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1.  Higher prevalence of elevated LDL-C than non-HDL-C and low statin treatment rate in elderly community-dwelling Chinese with high cardiovascular risk 
Scientific Reports  2016;6:34268.
Lipid levels are increasing in all age groups in the Chinese population, but the use of statin treatment in the elderly is not well documented. We examined serum lipids, statin usage and achievement of lipid goals in 3950 subjects aged ≥65 years. Established CVD was present in 7.77% of participants and increased CVD risk was common. Elevated LDL-C according to CVD risk level was present in 46.70% of all subjects and was more frequent (p < 0.01) than elevated non-HDL-C at 32.58%. With increasing age, LDL-C was unchanged but triglycerides and non-HDL-C decreased and HDL-C increased. Individuals at moderate risk for CVD had higher TC, LDL-C, and non-HDL-C than low-risk subjects, but the values were lower in high- and very-high-risk individuals, probably because of the use of statin which was 28.57% in high-risk subjects with established CVD and 37.60% in very-high-risk individuals, but only 2.62% in those with estimated high-risk and 3.75% in those with high-risk from diabetes. More subjects in each risk group reached the non-HDL-C goal than the LDL-C goal because of the relatively low triglycerides and VLDL-C levels. These findings demonstrate a high prevalence of elevated LDL-C but low rate of statin treatment in elderly community-dwelling Chinese.
PMCID: PMC5043234  PMID: 27686151
2.  Abdominal obesity is strongly associated with Cardiovascular Disease and its Risk Factors in Elderly and very Elderly Community-dwelling Chinese 
Scientific Reports  2016;6:21521.
Obesity is usually considered to predispose to atherosclerotic cardiovascular disease (ASCVD) but milder degrees of obesity or overweight may be protective in some elderly populations. We examined the relationships between general and abdominal obesity indices with ASCVD and its risk factors in elderly (aged ≥65 years) Shanghai community residents Among the 3950 participants, 21.5% had ASCVD, 56.2% had body mass index (BMI) ≥24 kg/m2, 50.1% had high waist circumference (WC) and 77.1% had waist-to-height ratio (WHtR) ≥0.50. WHtR increased with age in both men and women whereas WC increased with age only in women and BMI decreased with age only in men. The optimal WHtR cut-off value to predict the risk of ASCVD determined by receiver operating characteristic analysis was WHtR ≥0.53 with a prevalence of 55.8%. Having abdominal obesity was significantly associated with prevalent ASCVD with WHtR ≥0.53 having a higher value for the odds ratio than high WC, whereas high BMI was not associated. All three indices predicted high glucose, triglycerides and hsCRP levels but only the WHtR ≥0.53 showed a significant association with physical activity. Abdominal obesity indices, but not BMI, predicted prevalent ASCVD and its risk factors in this elderly Chinese population.
PMCID: PMC4756331  PMID: 26882876
3.  Achievement of specified lipid and high-sensitivity C-reactive protein levels with two statins in Chinese patients with hypercholesterolaemia 
Statins reduce plasma low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hsCRP) levels. Rosuvastatin 10 mg daily appears to be more potent in reducing LDL-C than simvastatin 40 mg, but the relative effect of these two statin doses on hsCRP is unknown.
Chinese hyperlipidaemic patients with high cardiovascular risk or familial hypercholesterolaemia (FH) were treated with rosuvastatin 10 mg and simvastatin 40 mg daily in an open-label crossover study. Lipid profiles were measured off treatment and after at least 4 weeks treatment with each of the two statins and hsCRP levels were measured on treatment with both statins.
Both treatments were well tolerated in 247 patients (age 55.7 ± 11.1 years; 100 male; 140 with FH) with good treatment compliance. There were statistically significant differences (P < 0.001) for rosuvastatin versus simvastatin for LDL-C reduction (−52.4 ± 11.9 % vs. -47.7 ± 10.8 %) and on-treatment LDL-C (2.62 ± 0.99 mmol/L vs. 2.86 ± 0.97 mmol/L), respectively, but the on-treatment hsCRP levels (1.33 ± 1.37 mg/L vs. 1.41 ± 1.57 mg/L, P > 0.05) were not significantly different. The lipid target (LDL-C <2.6 mmol/L) was achieved by 52.9 % with rosuvastatin compared with 42.6 % with simvastatin (P < 0.05). The proportions of patients attaining hsCRP targets of <2 and <1 mg/L were similar with the two statins (57.1 % and 74.6 % for rosuvastatin vs. 57.1 % and 80.1 % for simvastatin, P > 0.05).
A significantly greater proportion of patients achieved LDL-C targets with rosuvastatin 10 mg compared to simvastatin 40 mg in Chinese patients with hypercholesterolaemia, but there was no significant difference in achieving hsCRP target levels with the two statins.
PMCID: PMC4568069  PMID: 26365713
High-sensitivity C-reactive protein; Statins; Low-density lipoprotein cholesterol; Chinese
4.  Effects of Phenotypic and Genotypic Factors on the Lipid Responses to Niacin in Chinese Patients With Dyslipidemia 
Medicine  2015;94(20):e881.
The acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes DGAT1 and DGAT2 catalyze the final step in triglycerides biosynthesis. This study examined the relationships of baseline phenotypes and the common polymorphisms in DGAT1 and DGAT2 with the lipid responses to niacin.
Lipid responses in Chinese patients with dyslipidemia treated with the extended release (ER) niacin/laropiprant combination 1000/20 mg for 4 weeks and then 2000/40 mg for 8 weeks (n = 121, the primary study) or with ER niacin 1500 mg for at least 4 weeks (n = 68, the replication study) were analyzed according to genotypes of DGAT1 rs7003945 T>C and DGAT2 rs3060 T>C polymorphisms.
Treatment with ER niacin improved all lipid parameters in both studies. Absolute and percentage changes in lipids were related to their baseline levels, particularly for low-density lipoprotein cholesterol (LDL-C). The DGAT2 rs3060 T>C polymorphism was associated with lower baseline LDL-C, apoB, high-density lipoprotein cholesterol (HDL-C), and apoAI in patients on statin therapy in the primary study. Subjects with the DGAT2 rs3060 T>C variant had less reduction in LDL-C in the primary study and smaller changes in triglyceride and HDL-C in the replication study but these associations became non-significant after adjusting for baseline lipid values. The DGAT1 rs7003945 T>C polymorphism was not related to lipid baseline values or changes in either study. Concomitant statin therapy and lower body weight were also associated with greater reduction in LDL-C.
Baseline lipid levels were the main determinants of lipid responses especially for LDL-C. The DGAT2 rs3060 polymorphism might influence the lipid responses depending on baseline phenotype, but this association did not persist after adjustment for the baseline lipid levels.
PMCID: PMC4602879  PMID: 25997070
5.  Effect of Extended-Release Niacin/Laropiprant Combination on Plasma Adiponectin and Insulin Resistance in Chinese Patients with Dyslipidaemia 
Disease Markers  2015;2015:154014.
Objectives. This study examined whether the increase of adiponectin associated with extended-release (ER) niacin/laropiprant combination attenuates the adverse effect of niacin on glucose and insulin resistance in Hong Kong Chinese patients with dyslipidaemia. Methods. Patients (N = 121) were treated with ER niacin/laropiprant 1 g/20 mg for 4 weeks and then the dose was doubled for an additional 8 weeks. Measurements of fasting lipids, glucose, insulin, and adiponectin were performed at baseline and during the study. Results. There were significant (P < 0.001) increases in glucose (9.4 ± 13.1%), insulin (70.2 ± 91.0%), HOMA-IR (87.8 ± 103.9%), and adiponectin (169.3 ± 111.6%). The increase in adiponectin was significantly associated with increase in glucose (r = 0.221, P < 0.05), insulin (r = 0.184, P < 0.05), and HOMA-IR (r = 0.237, P < 0.01) and the association remained significant after adjustment for changes in body weight or body fat mass. Conclusion. Treatment with ER niacin/laropiprant led to a significant increase in adiponectin levels but worsening of glucose levels and insulin resistance, and the increase in adiponectin and insulin resistance were correlated suggesting the increase in adiponectin did not ameliorate the deterioration in insulin resistance. Clinical trial is registered with number on WHO-ICTRP: ChiCTR-ONC-10001038.
PMCID: PMC4429190  PMID: 26063948
6.  Bernard Lerer: Recipient of the 2014 Inaugural Werner Kalow Responsible Innovation Prize in Global Omics and Personalized Medicine (Pacific Rim Association for Clinical Pharmacogenetics) 
This article announces the recipient of the 2014 inaugural Werner Kalow Responsible Innovation Prize in Global Omics and Personalized Medicine by the Pacific Rim Association for Clinical Pharmacogenetics (PRACP): Bernard Lerer, professor of psychiatry and director of the Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. The Werner Kalow Responsible Innovation Prize is given to an exceptional interdisciplinary scholar who has made highly innovative and enduring contributions to global omics science and personalized medicine, with both vertical and horizontal (transdisciplinary) impacts. The prize is established in memory of a beloved colleague, mentor, and friend, the late Professor Werner Kalow, who cultivated the idea and practice of pharmacogenetics in modern therapeutics commencing in the 1950s. PRACP, the prize's sponsor, is one of the longest standing learned societies in the Asia-Pacific region, and was founded by Kalow and colleagues more than two decades ago in the then-emerging field of pharmacogenetics. In announcing this inaugural prize and its winner, we seek to highlight the works of prize winner, Professor Lerer. Additionally, we contextualize the significance of the prize by recalling the life and works of Professor Kalow and providing a brief socio-technical history of the rise of pharmacogenetics and personalized medicine as a veritable form of 21st century scientific practice. The article also fills a void in previous social science analyses of pharmacogenetics, by bringing to the fore the works of Kalow from 1995 to 2008, when he presciently noted the rise of yet another field of postgenomics inquiry—pharmacoepigenetics—that railed against genetic determinism and underscored the temporal and spatial plasticity of genetic components of drug response, with invention of the repeated drug administration (RDA) method that estimates the dynamic heritabilities of drug response. The prize goes a long way to cultivate transgenerational capacity and broader cognizance of the concept and practice of responsible innovation as an important criterion of 21st century omics science and personalized medicine. A new call is presently in place for the 2016 PRACP Werner Kalow prize. Nominations can be made in support of an exceptional individual interdisciplinary scholar, or alternatively, an entire research team, from any region in the world with a record of highly innovative contributions to global omics science and/or personalized medicine, in the spirit of responsible innovation. The application process is straightforward, requiring a signed, 1500-word nomination letter (by the applicant or sponsor) submitted not later than May 31, 2015.
Wanderer, your footsteps are
the road, and nothing more;
wanderer, there is no road,
the road is made by walking.
By walking one makes the road,
and upon glancing behind
one sees the path
that never will be trod again.
Wanderer, there is no road –
Only wakes upon the sea.
“The real voyage of discovery consists not in seeking new landscapes but in having new eyes.”
PMCID: PMC3976589  PMID: 24649998
7.  Sex Differences in Epidemiology and Risk Factors of Acute Coronary Syndrome in Chinese Patients with Type 2 Diabetes: A Long-Term Prospective Cohort Study 
PLoS ONE  2015;10(4):e0122031.
Diabetic patients with acute coronary syndrome (ACS) are at higher risk of poor outcome than are non-diabetic patients with ACS. Few studies have focused on sex-related ACS incidence, ACS-related mortality or risk factors to affects sex specific ACS in Chinese with Type 2 diabetes mellitus (T2DM). Based on a hospital-based cohort of Chinese patients with T2DM, we aimed to investigate whether there was sex difference in ACS or ACS-related mortality or risk factors of ACS.
Totally 2,135 Hong Kong Chinese with T2DM were recruited during 1994-1996 and followed up until August 2012. We systematically analyzed sex-related ACS incidence and ACS-related mortality and risk factors with χ2-squared test, descriptive statistics and survival analysis.
Regular follow-up was completed in 2,105 subjects (98.6%), with a median period of 14.53 years. The occurrence of ACS was recorded among 414 patients (19.7%) and ACS-related death among 104 patients (4.9%). ACS incidences increased with age in both men and women, and men had a higher prevalence of ACS than women across different age categories and different follow-up periods (log rank χ2=20.32, P<0.001). The transition of ACS incidences from slow to rapid increase were about 5 years earlier in men (at 51-55 years) than in women (55-60 years). Among ACS patients, cumulative ACS-related mortalities was similar between men and women (log rank χ2=0.063, P=0.802). Besides age and albuminuria, different profiles of risk factors accounted for the occurrence of ACS between men and women.
Our findings demonstrated sex differences in ACS incidence and risk factors, but not in ACS-related mortality in Chinese patients withT2DM. These findings suggest that screening and prevention campaigns should be optimized for men and women, which may help to identify diabetic patients at higher risk of coronary heart disease.
PMCID: PMC4382276  PMID: 25830291
8.  Targeting the ABCG2-overexpressing multidrug resistant (MDR) cancer cells by PPARγ agonists 
British Journal of Pharmacology  2013;170(5):1137-1151.
Background and Purpose
Multidrug resistance (MDR), usually mediated by overexpression of efflux transporters such as P-gp, ABCG2 and/or MRP1, remains a major obstacle hindering successful cancer chemotherapy. There has been great interest in the development of inhibitors towards these transporters to circumvent resistance. However, since the inhibition of transporter is not specific to cancer cells, a decrease in the cytotoxic drug dosing may be needed to prevent excess toxicity, thus undermining the potential benefit brought about by a drug efflux inhibitor. The design of potent MDR modulators specific towards resistant cancer cells and devoid of drug-drug interactions will be needed to effect MDR reversal.
Experimental Approach
Recent evidence suggests that the PTEN/PI3K/Akt pathway may be exploited to alter ABCG2 subcellular localization, thereby circumventing MDR. Three PPARγ agonists (telmisartan, pioglitazone and rosiglitazone) that have been used in the clinics were tested for their effect on the PTEN/PI3K/Akt pathway and possible reversal of ABCG2-mediated drug resistance.
Key Results
The PPARγ agonists were found to be weak ABCG2 inhibitors by drug efflux assay. They were also shown to elevate the reduced PTEN expression in a resistant and ABCG2-overexpressing cell model, which inhibit the PI3K-Akt pathway and lead to the relocalization of ABCG2 from the plasma membrane to the cytoplasma, thus apparently circumventing the ABCG2-mediated MDR.
Conclusions and Implications
Since this PPARγ/PTEN/PI3K/Akt pathway regulating ABCG2 is only functional in drug-resistant cancer cells with PTEN loss, the PPARγ agonists identified may represent promising agents targeting resistant cells for MDR reversal.
PMCID: PMC3949660  PMID: 24032744
ABCG2; multidrug resistance (MDR); PPARγ; phosphatase and tensin homologue deleted on chromosome 10 (PTEN); telmisartan; pioglitazone; rosiglitazone
9.  Long-Term Risk of Cardiovascular Disease among Type 2 Diabetic Patients with Asymptomatic Intracranial Atherosclerosis: A Prospective Cohort Study 
PLoS ONE  2014;9(9):e106623.
To investigate whether asymptomatic middle cerebral artery (MCA) stenosis is associated with risk of cardiovascular disease (CVD) in Chinese with type 2 diabetes.
In this prospective cohort study, 2,144 Hong Kong Chinese with type 2 diabetes and without history of stroke or atrial fibrillation were recruited in 1994–1996 and followed up for a median of 14.51 years. Participants were assessed at baseline for MCA stenosis using transcranial Doppler. We performed survival analysis to assess the association between asymptomatic MCA stenosis and first CVD event, defined as ischemic stroke, acute coronary syndrome (ACS) or cardiovascular death.
Of the 2,144 subjects, MCA stenosis at baseline was detected in 264 (12.3%). Rates of stroke, ACS and cardiovascular death per 100 were, respectively, 2.24, 2.92 and 1.11 among participants with stenosis, higher than among those without stenosis. Ten-year cumulative occurrence of stroke, ACS and cardiovascular death in subjects with MCA stenosis was 20%, 24% and 10%, respectively, higher than the corresponding values for subjects without stenosis(all P<0.001). After adjusting for covariates, MCA stenosis was found to be an independent predictor of stroke [hazard ratio (HR) 1.40, 95%CI 1.05–1.86; P = 0.02], ACS (HR 1.35, 95%CI 1.04–1.75; P = 0.02) and cardiovascular death(HR 1.56, 95%CI 1.04–2.33; P = 0.03).
Asymptomatic MCA stenosis is a risk factor for CVD in Chinese with type 2 diabetes, and detection of asymptomatic MCA stenosis by transcranial Doppler can identify diabetic individuals at high risk of future CVD. This finding is particularly important for diabetic individuals in Asia, where intracranial atherosclerosis is common.
PMCID: PMC4156359  PMID: 25192283
10.  Clinical Pharmacokinetics of Buffered Propranolol Sublingual Tablet (Promptol™)—Application of a New “Physiologically Based” Model to Assess Absorption and Disposition 
The AAPS Journal  2013;15(3):787-796.
Sublingual administration of certain buffered propranolol may improve the rate and extent of absorption compared to oral administration. The main objectives of this study were to (1) compare the plasma propranolol concentrations (Cp-prop) following sublingual administration of a specially buffered formulation (Promptol™) to that following oral administration of Inderal® and (2) evaluate the utility of a special pharmacokinetic model in describing the Cp-prop following sublingual administration. Eighteen healthy volunteers received 10 mg sublingual Promptol™ or oral Inderal®. Multiple Cp-prop were determined and their pharmacokinetics compared. Additional data following sublingual 40 mg Promptol™ or Inderal® were utilized for evaluation of a special advanced compartmental absorption and transit (ACAT) model. For model simulation, the physicochemical parameters were imported from AMET predictor, whereas the pharmacokinetic parameters were calculated and optimized by Gastroplus®. Based on this model, the quantity of drug absorbed via buccal/sublingual mucosa was estimated. Cp-prop was higher at earlier times with 3-fold greater relative bioavailability following sublingual Promptol™ compared to that from oral Inderal®. The special ACAT model provided excellent goodness of fit of Cp-prop-time curve and estimated a 56.6% increase in absorption rate from Promptol™ and higher initial Cp-prop compared to the regular formulation. The modified ACAT model provided a useful approach to describe sublingual absorption of propranolol and clearly demonstrated an improvement of absorption of Promptol™. The sublingual 10 mg Promptol™ achieved not only a similar systemic exposure as 30 mg oral Inderal® but an earlier effective Cp-prop which may be advantageous for certain clinical conditions.
PMCID: PMC3691420  PMID: 23605805
ACAT; buffered; pharmacokinetics; propranolol; sublingual
11.  Evaluation of a Crataegus-Based Multiherb Formula for Dyslipidemia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial 
Background. We for the first time examined the effects of a multiherb formula containing Crataegus pinnatifida (1 g daily), Alisma orientalis, Stigma maydis, Ganoderma lucidum, Polygonum multiflorum, and Morus alba on plasma lipid and glucose levels in Chinese patients with dyslipidemia. Methods. In this randomized, double-blind, placebo-controlled study, 42 patients were randomized at a ratio of 1 : 1 to receive the herbal formula or placebo for 12 weeks and 40 patients completed the study. Lipid profiles, glucose, glycated haemoglobin (HbA1c), and laboratory safety parameters were performed before and after treatment. Results. The difference in the changes in low-density lipoprotein cholesterol (LDL-C) levels between placebo and active treatment (−9%) was significantly (P < 0.05) better with active treatment. HbA1c levels significantly decreased by −3.9% in the active treatment group, but the change was not significantly different from that with placebo (−1.1%) (P = 0.098). There were no apparent adverse effects or changes in laboratory safety parameters with either treatment. Conclusions. The multiherb formula had mild beneficial effects on plasma LDL-C after 12-weeks treatment in subjects with dyslipidemia without any noticeable adverse effects.
PMCID: PMC4009229  PMID: 24834096
12.  Bench to Bed Evidences for Pharmacokinetic and Pharmacodynamic Interactions Involving Oseltamivir and Chinese Medicine 
Oseltamivir (OA), an ethyl ester prodrug of oseltamivir carboxylate (OC), is clinically used as a potent and selective inhibitor of neuraminidase. Chinese medicines have been advocated to combine with conventional drug for avian influenza. The current study aims to investigate the potential pharmacokinetic and pharmacodynamic interactions of a Chinese medicine formula, namely, Yin Qiao San and Sang Ju Yin (CMF1), commonly used for anti-influenza in combination with OA in both rat and human, and to reveal the underlined mechanisms. It was found that although Cmax, AUC and urinary recovery of OC, as well as metabolic ratio (AUCOC/AUCOA), were significantly decreased in a dose-dependent manner following combination use of CMF1 and OA in rat studies (P < 0.01), such coadministration in 14 healthy volunteers only resulted in a trend of minor decrease in the related parameters. Further mechanistic studies found that although CMF1 could reduce absorption and metabolism of OA, it appears to enhance viral inhibition of OA (P < 0.01). In summary, although there was potential interaction between OA and CMF1 found in rat studies, its clinical impact was expected to be minimal. The coadministration of OA and CMF1 at the clinical recommended dosages is, therefore, considered to be safe.
PMCID: PMC3912631  PMID: 24527044
13.  Safety of statins: an update 
Statins are widely used and have been proven to be effective in the prevention of atherosclerotic vascular disease events, primarily by reducing plasma low-density lipoprotein cholesterol concentrations. Although statins are generally well tolerated and present an excellent safety profile, adverse effects from muscle toxicity and liver enzyme abnormalities may occur in some patients. Myopathy and rhabdomyolysis are rare with statin monotherapy at the approved dose ranges, but the risk increases with use of higher doses, interacting drugs and genetic predisposition. Asymptomatic increases in liver transaminases with statin treatment do not seem to be associated with an increased risk of liver disease. Therefore, statin treatment can be safely used in patients with mild to moderately abnormal liver tests that are potentially attributable to nonalcoholic fatty liver disease and can improve liver tests and reduce cardiovascular morbidity in this group of patients. The risks of other unfavorable effects such as the slightly increased risk of new-onset diabetes and potentially increased risk of haemorrhagic stroke are much smaller than the cardiovascular benefits with the use of statins.
PMCID: PMC4110822  PMID: 25083232
cardiovascular disease; drug safety; myopathy; rhabdomyolysis; statins
14.  Correction: A Genome-Wide Linkage and Association Scan Reveals Novel Loci for Hypertension and Blood Pressure Traits 
PLoS ONE  2012;7(6):10.1371/annotation/4415f88f-ab10-44dd-8ba9-1a57ade740c1.
PMCID: PMC3371059
15.  Identification of IGF1, SLC4A4, WWOX, and SFMBT1 as Hypertension Susceptibility Genes in Han Chinese with a Genome-Wide Gene-Based Association Study 
PLoS ONE  2012;7(3):e32907.
Hypertension is a complex disorder with high prevalence rates all over the world. We conducted the first genome-wide gene-based association scan for hypertension in a Han Chinese population. By analyzing genome-wide single-nucleotide-polymorphism data of 400 matched pairs of young-onset hypertensive patients and normotensive controls genotyped with the Illumina HumanHap550-Duo BeadChip, 100 susceptibility genes for hypertension were identified and also validated with permutation tests. Seventeen of the 100 genes exhibited differential allelic and expression distributions between patient and control groups. These genes provided a good molecular signature for classifying hypertensive patients and normotensive controls. Among the 17 genes, IGF1, SLC4A4, WWOX, and SFMBT1 were not only identified by our gene-based association scan and gene expression analysis but were also replicated by a gene-based association analysis of the Hong Kong Hypertension Study. Moreover, cis-acting expression quantitative trait loci associated with the differentially expressed genes were found and linked to hypertension. IGF1, which encodes insulin-like growth factor 1, is associated with cardiovascular disorders, metabolic syndrome, decreased body weight/size, and changes of insulin levels in mice. SLC4A4, which encodes the electrogenic sodium bicarbonate cotransporter 1, is associated with decreased body weight/size and abnormal ion homeostasis in mice. WWOX, which encodes the WW domain-containing protein, is related to hypoglycemia and hyperphosphatemia. SFMBT1, which encodes the scm-like with four MBT domains protein 1, is a novel hypertension gene. GRB14, TMEM56 and KIAA1797 exhibited highly significant differential allelic and expressed distributions between hypertensive patients and normotensive controls. GRB14 was also found relevant to blood pressure in a previous genetic association study in East Asian populations. TMEM56 and KIAA1797 may be specific to Taiwanese populations, because they were not validated by the two replication studies. Identification of these genes enriches the collection of hypertension susceptibility genes, thereby shedding light on the etiology of hypertension in Han Chinese populations.
PMCID: PMC3315540  PMID: 22479346
16.  A Genome-Wide Linkage and Association Scan Reveals Novel Loci for Hypertension and Blood Pressure Traits 
PLoS ONE  2012;7(2):e31489.
Hypertension is caused by the interaction of environmental and genetic factors. The condition which is very common, with about 18% of the adult Hong Kong Chinese population and over 50% of older individuals affected, is responsible for considerable morbidity and mortality. To identify genes influencing hypertension and blood pressure, we conducted a combined linkage and association study using over 500,000 single nucleotide polymorphisms (SNPs) genotyped in 328 individuals comprising 111 hypertensive probands and their siblings. Using a family-based association test, we found an association with SNPs on chromosome 5q31.1 (rs6596140; P<9×10−8) for hypertension. One candidate gene, PDC, was replicated, with rs3817586 on 1q31.1 attaining P = 2.5×10−4 and 2.9×10−5 in the within-family tests for DBP and MAP, respectively. We also identified regions of significant linkage for systolic and diastolic blood pressure on chromosomes 2q22 and 5p13, respectively. Further family-based association analysis of the linkage peak on chromosome 5 yielded a significant association (rs1605685, P<7×10−5) for DBP. This is the first combined linkage and association study of hypertension and its related quantitative traits with Chinese ancestry. The associations reported here account for the action of common variants whereas the discovery of linkage regions may point to novel targets for rare variant screening.
PMCID: PMC3286457  PMID: 22384028
17.  Study of the Effects of Total Flavonoids of Astragalus on Atherosclerosis Formation and Potential Mechanisms 
Astragalus mongholicus Bunge has long been used to treat cardiovascular disease in Chinese traditional medicine. However, its mechanisms are not fully understood. In this study, we explored potential mechanisms and protective effects of total flavonoids of Astragalus (TFA) on cardiovascular disease using in vitro experiments and diet-induced atherosclerotic rabbits. We identified six components and their proportion in TFA. The animal experiments showed that TFA significantly reduced plasma levels of total cholesterol and LDL cholesterol (P < 0.05 to 0.01), increased HDL cholesterol levels (P < 0.01), and reduced the aortic fatty streak area by 43.6 to 63.6% (P < 0.01). We also found that TFA scavenged superoxide and hydroxyl radicals and this effect increased with higher TFA concentration. In in vivo experiments, TFA effectively inhibited the free radical spectrum in the ischemia-reperfusion module. In conclusion, TFA was the active component of Astragalus mongholicus Bunge, which benefits cardiovascular disease attributing to the potent antioxidant activity to improve the atherosclerosis profile.
PMCID: PMC3306992  PMID: 22496932
18.  A single nucleotide polymorphism in APOA5 determines triglyceride levels in Hong Kong and Guangzhou Chinese 
European Journal of Human Genetics  2010;18(11):1255-1260.
Single nucleotide polymorphisms (SNPs) in the apolipoprotein A5 (APOA5) gene have been associated with hypertriglyceridaemia. We investigated which SNPs in the APOA5 gene were associated with triglyceride levels in two independent Chinese populations. In all, 1375 subjects in the Hong Kong Cardiovascular Risk Factor Prevalence Study were genotyped for five tagging SNPs chosen from HapMap. Replication was sought in 1996 subjects from the Guangzhou Biobank Cohort Study. Among the five SNPs, rs662799 (-1131T>C) was strongly related to log-transformed triglyceride levels among Hong Kong subjects (β=0.192, P=2.6 × 10−13). Plasma triglyceride level was 36.1% higher in CC compared to TT genotype. This association was confirmed in Guangzhou subjects (β=0.159, P=1.3 × 10−12), and was significantly irrespective of sex, age group, obesity, metabolic syndrome, hypertension, diabetes, smoking and alcohol drinking. The odds ratios and 95% confidence interval for plasma triglycerides ≥1.7 mmol/l associated with TC and CC genotypes were, respectively, 1.81 (1.37–2.39) and 2.22 (1.44–3.43) in Hong Kong and 1.27 (1.05–1.54) and 1.97 (1.42–2.73) in Guangzhou. Haplotype analysis suggested the association was due to rs662799 only. The corroborative findings in two independent populations indicate that the APOA5-1131T>C polymorphism is an important and clinically relevant determinant of plasma triglyceride levels in the Chinese population.
PMCID: PMC2987477  PMID: 20571505
apolipoproteins; triglycerides; hypertriglyceridaemia; single nucleotide polymorphisms
19.  Effects of Some Common Food Constituents on Cardiovascular Disease 
ISRN Cardiology  2011;2011:397136.
Cardiovascular diseases are the major cause of morbidity and mortality worldwide, and there is considerable interest in the role of dietary constituents and supplements in the prevention and treatment of these disorders. We reviewed the major publications related to potential effects on cardiovascular risk factors and outcomes of some common dietary constituents: carotenoids, flavonoid-rich cocoa, tea, red wine and grapes, coffee, omega-3 fatty acids, and garlic. Increased intake of some of these has been associated with reduced all-cause mortality or reduced incidence of myocardial infraction, stroke, and hypertension. However, although the evidence from observational studies is supportive of beneficial effects for most of these foodstuffs taken as part of the diet, potential benefits from the use of supplements derived from these natural products remain largely inconclusive.
PMCID: PMC3262529  PMID: 22347642
20.  Linkage of Angiotensinogen Gene Polymorphisms with Hypertension in a Sibling Study of Hong Kong Chinese 
Journal of hypertension  2010;28(6):1203-1209.
The angiotensinogen gene has been linked with human essential hypertension in Caucasians but the relationship in Asian populations has been less consistent. This study aimed to examine genetic associations between hypertension and the M235T, T174M, and G-217A polymorphisms of the angiotensinogen gene in Chinese siblings.
We studied members of 126 families with a hypertensive proband, including 434 siblings, of which 178 were hypertensive. Parental history of hypertension was recorded. The M235T, T174M, and G-217A polymorphisms were examined using a microarray method, validated by sequencing. The transmission disequilibrium test was applied to identify whether the genetic polymorphism loci were related to hypertension. Haplotype analysis of the combined polymorphisms was applied using the TRANSMIT program. Linkage study was conducted by applying the affected pedigree member method.
A significant over-transmission was observed for the T235 allele at the M235T polymorphism and hypertension (χ2=4.41, p=0.036), but not for the T174M and G-217A polymorphisms. The haplotype analysis showed a significant association with the haplotypes of paired markers (T174 and T235) with χ2 value of 8.131, p=0.004 (global test χ2=9.131, p=0.028). Linkage between M235T and hypertension was detected (T=-2.25, P=0.019), and a tendency for linkage with central obesity-related hypertension was found for the M235T and T174M polymorphisms (P=0.0087 and P=0.01).
The M235T and T174M variants, especially the T235 allele, contribute to an increased risk of hypertension in these Chinese subjects.
PMCID: PMC2908179  PMID: 20216084
angiotensinogen; hypertension; sibling study
21.  Febuxostat in the management of hyperuricemia and chronic gout: a review 
Febuxostat is a novel, potent, non-purine selective xanthine oxidase inhibitor, which in clinical trials demonstrated superior ability to lower and maintain serum urate levels below 6 mg/dL compared with conventionally used doses of allopurinol. Febuxostat was well tolerated in long term treatment in patients with hyperuricemia including those experiencing hypersensitity/intolerance to allopurinol. Dose adjustment appears unnecessary in patients with mild to moderate renal or liver insufficiency or advanced age. The most common adverse reactions reported were abnormal liver function tests, headache, and gastrointestinal symptoms, which were usually mild and transient. However, whether hepatotoxicity becomes a limitation in the use of febuxostat needs to be determined in further studies. An increased frequency of gout flares occurs for a prolonged period after treatment initiation, as with any aggressive lowering of serum urate, and prolonged prophylaxis with colchicine or NSAIDs is usually required. Febuxostat has been granted marketing authorization by the European Commission in early 2008 for the treatment of chronic hyperuricemia and gout. Febuxostat is the first major treatment alternative for gout in more than 40 years and is a promising alternative to allopurinol, although continued long-term surveillance on safety and efficacy is required.
PMCID: PMC2643102  PMID: 19337428
febuxostat; TEI-6720; TMX-67; gout; hyperuricemia; xanthine oxidase inhibitor
23.  Association between adherence to statin therapy and lipid control in Hong Kong Chinese patients at high risk of coronary heart disease 
To examine the pattern of adherence to statin therapy and to determine the association of adherence to statin therapy and the control of serum low-density lipoprotein (LDL)-cholesterol in a cohort of Hong Kong Chinese patients at high risk of coronary heart disease (CHD).
This was a prospective observational cohort study conducted at the outpatient clinics of a public teaching hospital in Hong Kong. Patients at high risk of CHD who had been initiated on statin monotherapy for <12 months were recruited. The statin prescription was dispensed in a bottle with the Medication Event Monitoring System (MEMS). Adherence was assessed in two dimensions: dose-count was defined as the percentage of doses taken, and dose-time was defined as the percentage of doses taken within the suggested time interval. Lipid profiles were obtained at baseline and during two follow-up visits at month 3 and month 6.
Eighty-three patients completed the study. The median adherence to dose-count and to dose-time were 95% (25-75th percentile = 87–99%) and 78% (25–75th percentile = 17–92%), respectively. Both dose-count and dose-time adherence declined slightly over the first 6 months of therapy. Living with family [relative risk (RR) = 0.79, 95% confidence interval (CI) 0.63, 0.91] and duration of therapy (RR = 0.99, 95% CI 0.98, 1.00) were negative predictors while number of family members (among those living with family) (RR = 1.05, 95% CI 1.00, 1.08) was a positive predictor for adherence to dose-count. Monthly household income (RR = 1.01, 95% CI 1.00, 1.02) and angina (RR = 1.29, 95% CI 1.05, 1.58) were positive predictors while living with family (RR = 0.74, 95% CI 0.55, 0.90) was a negative predictor for dose-time adherence. Percent reduction in serum LDL-cholesterol was correlated to dose-count (P < 0.001) and dose-time (P = 0.047) adherence. Statistically significant correlations were observed between adherence to dose-count and LDL reduction (R2 = 0.130; P = 0.001), and between dose-time adherence and LDL reduction (R2 = 0.048; P = 0.047).
High adherence to statin therapy was found in a cohort of Chinese patients at high risk of CHD and the adherence declined slightly over time. A weak association between adherence to statin dose-count and LDL reduction and a marginal association between dose-time adherence and LDL reduction were observed.
PMCID: PMC1884622  PMID: 15521901
Chinese patients; LDL reduction; patient adherence; statin
24.  Human Metapneumovirus-associated Atypical Pneumonia and SARS 
Emerging Infectious Diseases  2004;10(3):497-500.
Acute pneumonia developed in a previously healthy man during the outbreak of severe acute respiratory syndrome (SARS) in southern China in March 2003. Antibiotic treatment was ineffective, and he died 8 days after illness onset. Human metapneumovirus was isolated from lung tissue. No other pathogen was found. Other etiologic agents should thus be sought in apparent SARS cases when coronavirus infection cannot be confirmed.
PMCID: PMC3322781  PMID: 15109421
human metapneumovirus; respiratory tract infection; postmortem; SARS
25.  Lessons from the Severe Acute Respiratory Syndrome Outbreak in Hong Kong 
Emerging Infectious Diseases  2003;9(9):1042-1045.
Severe acute respiratory syndrome (SARS) is now a global public health threat with many medical, ethical, social, economic, political, and legal implications. The nonspecific signs and symptoms of this disease, coupled with a relatively long incubation period and the initial absence of a reliable diagnostic test, limited the understanding of the magnitude of the outbreak. This paper outlines our experience with public health issues that have arisen during this outbreak of SARS in Hong Kong. We confirmed that case detection, reporting, clear and timely dissemination of information, and strict infection control measures are essential in handling such an infectious disease outbreak. The need for an outbreak response unit is crucial to combat any future outbreak.
PMCID: PMC3016765  PMID: 14519237
Severe acute respiratory syndrome (SARS); Hong Kong; emerging infectious disease; outbreak control

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