FTO variants are associated with obesity in the Chinese and Malay populations in Singapore

OBJECTIVE— Association between genetic variants at the FTO locus and obesity has been consistently observed in populations of European ancestry and inconsistently in non-Europeans. The aim of this study was to examine the effects of FTO variants on obesity and type 2 diabetes in Southeast Asian populations.RESEARCH DESIGN AND METHODS— We examined associations between nine previously reported FTO single nucleotide polymorphisms (SNPs) with obesity, type 2 diabetes, and related traits in 4,298 participants (2,919 Chinese, 785 Malays, and 594 Asian Indians) from the 1998 Singapore National Health Survey (NHS98) and 2,996 Malays from the Singapore Malay Eye Study (SiMES).RESULTS— All nine SNPs exhibited strong linkage disequilibrium (r² = 0.6–0.99), and minor alleles were associated with obesity in the same direction as previous studies with effect sizes ranging from 0.42 to 0.68 kg/m² (P < 0.0001) in NHS98 Chinese, 0.65 to 0.91 kg/m² (P < 0.02) in NHS98 Malays, and 0.52 to 0.64 kg/m² (P < 0.0001) in SiMES Malays after adjustment for age, sex, smoking, alcohol consumption, and exercise. The variants were also associated with type 2 diabetes, though not after adjustment for BMI (with the exception of the SiMES Malays: odds ratio 1.17–1.22; P ≤ 0.026).CONCLUSIONS— FTO variants common among European populations are associated with obesity in ethnic Chinese and Malays in Singapore. Our data do not support the hypothesis that differences in allele frequency or genetic architecture underlie the lack of association observed in some populations of Asian ancestry. Examination of gene-environment interactions involving variants at this locus may provide further insights into the role of FTO in the pathogenesis of human obesity and diabetes.A recent genome-wide association study for type 2 diabetes using a U.K.-based population revealed a novel locus associated with BMI: the fat mass–and obesity-related gene (FTO) on chromosome 16 (1). The representative single-nucleotide polymorphism (SNP), rs9939609, was confirmed to be associated with elevated BMI after replication in more than 38,000 study participants of European ancestry. Further replication of this association has been observed in several populations of distinctly European ancestry (2–6). However, this association is inconsistent in populations of non-European ancestry. A study in Japanese showed an association between variants at this locus and obesity (7) that was not observed in African Americans (6) or Han Chinese (8). The aims of this study were 1) to determine the associations between previously identified obesity-associated SNPs at the FTO locus with obesity and type 2 diabetes in Chinese, Malays, and Asian-Indians and 2) to examine whether any associations were modulated by exercise.     

PAX4 R192H is associated with younger onset of Type 2 diabetes in East Asians in Singapore

Aims

Young-onset T2D (YT2D) is associated with a more fulminant course and greater propensity for diabetic complications. The association of PAX4 R192H (rs2233580) variation with YT2D was inconsistent partly because of its Asian-specificity and under-representation of Asians in international consortiums. Interestingly, in our preliminary YT2D (mean?=?25?years old) cohort, the prevalence of PAX4 R192H variant was remarkably higher (21.4%) than the general population. Therefore, we sought to determine whether PAX4 R192H is associated with younger onset of T2D in our East Asian (Chinese) population.

Shortened Telomere Length in Sputum Cells of Bronchiectasis Patients is Associated with Dysfunctional Inflammatory Pathways

Telomere attrition is an established ageing biomarker and shorter peripheral blood leukocyte telomere length has been associated with increased risks of respiratory diseases. However, whether telomere length in disease-relevant sputum immune cells of chronic respiratory disease patients is shortened and which pathways are dysfunctional are not clear. Here we measured telomere length from sputum samples of bronchiectasis and asthmatic subjects and determined that telomere length in sputum of bronchiectasis subjects was significantly shorter (Beta?=????1.167, P_Adj?=?2.75?×?10^?4). We further performed global gene expression analysis and identified genes involved in processes such as NLRP3 inflammasome activation and regulation of adaptive immune cells when bronchiectasis sputum telomere length was shortened. Our study provides insights on dysfunctions related to shortened telomere length in sputum immune cells of bronchiectasis patients.

     

Rectal Cancer Surveillance—Recurrence Patterns and Survival Outcomes from a Cohort Followed up Beyond 10 Years

Aim

The intensity and duration of surveillance for rectal cancer after surgical resection remain contentious. We evaluated the pattern of recurrences in a rectal cancer cohort followed up beyond 10 years.

Methods

An analysis was performed on a retrospective database of 326 patients with rectal cancer who underwent curative surgical resection from 1999 to 2007. The above study duration was chosen to ensure at least 10 years of follow-up. Data on patient demographics, peri-operative details, and follow-up outcomes were extracted from the database. The pattern of recurrences and investigative modality that detected recurrences was identified. Patients were followed up until either year 2016 or the day of their demise.

Results

Two hundred seventeen patients (66.6%) were male and 109 patients (33.3%) female. Median age was 64 years old. Close to a third of the patients received adjuvant therapy (34%). Among the 326 patients studied, 29.8% of (97/326) patients developed recurrence. 7.7% (25/326) had loco-regional recurrence while 22.1% (72/326) had distant metastasis. Median time to recurrence was 16 months (4–83) and 18 months (3–81), respectively. Computed tomography scan was the best modality to detect both loco-regional and distant recurrences (48% in loco-regional and 41.7% in distant metastasis). The most common site of distant metastasis is the lung (34.7%). The salvage rate for loco-regional and distant recurrences was 52 and 12.5%, respectively.

Conclusion

The predominant pattern of recurrence in rectal cancer is distant disease. Surveillance regimes may need to be altered to increase early detection of distant metastases.

     

Prediction of overall survival following colorectal cancer surgery in elderly patients

BACKGROUND With advanced age and chronic illness,the life expectancy of a patient with colorectal cancer(CRC) becomes less dependent on the malignant disease and more on their pre-morbid condition.Justifying major surgery for these elderly patients can be challenging.An accurate tool demonstrating post-operative survival probability would be useful for surgeons and their patients.AIM To integrate clinically significant prognostic factors relevant to elective colorectal surgery in the elderly into a validated pre-operative scoring system.METHODS In this retrospective cohort study,patients aged 70 and above who underwent surgery for CRC at Singapore General Hospital between 1 January 2005 and 31 December 2012 were identified from a prospectively maintained database.Patients with evidence of metastatic disease,and those who underwent emergency surgery or had surgery for benign colorectal conditions wereexcluded from the analysis.The primary outcome was overall 3-year overall survival(OS) following surgery.A multivariate model predicting survival was derived and validated against an equivalent external surgical cohort from Kyungpook National University Chilgok Hospital,South Korea.Statistical analyses were performed using Stata/MP Version 15.1.RESULTS A total of 1267 patients were identified for analysis.The median post-operative length of stay was 8 [interquartile range(IQR) 6-12] d and median follow-up duration was 47(IQR 19-75) mo.Median OS was 78(IQR 65-85) mo.Following multivariate analysis,the factors significant for predicting overall mortality were serum albumin 35 g/dL,serum carcinoembryonic antigen ≥ 20 μg/L,T stage 3 or 4,moderate tumor cell differentiation or worse,mucinous histology,rectal tumors,and pre-existing chronic obstructive lung disease.Advanced age alone was not found to be significant.The Korean cohort consisted of 910 patients.The Singapore cohort exhibited a poorer OS,likely due to a higher proportion of advanced cancers.Despite the clinicopathologic differences,there was successful validation of the model following recalibration.An interactive online calculator was designed to facilitate post-operative survival prediction,available at http://bit.ly/sgh_crc.The main limitation of the study was selection bias,as patients who had undergone surgery would have tended to be physiologically fitter.CONCLUSION This novel scoring system generates an individualized survival probability following colorectal resection and can assist in the decision-making process.Validation with an external population strengthens the generalizability of this model.     

The association of genetically determined serum glycine with cardiovascular risk in East Asians

Background and aimsGlycine is involved in a wide range of metabolic pathways and increased circulating glycine is associated with reduced risk of cardio-metabolic diseases in Europeans but the genetic association between circulating glycine and cardiovascular risk is largely unknown in East Asians.Methods and resultsWe conducted a genome-wide association study (GWAS) in Singaporean Chinese participants and investigated if genetically determined serum glycine were associated with incident coronary artery disease (CAD) (711 cases and 1,246 controls), cardiovascular death (1,886 cases and 21,707 controls) and angiographic CAD severity (as determined by the Modified Gensini score, N = 1,138).ConclusionOur study, a first in East Asians, suggest a protective role of glycine against CAD.     

DNA methylation and breast cancer-associated variants

Breast Cancer Research and Treatment - A breast cancer polygenic risk score (PRS) comprising 313 common variants reliably predicts disease risk. We examined possible relationships between genetic...     

Augmenting Product Defect Surveillance Through Web Crawling and Machine Learning in Singapore

Introduction

Substandard medicines are medicines that fail to meet their quality standards and/or specifications. Substandard medicines can lead to serious safety issues affecting public health. With the increasing number of pharmaceuticals and the complexity of the pharmaceutical manufacturing supply chain, monitoring for substandard medicines via manual environmental scanning can be laborious and time consuming.

Methods

A web crawler was developed to automatically detect and extract alerts on substandard medicines published on the Internet by regulatory agencies. The crawled data were labelled as related to substandard medicines or not. An expert-derived keyword-based classification algorithm was compared against machine learning algorithms to identify substandard medicine alerts on two validation datasets (n = 4920 and n = 2458) from a later time period than training data. Models were comparatively assessed for recall, precision and their F1 scores (harmonic mean of precision and recall).

Results

The web crawler routinely extracted alerts from the 46 web pages belonging to nine regulatory agencies. From October 2019 to May 2020, 12,156 unique alerts were crawled of which 7378 (60.7%) alerts were set aside for validation and contained 1160 substandard medicine alerts (15.7%). An ensemble approach of combining machine learning and keywords achieved the best recall (94% and 97%), precision (85% and 80%) and F1 scores (89% and 88%) on temporal validation.

Conclusions

Combining robust web crawler programmes with rigorously tested filtering algorithms based on machine learning and keyword models can automate and expand horizon scanning capabilities for issues relating to substandard medicines.

     

Association of mitochondrial DNA content in peripheral blood with cancer-related fatigue and chemotherapy-related cognitive impairment in early-stage breast cancer patients: a prospective cohort study

Purpose

Cancer-related fatigue (CRF) and chemotherapy-related cognitive impairment (CRCI) are reported to be associated with mitochondrial dysfunction. Hence, mitochondrial DNA (mtDNA) content, a biomarker of mitochondrial dysfunction, is hypothesized to correlate with the onset of CRF and CRCI. This study aims to evaluate the association between peripheral blood mtDNA content reduction and severity of CRF and CRCI in patients receiving chemotherapy.

Methods

This was a prospective cohort study. Early-stage breast cancer patients receiving anthracycline- or taxane-based chemotherapy were recruited. CRF was assessed using MFSI-SF, and CRCI was assessed using FACT-Cog and CANTAB at two timepoints: baseline (T1; prior to treatment) and 6 weeks after initiation of treatment (T2). mtDNA content was measured at both timepoints using real-time quantitative polymerase chain reaction. Multiple logistic regression was utilized to evaluate the association between mtDNA reduction and worsening of CRF and CRCI, adjusting for age, anxiety, insomnia, plasma cytokines concentrations, and other clinically important covariates.

Results

A total of 108 patients (age 52.0 ± 9.2 years; 82.4% Chinese; 64.8% receiving anthracycline-based chemotherapy) were recruited. Proportions of patients with worsening of CRF increased from the lower to the upper quartiles of mtDNA reduction (22.2, 33.3, 55.6, and 63.0% in quartiles 1, 2, 3, and 4, respectively, p = 0.001 for trend). Reduction of mtDNA content was significantly greater among those with worsening of CRF and CRCI compared to those without CRF [mean reduction (± SD): 36.5 (46.1) vs. 9.4 (34.5), p < 0.001]. After adjusting for covariates, every 1-unit reduction of the mtDNA content was associated with a 4% increased risk for worsening of CRF (95% CI, 1–6%; p = 0.009).

Conclusions

This is the first study to show that the reduction of mtDNA content in peripheral blood is associated with the onset of CRF in patients receiving chemotherapy. Further validation studies are required to confirm the findings.