The contribution of recently identified adult BMI risk loci to paediatric obesity in a Singaporean Chinese childhood dataset.

INTRODUCTION: Recent genome-wide association studies have identified 103 adult obesity risk loci; however, it is unclear if these findings are relevant to East-Asian childhood body mass index (BMI) levels. METHODS AND RESULTS: We evaluated for paediatric obesity associations at these risk loci utilizing genome-wide data from Chinese childhood subjects in the Singapore Cohort study Of the Risk factors for Myopia study (N = 1006). A weighted gene-risk score of all adult obesity risk loci in the Singapore Cohort study Of the Risk factors for Myopia study showed strong associations with BMI at age 9 (p-value = 3.40 × 10-12 ) and 4-year average BMI (age 9 to 12, p-value = 6.67 × 10-8 ). Directionally consistent nominal associations for 15 index single nucleotide polymorphisms (SNPs) (p-value < 0.05) were observed. Pathway analysis with genes from these 15 replicating loci revealed over-representation for the G-protein-coupled receptor (GPCR)-mediated integration of entero-endocrine signalling pathway exemplified by L-cell (adjusted p-value = 0.018). Evaluations of birth weight to modify the effects of BMI risk SNPs in paediatric obesity did not reveal significant interactions, and these SNPs were generally not associated with birth weight. CONCLUSIONS: At least some common adult BMI risk variants predispose to paediatric obesity risk in East-Asians.

Pharmacogenomic diversity in Singaporean populations and Europeans.

Differences in the frequency of pharmacogenomic variants may influence inter-population variability in drug efficacy and risk of adverse drug reactions (ADRs). We investigated the diversity of ∼ 4500 genetic variants in key drug-biotransformation and -response genes among three South East Asian populations compared with individuals of European ancestry. We compared rates of reported ADRs in these Asian populations to determine if the allelic differentiation corresponded to an excess of the associated ADR. We identified an excess of ADRs related to clopidogrel in Singaporean Chinese, consistent with a higher frequency of a known risk variant in CYP2C19 in that population. We also observed an excess of ADRs related to platinum compounds in Singaporean CHS, despite a very low frequency of known ADR risk variants, suggesting the presence of additional genetic and non-genetic risk factors. Our results point to substantial diversity at specific pharmacogenomic loci that may contribute to inter-population variability in drug response phenotypes.

Replication of 13 obesity loci among Singaporean Chinese, Malay and Asian-Indian populations.

OBJECTIVE: Recent genome-wide association studies (GWAS) have identified 38 obesity-associated loci among European populations. However, their contribution to obesity in other ethnicities is largely unknown. METHODS: We utilised five GWAS (N=10 482) from Chinese (three cohorts, including one with type 2 diabetes and another one of children), Malay and Indian ethnic groups from Singapore. Data sets were analysed individually and subsequently in combined meta-analysis for Z-score body-mass index (BMI) associations. RESULTS: Variants at the FTO locus showed the strongest associations with BMI Z-score after meta-analysis (P-values 1.16 × 10(-7)-7.95 × 10(-7)). We further detected associations with nine other index obesity variants close to the MC4R, GNPDA2, TMEM18, QPCTL/GIPR, BDNF, ETV5, MAP2K5/SKOR1, SEC16B and TNKS/MSRA loci (meta-analysis P-values ranging from 3.58 × 10(-4)-1.44 × 10(-2)). Three other single-nucleotide polymorphisms (SNPs) from CADM2, PTBP2 and FAIM2 were associated with BMI (P-value ≤ 0.0418) in at least one dataset. The neurotrophin/TRK pathway (P-value=0.029) was highlighted by pathway-based analysis of loci that had statistically significant associations among Singaporean populations. CONCLUSION: Our data confirm the role of FTO in obesity predisposition among Chinese, Malays and Indians, the three major Asian ethnic groups. We additionally detected associations for 12 obesity-associated SNPs among Singaporeans. Thus, it is likely that Europeans and Asians share some of the genetic predisposition to obesity. Furthermore, the neurotrophin/TRK signalling may have a central role for common obesity among Asians.

Drug screening of patients who deliberately harm themselves admitted to the emergency department.

This study was a retrospective analysis of drugs present in blood and urine samples taken from patients (n = 200) admitted to the emergency department of a major teaching hospital with a provisional diagnosis of deliberate self-harm. The aim was to assess the current limited drug screening strategy to see whether it needed to be changed in any way. Drugs present in blood and urine were identified by immunoassay or chromatography, categorized, and concentration-toxicity effects evaluated when practicable. For each case, the various drugs/drug classes detected were correlated with those reported by the patient. A questionnaire evaluation of doctor's perceptions of the influence of the primary blood drug screen on patient destinations was administered. The rapid primary drug screen using a blood/plasma sample detected some 46% of all drugs identified. The doctors considered that it was influential in deciding on immediate patient destination, and therefore, it is likely to be a cost-effective measure. In addition, the screen detected toxic concentrations of drugs in a significant proportion of patients who did not report their ingestion correctly. A primary drug screen using a urine sample detected opiates, cannabinoids, and amphetamines but such detection was considered unlikely to alter short-term treatment. A high-performance liquid chromatography and gas chromatography-mass spectroscopy secondary screen using blood and urine detected a significant number of additional drugs, but was slow, costly, and not likely to alter short-term treatment. The authors conclude that the primary screen for alcohol, benzodiazepines, paracetamol, salicylate, and tricyclic antidepressants remains the optimal drug screening strategy. Quantitative or qualitative estimation of patient-reported drugs such as quinine, theophylline, verapamil, and antiepileptics may be justifiable in individual patients.

Plasma concentrations of dothiepin and its metabolites are not correlated with clinical efficacy in major depressive illness.

Plasma concentration-antidepressant response relationships for dothiepin, nordothiepin, dothiepin-S-oxide, and nordothiepin-S-oxide were investigated in 50 patients (33 women and 17 men), who had had a major depressive episode. Depression and anxiety were assessed at the start of therapy and after 2 and 4 weeks by measurement of a Hamilton rating score for depression (HRSD), a Beck depression inventory (BECK), visual analog scores for depression (VASDEP) and anxiety (VASANX), and a physician's global (GLOBAL) score. There were significant (p < 0.001) decreases in both mean depression (32-69%) and mean anxiety (30-44%) scores at weeks 2 and 4, but there were no robust linear or polynomial correlations between percent decrease in depression or anxiety scores and plasma concentrations of dothiepin or its metabolites at week 4. It is suggested that measurement of the nordothiepin/dothiepin ratio may assist in the assessment of compliance.

Patterns of drug use by participants in the Western Australian methadone program, 1984-1991.

OBJECTIVES: To establish the extent to which participants in the WA methadone treatment program used opiates, cannabinoids, benzodiazepines, cocaine and amphetamines, and to define the pattern of such use over time. In addition, the relationships between methadone daily dose and the use of the various drug groups was examined. DESIGN: A retrospective analysis of data from 1678 samples from urinalysis screening over 13 separate surveys between 1984 and 1991. A mean of 35.9% of patients in the program was sampled on each occasion with each patient contributing only one sample in any one survey. Analytical techniques used included enzyme-multiplied immunoassay, thin-layer chromatography and gas chromatography-mass spectrometry. RESULTS: Methadone and/or its major metabolite were detected in most urine samples, indicating satisfactory compliance by patients. The detection of opiates increased from a mean of 27.1% of samples in 1984-1989 to a mean of 44.2% of samples in 1990-1991. Codeine or morphine were most frequently detected (94% of all opiate-positive samples) and were found together in 38.2% of opiate-positive samples. Detection of cannabinoids also increased from a mean of 45.2% of all samples during 1984-1987 to a mean of 56.4% of samples during 1990-1991. Benzodiazepines were found in a mean of 26.7% of samples but use was not time-related. Detection of amphetamine-class drugs doubled from a mean of 8.3% of all samples (mid 1989 to mid 1990) to 16.8% of samples (mid 1990 to mid 1991). The major representatives of the latter group were methylamphetamine (47.3% of amphetamine-positive urines), amphetamine (15.7%) and ephedrine/pseudoephedrine (44.6%). Opiate use was significantly lower (P < 0.05) in those patients taking more than 80 mg methadone/day. In addition, benzodiazepine use increased significantly (P < 0.05) with increasing methadone daily dose. There was no relationship between methadone daily dose and use of cannabinoids or amphetamines. CONCLUSIONS: The increase in the use of opiates, cannabinoids and amphetamines over the period 1984-1991 occurred about four years after the adoption of a harm minimisation treatment philosophy by the WA methadone program. The high prevalence of codeine and morphine in opiate-positive urine samples strongly suggested the use of "home-bake" heroin. In addition, the data showed that methylamphetamine and ephedrine/pseudoephedrine were the most frequently used psychostimulants. Suppression of opiate use in those clients receiving more than 80 mg methadone/day was consistent with earlier studies. However, the significant increase in use of benzodiazepines with increasing methadone daily dose requires further study.

Effect of urine pH on the stability of doxorubicin and its recovery from bladder instillations.

Doxorubicin (1 mg/ml) was shown to be stable when added to urine samples with a mean natural pH of 5.4 and in urine buffered to a mean pH of 4.6. However, at alkaline pH (mean = 8.1) there was a biphasic degradation of doxorubicin (mean t1/2 = 3.24 and 89 h respectively). The data indicate that buffering intravesical doxorubicin to pH 4.6 (acetate buffer) or pre-dosing of patients with ammonium chloride may minimise loss of active drug during the time for which the drug is retained in the bladder. Recovery of doxorubicin following 1 hour's retention in the bladder was similar (77%) for doses of 38/48 or 78 mg. It is suggested that a dose of 50 mg (1 mg/ml) is sufficient to ensure an adequate delivery of active drug to the bladder wall.

Systemic lupus erythematosus and dermatitis herpetiformis: concurrence with Marfan's syndrome.

There is increasing evidence that, as in systemic lupus erythematosus (SLE), deposition of immune complexes plays a role in the pathogenesis of dermatitis herpetiformis (DH). Dermatitis herpetiformis and SLE were diagnosed in a 15-year-old girl with Marfan's syndrome who died of cardiac tamponade secondary to cystic medial necrosis of the ascending aorta. The concurrence of these diseases suggests that predisposition to immune-mediated disorders may be associated with the expression of multiple clinical entities.