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. METHODS: Genotyping of PAX4 R192H was carried out using Illumina OmniExpress BeadChips as part of a genome-wide association study. Data analysis was performed using SPSS Ver. 22. RESULTS: PAX4 R192H genotype was associated with younger onset age (CC: 47.1, CT: 46.0, TT: 42.6) after adjusting for gender, F = 5.402, p = 0.005. Independently, onset of diabetes was younger among males by 2.52 years, 95% CI [-3.45, -1.59], p < 0.0001. HOMA-IR and HOMA-%B were not significantly different across genotypes for a subset (n = 1045) of the cohort. CONCLUSIONS: Minor allele (T) of PAX4 R192H is associated with younger onset diabetes among Chinese in Singapore. Determining this genotype is important for identifying at-risk individuals for earlier onset diabetes and diabetic complications.

Prevalence of Chronic Kidney Disease in Adults with Type 2 Diabetes Mellitus.

INTRODUCTION: Diabetes mellitus (DM) is a major cause of chronic kidney disease (CKD). The epidemiology of CKD secondary to type 2 DM (T2DM) (i.e. diabetic nephropathy (DN)) has not been well studied in Singapore, a multi-ethnic Asian population. We aimed to determine the prevalence of CKD in adult patients with T2DM. MATERIALS AND METHODS: We conducted a cross-sectional study on patients (n = 1861) aged 21 to 89 years with T2DM who had attended the DM centre of a single acute care public hospital or a primary care polyclinic between August 2011 and November 2013. Demographic and clinical data were obtained from patients using a standard questionnaire. Spot urine and fasting blood samples were sent to an accredited hospital laboratory for urinary albumin, serum creatinine, HbA1c and lipid measurement. CKD was defined and classified using the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines and classification. RESULTS: The distribution by risk of adverse CKD outcomes was: low risk, 47%; moderate risk, 27.2%; high risk, 12.8%; and very high risk, 13%. The prevalence of CKD in patients with T2DM was 53%. Variables significantly associated with CKD include neuropathy, blood pressure ≥140/80 mmHg, triglycerides ≥1.7 mmol, body mass index, duration of diabetes, HbA1c ≥8%, age, cardiovascular disease, and proliferative retinopathy. CONCLUSION: CKD was highly prevalent among patients with T2DM in Singapore. Several risk factors for CKD are well recognised and amenable to intervention. Routine rigorous screening for DN and enhanced programme for global risk factors reduction will be critical to stem the tide of DN.

Ethnic disparity in central arterial stiffness and its determinants among Asians with type 2 diabetes.

OBJECTIVE: We previously reported ethnic disparity in adverse outcomes among Asians with type 2 diabetes (T2DM) in Singapore. Central arterial stiffness can aggravate systemic vasculopathy by propagating elevated systolic and pulse pressures forward, thereby accentuating global vascular injury. We aim to study ethnic disparity in central arterial stiffness and its determinants in a multi-ethnic T2DM Asian cohort. METHODS: Arterial stiffness was estimated by carotid-femoral pulse wave velocity (PWV) and augmentation index (AI) using applanation tonometry method in Chinese (N = 1045), Malays (N = 458) and Indians (N = 468). Linear regression model was used to evaluate predictors of PWV and AI. RESULTS: PWV was higher in Malays (10.1 ± 3.0 m/s) than Chinese (9.7 ± 2.8 m/s) and Indians (9.6 ± 3.1 m/s) (P = 0.018). AI was higher in Indians (28.1 ± 10.8%) than Malays (25.9 ± 10.1%) and Chinese (26.1 ± 10.7%) (P < 0.001). Malays remain associated with higher PWV (ß = 0.299, P = 0.048) post-adjustment for age, gender, duration of diabetes, hemoglobin A1c, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), soluble receptor for advanced glycation end-products, urinary albumin-to-creatinine ratio, and insulin usage, which were all independent predictors of PWV. Indians remain associated with higher AI (ß = 2.776, P < 0.001) post-adjustment for age, gender, BMI, SBP, DBP, and height, which were independent predictors of AI. These variables explained 27.7% and 33.4% of the variance in PWV and AI respectively. CONCLUSIONS: Malays and Indians with T2DM have higher central arterial stiffness, which may explain their higher risk for adverse outcomes. Modifying traditional major vascular risk factors may partially alleviate their excess cardiovascular risk through modulating arterial stiffness.

Vascular cell adhesion molecule-1, but not intercellular adhesion molecule-1, is associated with diabetic kidney disease in Asians with type 2 diabetes.

BACKGROUND AND AIMS: The association of adhesion molecules ICAM-1 and VCAM-1 with cardiovascular diseases has been well-studied. However, their roles in diabetic kidney disease (DKD) are incompletely understood. We aim to study the association of plasma ICAM-1 and VCAM-1 with DKD in Asians with type 2 diabetes (T2DM). SUBJECTS AND METHODS: A total of 1950 Asians with T2DM were included in this cross-sectional study. Plasma ICAM-1 and VCAM-1 were measured by immunoassays. RESULTS: Renal filtration function (eGFR) declined and urinary albumin-to-creatinine ratio (ACR) levels increased progressively with the increase in plasma VCAM-1 levels. In contrast, no significant changes in eGFR and ACR were observed in subjects across different plasma ICAM-1 levels. Both ICAM-1 and VCAM-1 were correlated with ACR (rho = 0.153, p < 0.001 for VCAM-1 and ACR; rho = 0.053, p = 0.020 for ICAM-1 and ACR) in bivariate correlation analysis. However, only VCAM-1 was correlated with eGFR (rho = -0.228, p < 0.001). Multivariable linear regression models revealed that VCAM-1, but not ICAM-1, was independently associated with eGFR and albuminuria. Backward linear regression suggested that plasma VCAM-1 variability was mainly determined by eGFR whereas plasma ICAM-1 level was mainly determined by C-reactive protein in patients with T2DM. CONCLUSIONS: Plasma VCAM-1 level, but not ICAM-1 level, was independently associated with prevalent DKD in Asians with T2DM. High level of ICAM-1 may be indicative of systemic inflammation and portends increase risk of incipient DKD.