Identification of a Common Variant for Coronary Heart Disease at PDE1A Contributes to Individualized Treatment Goals and Risk Stratification of Cardiovascular Complications in Chinese Patients With Type 2 Diabetes.

OBJECTIVE: In this study we aim to unravel genetic determinants of coronary heart disease (CHD) in type 2 diabetes (T2D) and explore their applications. RESEARCH DESIGN AND METHODS: We performed a two-stage genome-wide association study for CHD in Chinese patients with T2D (3,596 case and 8,898 control subjects), followed by replications in European patients with T2D (764 case and 4,276 control subjects) and general populations (n = 51,442-547,261). Each identified variant was examined for its association with a wide range of phenotypes and its interactions with glycemic, blood pressure (BP), and lipid controls in incident cardiovascular diseases. RESULTS: We identified a novel variant (rs10171703) for CHD (odds ratio 1.21 [95% CI 1.13-1.30]; P = 2.4 × 10-8) and BP (ß ± SE 0.130 ± 0.017; P = 4.1 × 10-14) at PDE1A in Chinese T2D patients but found only a modest association with CHD in general populations. This variant modulated the effects of BP goal attainment (130/80 mmHg) on CHD (Pinteraction = 0.0155) and myocardial infarction (MI) (Pinteraction = 5.1 × 10-4). Patients with CC genotype of rs10171703 had >40% reduction in either cardiovascular events in response to BP control (2.9 × 10-8 < P < 3.6 × 10-5), those with CT genotype had no difference (0.0726 < P < 0.2614), and those with TT genotype had a threefold increase in MI risk (P = 6.7 × 10-3). CONCLUSIONS: We discovered a novel CHD- and BP-related variant at PDE1A that interacted with BP goal attainment with divergent effects on CHD risk in Chinese patients with T2D. Incorporating this information may facilitate individualized treatment strategies for precision care in diabetes, only when our findings are validated.

A study on clinical outcomes of Rathke's cleft cyst in patients managed conservatively.

OBJECTIVES: The primary objective was to investigate the clinical presentation, hormonal dysfunction, imaging characteristics and natural history of RCCs that were managed conservatively. Secondary objective was to identify factors associated with cyst progression. METHODS: A retrospective review of patients with the clinical diagnosis of RCC-identified from word search from radiology reports that were followed up from January 1999 to March 2019 was performed. The demographics, clinical data, radiological features and outcomes were reviewed and analyzed. RESULTS: 105 patients were identified with a median follow up of 6 years. 68 patients (64.8%) were managed conservatively from diagnosis till last follow up while 37 patients (35.2%) underwent surgery, with 26 operated at time of diagnosis and 11 operated upon monitoring. For patients managed conservatively from diagnosis till last follow up, incidental finding was the most common presentation. 19.1% had either one or more axes of hormonal dysfunction, with hypogonadism and hypocortisolemia being the commonest ones. Imaging features were variable. 66.2% of patients had T2W hyperintensity on MRI. Pathognomonic feature of intracystic nodule was present in only 14.7% of patients. Among the 79 patients with repeated MRI imaging (68 from conservative group and 11 from surgical group), 32.9% of patients developed cyst progression while 67.1% had either static disease or regression in size of RCC. Median time to progression of cyst was 14 months. Longer median follow up duration and presence of pituitary stalk displacement at presentation were associated with cyst progression. Only one patient developed new endocrine dysfunction. CONCLUSION: 2/3 of the RCCs had static disease or even regression in the size of the cyst. They rarely gave rise to additional endocrine dysfunction by adopting observant approach. Cyst progression was demonstrated in 1/3 of patients. Conservative treatment remained a reasonable treatment for patients without significant symptoms.

Development of genome-wide polygenic risk scores for lipid traits and clinical applications for dyslipidemia, subclinical atherosclerosis, and diabetes cardiovascular complications among East Asians.

BACKGROUND: The clinical utility of personal genomic information in identifying individuals at increased risks for dyslipidemia and cardiovascular diseases remains unclear. METHODS: We used data from Biobank Japan (n = 70,657-128,305) and developed novel East Asian-specific genome-wide polygenic risk scores (PRSs) for four lipid traits. We validated (n = 4271) and subsequently tested associations of these scores with 3-year lipid changes in adolescents (n = 620), carotid intima-media thickness (cIMT) in adult women (n = 781), dyslipidemia (n = 7723), and coronary heart disease (CHD) (n = 2374 cases and 6246 controls) in type 2 diabetes (T2D) patients. RESULTS: Our PRSs aggregating 84-549 genetic variants (0.251 < correlation coefficients (r) < 0.272) had comparably stronger association with lipid variations than the typical PRSs derived based on the genome-wide significant variants (0.089 < r < 0.240). Our PRSs were robustly associated with their corresponding lipid levels (7.5 × 10- 103 < P < 1.3 × 10- 75) and 3-year lipid changes (1.4 × 10- 6 < P < 0.0130) which started to emerge in childhood and adolescence. With the adjustments for principal components (PCs), sex, age, and body mass index, there was an elevation of 5.3% in TC (ß ± SE = 0.052 ± 0.002), 11.7% in TG (ß ± SE = 0.111 ± 0.006), 5.8% in HDL-C (ß ± SE = 0.057 ± 0.003), and 8.4% in LDL-C (ß ± SE = 0.081 ± 0.004) per one standard deviation increase in the corresponding PRS. However, their predictive power was attenuated in T2D patients (0.183 < r < 0.231). When we included each PRS (for TC, TG, and LDL-C) in addition to the clinical factors and PCs, the AUC for dyslipidemia was significantly increased by 0.032-0.057 in the general population (7.5 × 10- 3 < P < 0.0400) and 0.029-0.069 in T2D patients (2.1 × 10- 10 < P < 0.0428). Moreover, the quintile of TC-related PRS was moderately associated with cIMT in adult women (ß ± SE = 0.011 ± 0.005, Ptrend = 0.0182). Independent of conventional risk factors, the quintile of PRSs for TC [OR (95% CI) = 1.07 (1.03-1.11)], TG [OR (95% CI) = 1.05 (1.01-1.09)], and LDL-C [OR (95% CI) = 1.05 (1.01-1.09)] were significantly associated with increased risk of CHD in T2D patients (4.8 × 10- 4 < P < 0.0197). Further adjustment for baseline lipid drug use notably attenuated the CHD association. CONCLUSIONS: The PRSs derived and validated here highlight the potential for early genomic screening and personalized risk assessment for cardiovascular disease.

Obesity, clinical, and genetic predictors for glycemic progression in Chinese patients with type 2 diabetes: A cohort study using the Hong Kong Diabetes Register and Hong Kong Diabetes Biobank.

BACKGROUND: Type 2 diabetes (T2D) is a progressive disease whereby there is often deterioration in glucose control despite escalation in treatment. There is significant heterogeneity to this progression of glycemia after onset of diabetes, yet the factors that influence glycemic progression are not well understood. Given the tremendous burden of diabetes in the Chinese population, and limited knowledge on factors that influence glycemia, we aim to identify the clinical and genetic predictors for glycemic progression in Chinese patients with T2D. METHODS AND FINDINGS: In 1995-2007, 7,091 insulin-naïve Chinese patients (mean age 56.8 ± 13.3 [SD] years; mean age of T2D onset 51.1 ± 12.7 years; 47% men; 28.4% current or ex-smokers; median duration of diabetes 4 [IQR: 1-9] years; mean HbA1c 7.4% ± 1.7%; mean body mass index [BMI] 25.3 ± 4.0 kg/m2) were followed prospectively in the Hong Kong Diabetes Register. We examined associations of BMI and other clinical and genetic factors with glycemic progression defined as requirement of continuous insulin treatment, or 2 consecutive HbA1c ≥8.5% while on ≥2 oral glucose-lowering drugs (OGLDs), with validation in another multicenter cohort of Hong Kong Diabetes Biobank. During a median follow-up period of 8.8 (IQR: 4.8-13.3) years, incidence of glycemic progression was 48.0 (95% confidence interval [CI] 46.3-49.8) per 1,000 person-years with 2,519 patients started on insulin. Among the latter, 33.2% had a lag period of 1.3 years before insulin was initiated. Risk of progression was associated with extremes of BMI and high HbA1c. On multivariate Cox analysis, early age at diagnosis, microvascular complications, high triglyceride levels, and tobacco use were additional independent predictors for glycemic progression. A polygenic risk score (PRS) including 123 known risk variants for T2D also predicted rapid progression to insulin therapy (hazard ratio [HR]: 1.07 [95% CI 1.03-1.12] per SD; P = 0.001), with validation in the replication cohort (HR: 1.24 [95% CI 1.06-1.46] per SD; P = 0.008). A PRS using 63 BMI-related variants predicted BMI (beta [SE] = 0.312 [0.057] per SD; P = 5.84 × 10-8) but not glycemic progression (HR: 1.01 [95% CI 0.96-1.05] per SD; P = 0.747). Limitations of this study include potential misdiagnosis of T2D and lack of detailed data of drug use during follow-up in the replication cohort. CONCLUSIONS: Our results show that approximately 5% of patients with T2D failed OGLDs annually in this clinic-based cohort. The independent associations of modifiable and genetic risk factors allow more precise identification of high-risk patients for early intensive control of multiple risk factors to prevent glycemic progression.

The efficacy and tolerability of risedronate on bone mineral density and bone turnover markers in osteoporotic Chinese women: a randomized placebo-controlled study.

Osteoporosis has become an important health problem in postmenopausal Asian populations as the prevalence of hip and vertebral fractures in some Asian countries has risen to approach that of Caucasian populations. Risedronate, a pyridinyl-bisphosphonate agent, is a potent inhibitor of bone resorption. Risedronate increases bone mineral density (BMD), reduces markers of bone turnover, and reduces the risk of fractures in Caucasian postmenopausal women. To determine the efficacy and tolerability of risedronate in Chinese, a multicenter, randomized, double blind, placebo controlled study was performed in Hong Kong. Sixty-five (65) postmenopausal osteoporotic Southern Chinese women, aged 67+/-6 years, were randomly assigned to receive either risedronate 5 mg daily (n=31) or placebo (n=34) for 12 months. All women received calcium carbonate 500 mg daily and vitamin D 400 IU daily. Mean baseline BMD T-score at the spine and total hip was -3.4 and -2.6, respectively. A significant increase in spine BMD was already evident at month 3 of risedronate treatment (P<0.001). Risedronate significantly increased BMD and reduced bone turnover markers as compared with placebo. The risedronate group had significant increase in BMD at 12 months at both the spine and hip when compared with the placebo group (L1-4 6.6% vs. 0.4%, P<0.001; total hip 2.7% vs. 0.3, P<0.0001; femoral neck 1.8% vs. 1.1%, P<0.02; trochanter 4% vs. 1.1%, P<0.0001, respectively). Significant changes in urine N-telopeptide (NTx) and serum osteocalcin were evident as early as 1 and 3 months, respectively, with risedronate treatment. No significant changes were seen in both BMD and bone markers in the placebo group. Risedronate was well tolerated without major adverse effects. We conclude that risedronate is an effective and well-tolerated agent for the treatment of postmenopausal osteoporosis in Asian population.