate for sPLA2-V levels) and CHD events. The evidence does not support a causal role for sPLA2-V in CHD.

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. In total 13 studies (including unpublished data from eight cohorts) with 10,134 CHD events in 130,004 individuals of European descent were identified. The odds ratio (OR) for CHD risk from APOE genotype (ε4 carriers versus non-carriers) was 1.06 (95% confidence interval (CI): 1.01, 1.12) and for smoking (present vs. past/never smokers) was OR 2.05 (95%CI: 1.95, 2.14). When the association between APOE genotype and CHD was stratified by smoking status, compared to non-ε4 carriers, ε4 carriers had an OR of 1.11 (95%CI: 1.02, 1.21) in 28,789 present smokers and an OR of 1.04 (95%CI 0.98, 1.10) in 101,215 previous/never smokers, with no evidence of effect modification (P-value for heterogeneity = 0.19). Analysis of pack years in individual participant data of >60,000 with adjustment for cardiovascular traits also failed to identify evidence of effect modification. CONCLUSIONS: In the largest analysis to date, we identified no evidence for effect modification by smoking status in the association between APOE genotype and risk of CHD.

Association of TERC and OBFC1 haplotypes with mean leukocyte telomere length and risk for coronary heart disease.

OBJECTIVE: To replicate the associations of leukocyte telomere length (LTL) with variants at four loci and to investigate their associations with coronary heart disease (CHD) and type II diabetes (T2D), in order to examine possible causal effects of telomere maintenance machinery on disease aetiology. METHODS: Four SNPs at three loci BICD1 (rs2630578 GγC), 18q12.2 (rs2162440 GγT), and OBFC1 (rs10786775 CγG, rs11591710 AγC) were genotyped in four studies comprised of 2353 subjects out of which 1148 had CHD and 566 T2D. Three SNPs (rs12696304 CγG, rs10936601G>T and rs16847897 GγC) at the TERC locus were genotyped in these four studies, in addition to an offspring study of 765 healthy students. For all samples, LTL had been measured using a real-time PCR-based method. RESULTS: Only one SNP was associated with a significant effect on LTL, with the minor allele G of OBFC1 rs10786775 SNP being associated with longer LTL (ß=0.029, P=0.04). No SNPs were significantly associated with CHD or T2D. For OBFC1 the haplotype carrying both rare alleles (rs10786775G and rs11591710C, haplotype frequency 0.089) was associated with lower CHD prevalence (OR: 0.77; 95% CI: 0.61-0.97; P= 0.03). The TERC haplotype GTC (rs12696304G, rs10936601T and rs16847897C, haplotype frequency 0.210) was associated with lower risk for both CHD (OR: 0.86; 95% CI: 0.75-0.99; P=0.04) and T2D (OR: 0.74; 95% CI: 0.61-0.91; P= 0.004), with no effect on LTL. Only the last association remained after adjusting for multiple testing. CONCLUSION: Of reported associations, only that between the OBFC1 rs10786775 SNP and LTL was confirmed, although our study has a limited power to detect modest effects. A 2-SNP OBFC1 haplotype was associated with higher risk of CHD, and a 3-SNP TERC haplotype was associated with both higher risk of CHD and T2D. Further work is required to confirm these results and explore the mechanisms of these effects.

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. SETTING: Regional government hospital. PATIENTS: From July 2004 to January 2005, patients older than 16 years and with Forrest type I and IIa peptic ulcer hemorrhages were included in the study. INTERVENTIONS: TriClips were used for initial hemostasis. Salvage procedures, including adrenalin injection, heat probe application, argon plasma coagulation, or surgery will be carried out appropriately if TriClip failed to control bleeding alone. An endoscopy was repeated 24 hours later for the security of the TriClip and for any endoscopic evidence of recurrent bleeding. A follow-up endoscopy was performed 8 weeks later to assess ulcer healing. MAIN OUTCOME MEASUREMENTS: Procedure time, successful hemostatic rate, number of clips used, ulcer recurrent bleeding rate, complications, and ulcer healing rate were measured. LIMITATIONS: No comparative arm; pilot study only. RESULT: A total of 27 cases (11 women, 16 men) were included in the study, with a median age of 70 years (range 18-88 years). There were 19 cases of duodenal ulcer and 8 cases of gastric ulcer, with median size of 8 mm (range 2-20 mm). The rate of successful hemostasis in the first endoscopy by TriClips alone was 81.5% (22/27), with a median procedure time of 10 minutes (range 3-30 minutes). In the second endoscopy, the endoscopic recurrent bleeding rate was 14.8% (4/27) and the TriClips were found dislodged in 11 patients (40.7%). The permanent hemostasis rate was 67% (18/27). The overall failure rate was 33% (9/27). Three patients required blood transfusion before the first endoscopy. There was no morbidity or mortality observed in all cases. All ulcers healed after 8 weeks. CONCLUSIONS: The use of the TriClip is feasible in the initial control of peptic ulcer hemorrhage. However, we could not detect any obvious advantages in arresting bleeding vessels by using this new clipping device.