Diabetes and infection: review of the epidemiology, mechanisms and principles of treatment.

An association between diabetes and infection has been recognised for many years, with infection being an important cause of death and morbidity in people with diabetes. The COVID-19 pandemic has re-kindled an interest in the complex relationship between diabetes and infection. Some infections occur almost exclusively in people with diabetes, often with high mortality rates without early diagnosis and treatment. However, more commonly, diabetes is a complicating factor in many infections. A reciprocal relationship occurs whereby certain infections and their treatments may also increase the risk of diabetes. People with diabetes have a 1.5- to 4-fold increased risk of infection. The risks are the most pronounced for kidney infection, osteomyelitis and foot infection, but are also increased for pneumonia, influenza, tuberculosis, skin infection and general sepsis. Outcomes from infection are worse in people with diabetes, with the most notable example being a twofold higher rate of death from COVID-19. Hyperglycaemia has deleterious effects on the immune response. Vascular insufficiency and neuropathy, together with altered skin, mucosal and gut microbial colonisation, contribute to the increased risk of infection. Vaccination is important in people with diabetes although the efficacy of certain immunisations may be compromised, particularly in the presence of hyperglycaemia. The principles of treatment largely follow those of the general population with certain notable exceptions.

Acute encephalopathy associated with influenza A infection in adults.

We report acute encephalopathy associated with influenza A infection in 3 adults. We detected high cerebrospinal fluid (CSF) and plasma concentrations of CXCL8/IL-8 and CCL2/MCP-1 (CSF/plasma ratios > or =3), and interleukin-6, CXCL10/IP-10, but no evidence of viral neuroinvasion. Patients recovered without sequelae. Hyperactivated cytokine response may play a role in pathogenesis.

Cytokine responses in a severe case of glandular fever treated successfully with foscarnet combined with prednisolone and intravenous immunoglobulin.

Viral loads and cytokine responses Epstein-Barr virus (EBV) were measured in an 18-year-old boy with severe glandular fever complicated by a mild anaemia, severe thrombocytopaenia and neutropaenia. Hepatosplenomegaly was detected by abdominal ultrasound in the presence of significant hepatitis. Cytokine testing demonstrated elevated cell-mediated Th1 (IFN-gamma, IL-12, sTNFR1, CXCL10, CXCL9 and CCL3) and humoral Th2 (IL-4) immune responses. Serum antibodies to EBV virus capsid antigen (VCA) IgM and IgG antibodies were detected, together with a raised EBV DNA level (up to about 70,000 DNA copies/mL) in the acute phase of the illness. This EBV DNA load decreased rapidly in response to treatment with a combination of foscarnet, intravenous immunoglobulin and prednisolone, and the boy's symptoms settled eventually after approximately 50 days of illness, following this combined antiviral and immune-modulating therapy. Detailed immunological, virological, haematological and biochemical laboratory parameters are presented to document this patient's severe EBV disease and eventual recovery.

Role of 'atypical pathogens' among adult hospitalized patients with community-acquired pneumonia.

BACKGROUND AND OBJECTIVE: Agents such as Mycoplasma pneumoniae, Chlamydophila pneumoniae and Legionella pneumophila are recognized as important causes of community-acquired pneumonia (CAP) worldwide. This study examined the role of these 'atypical pathogens' (AP) among adult hospitalized patients with CAP. METHODS: A prospective, observational study of consecutive adult CAP (clinico-radiological diagnosis) patients hospitalized during 2004-2005 was conducted. Causal organisms were determined using cultures, antigen testing and paired serology. Clinical/laboratory/radiological variables and outcomes were compared between different aetiologies, and a clinical prediction rule for AP was constructed. RESULTS: There were 1193 patients studied (mean age 70.8 +/- 18.0 years, men 59.3%). Causal organisms were identified in 468 (39.2%) patients: 'bacterial' (48.7%), 'viral' (26.9%), 'AP' (28.6%). The AP infections comprised Mycoplasma or Chlamydophila pneumoniae (97.8%) and co-infection with bacteria/virus (30.6%). The majority of AP infections involved elderly patients (63.4%) with comorbidities (41.8%), and more than one-third of patients were classified as 'intermediate' or 'high' risk CAP on presentation (pneumonia severity index IV-V (35.1%); CURB-65 2-5 (42.5%)). Patients with AP infections had disease severities and outcomes similar to patients with CAP due to other organisms (oxygen therapy 29.1% vs 29.8%; non-invasive ventilation 3.7% vs 3.3%; admission to the intensive care unit 4.5% vs 2.7%; length of hospitalization 6 day vs 7 day; 30-day mortality: 2.2% vs 6.0%; overall P > 0.05). Age <65 years, female gender, fever > or =38.0 degrees C, respiratory rate <25/min, pulse rate <100/min, serum sodium >130 mmol/L, leucocyte count <11 x 10(9)/L and Hb < 11 g/dL were features associated with AP infection, but the derived prediction rule failed to reliably discriminate CAP caused by AP from bacterial CAP (area under the curve 0.75). CONCLUSIONS: M. pneumoniae and C. pneumoniae as single/co-pathogens are important causes of severe pneumonia among older adults. No reliable clinical indicators exist, so empirical antibiotic coverage for hospitalized CAP patients may need to be considered.

Development and validation of an all-cause mortality risk score in type 2 diabetes.

BACKGROUND: Diabetes reduces life expectancy by 10 to 12 years, but whether death can be predicted in type 2 diabetes mellitus remains uncertain. METHODS: A prospective cohort of 7583 type 2 diabetic patients enrolled since 1995 were censored on July 30, 2005, or after 6 years of follow-up, whichever came first. A restricted cubic spline model was used to check data linearity and to develop linear-transforming formulas. Data were randomly assigned to a training data set and to a test data set. A Cox model was used to develop risk scores in the test data set. Calibration and discrimination were assessed in the test data set. RESULTS: A total of 619 patients died during a median follow-up period of 5.51 years, resulting in a mortality rate of 18.69 per 1000 person-years. Age, sex, peripheral arterial disease, cancer history, insulin use, blood hemoglobin levels, linear-transformed body mass index, random spot urinary albumin-creatinine ratio, and estimated glomerular filtration rate at enrollment were predictors of all-cause death. A risk score for all-cause mortality was developed using these predictors. The predicted and observed death rates in the test data set were similar (P > .70). The area under the receiver operating characteristic curve was 0.85 for 5 years of follow-up. Using the risk score in ranking cause-specific deaths, the area under the receiver operating characteristic curve was 0.95 for genitourinary death, 0.85 for circulatory death, 0.85 for respiratory death, and 0.71 for neoplasm death. CONCLUSIONS: Death in type 2 diabetes mellitus can be predicted using a risk score consisting of commonly measured clinical and biochemical variables. Further validation is needed before clinical use.

Predicting values of lipids and white blood cell count for all-site cancer in type 2 diabetes.

Type 2 diabetic patients have increased cancer risk. We developed and validated an all-site cancer risk score in a prospective cohort of 7374 Chinese type 2 diabetic patients free of known history of cancer at enrolment, using split-half validation. Spline Cox model was used to detect common risk factors of cancer and to guide linear transformation of non-linear risk factors. After a median follow-up period of 5.45 years, 365 patients (4.95%) developed cancer. Body mass index (BMI; <24.0 or > or =27.6 kg/m2), triglyceride (> or =0.81 to <1.41 mmol/l), high-density lipoprotein cholesterol (<0.9 or > or =1.8 mmol/l), total cholesterol (<4.3 mmol/l) and white blood cell (WBC) count (<5.8x10(9) count per litre) were associated with increased cancer risks and exhibited non-linear relationships. We further linear transformed these terms for selection using backward Cox regression (P<0.05 for stay) in the training dataset. In the test dataset, calibration was checked using Hosmer-Lemeshow test and discrimination checked using area under receiver operating characteristic curve. In addition to age and current smoking, only linear-transformed total cholesterol and WBC count were selected. The risk score was 0.0488xage (years)-0.5810xtotal cholesterol (mmol/l, coded to 4.3 if >4.3)-0.3596xWBC count (10(9) counts/l, 5.8 if >5.8)+0.6390xcurrent smoking status (1 if yes). The 5-year probability of cancer was 1-0.9590(EXP(0.9382x(RISK SCORE+1.5903))). The predicted cancer probability was not significantly different from the observed cancer probability during the 5-year follow-up. The adjusted area under receiver operating characteristic curve was 0.712. In conclusion, BMI, lipids and WBC count have predicting values for cancer.

Development and validation of a total coronary heart disease risk score in type 2 diabetes mellitus.

There are no validated risk scores for predicting coronary heart disease (CHD) in Chinese patients with type 2 diabetes mellitus. This study aimed to validate the UKPDS risk engine and, if indicated, develop CHD risk scores. A total of 7,067 patients without CHD at baseline were analyzed. Data were randomly assigned to a training data set and a test data set. Cox models were used to develop risk scores to predict total CHD in the training data set. Calibration was assessed using the Hosmer-Lemeshow test, and discrimination was examined using the area under the receiver-operating characteristic curve in the test data set. During a median follow-up of 5.40 years, 4.97% of patients (n = 351) developed incident CHD. The UKPDS CHD risk engine overestimated the risk of CHD with suboptimal discrimination, and a new total CHD risk score was developed. The developed total CHD risk score was 0.0267 x age (years) - 0.3536 x sex (1 if female) + 0.4373 x current smoking status (1 if yes) + 0.0403 x duration of diabetes (years) - 0.4808 x Log(10) (estimated glomerular filtration rate [ml/min/1.73 m(2)]) + 0.1232 x Log(10) (1 + spot urinary albumin-creatinine ratio [mg/mmol]) + 0.2644 x non-high-density lipoprotein cholesterol (mmol/L). The 5-year probability of CHD = 1 - 0.9616(EXP(0.9440 x [RISK SCORE - 0.7082])). Predicted CHD probability was not significantly different from observed total CHD probability, and the adjusted area under the receiver-operating characteristic curve was 0.74 during 5 years of follow-up. In conclusion, the UKPDS CHD risk engine overestimated the risk of Chinese patients with type 2 diabetes mellitus and the newly developed total CHD risk score performed well in the test data set. External validations are required in other Chinese populations.

Failure to confirm HIV infection in two end-stage HIV/AIDS patients using a popular commercial line immunoassay.

Immunoassays using either viral lysate (Western blot) or recombinant/synthetic antigen (immunoblot) for anti-HIV capture are still the preferred method to confirm HIV infection. Two cases of HIV-1-infected patients presented with acquired immunodeficiency syndrome (AIDS)-defining illnesses. Laboratory tests were performed using multiple commercial HIV test kits on multiple sera from both patients over several weeks. Both patients were strongly positive on the anti-HIV/p24 antigen combined screening assay. Yet, HIV-1 infection could not be confirmed using a popular commercial immunoassay. Eventually, HIV infection was confirmed using an alternative commercial Western blot assay as well as an HIV quantitative PCR test. In laboratories without nucleic acid testing (NAT) for HIV, indeterminate results may delay confirmation of HIV infection, if commercial line immunoassays alone are available. Some end-stage HIV/AIDS patients may not produce antibodies to specific HIV antigens and may therefore give indeterminant or negative results on some immunoassays, depending on the type of antigen used. This report highlights the utility of having NAT available when diagnosing difficult cases of HIV infection, especially in light of the recent Centers for Disease Control and Prevention move towards more universal, routine, HIV testing.

Development and validation of a risk score for hospitalization for heart failure in patients with Type 2 diabetes mellitus.

BACKGROUND: There are no risk scores available for predicting heart failure in Type 2 diabetes mellitus (T2DM). Based on the Hong Kong Diabetes Registry, this study aimed to develop and validate a risk score for predicting heart failure that needs hospitalisation in T2DM. METHODS: 7067 Hong Kong Chinese diabetes patients without history of heart failure, and without history and clinical evidence of coronary heart disease at baseline were analyzed. The subjects have been followed up for a median period of 5.5 years. Data were randomly and evenly assigned to a training dataset and a test dataset. Sex-stratified Cox proportional hazard regression was used to obtain predictors of HF-related hospitalization in the training dataset. Calibration was assessed using Hosmer-Lemeshow test and discrimination was examined using the area under receiver's operating characteristic curve (aROC) in the test dataset. RESULTS: During the follow-up, 274 patients developed heart failure event/s that needed hospitalisation. Age, body mass index (BMI), spot urinary albumin to creatinine ratio (ACR), HbA1c, blood haemoglobin (Hb) at baseline and coronary heart disease during follow-up were predictors of HF-related hospitalization in the training dataset. HF-related hospitalization risk score = 0.0709 x age (year) + 0.0627 x BMI (kg/m2) + 0.1363 x HbA1c(%) + 0.9915 x Log10(1+ACR) (mg/mmol) - 0.3606 x Blood Hb(g/dL) + 0.8161 x CHD during follow-up (1 if yes). The 5-year probability of heart failure = 1-S0(5)EXP{0.9744 x (Risk Score - 2.3961)}. Where S0(5) = 0.9888 if male and 0.9809 if female. The predicted and observed 5-year probabilities of HF-related hospitalization were similar (p > 0.20) and the adjusted aROC was 0.920 for 5 years of follow-up. CONCLUSION: The risk score had adequate performance. Further validations in other cohorts of patients with T2DM are needed before clinical use.

Thresholds of risk factors for ischemic stroke in type 2 diabetic patients with and without albuminuria: a non-linear approach.

OBJECTIVES: Multiple risk factors in type 2 diabetes may explain their high risk for ischemic stroke (IS). However, it remains unknown whether these risk factors exhibit threshold characteristics and whether these relationships are influenced by albuminuria. The study aims to investigate whether risk factors exhibit any albuminuria specific threshold for IS. PATIENTS AND METHODS: This is a prospective cohort study with 6969 Chinese type 2 diabetic patients without history of stroke after a median follow-up of 5.36 years. We identified thresholds of risk factors for IS using hazard ratio plots followed by confirmation using traditional Cox regression analysis. RESULTS: In the non-albuminuric group (n=4008), IS risk started to increase rapidly at a body mass index threshold of 24 kg/m(2). The risk of IS declined with increasing blood hemoglobin reaching a threshold value of 14 g/dl. Using these threshold values as cutoff point, body mass index > or =24 kg/m(2) and hemoglobin <14 g/dl were associated with 2-fold increased risk of IS in these subjects. In the albuminuric group (n=2961). IS risk started to increase rapidly from a systolic blood pressure threshold of 135 mmHg and declined with increasing estimated glomerular filtration rate (eGFR) reaching a trough of 115 ml/min per 1.73 m(2). Using these values as cutoff points, patients with systolic blood pressure > or =135 mmHg and eGFR <115 ml/min per 1.73 m(2) had 2-fold increased risk of IS. CONCLUSION: In type 2 diabetic patients, body mass index, hemoglobin, systolic blood pressure and eGFR exhibit different risk relationships and thresholds for IS contingent upon presence or absence of albuminuria.

A novel CASR gene mutation in an octogenarian with asymptomatic hypercalcaemia.

An increasing number of patients are diagnosed with primary hyperparathyroidism after having hypercalcaemia detected incidentally during routine biochemical screening. Many are asymptomatic at the time of diagnosis. An 80-year-old woman was found to have asymptomatic hypercalcaemia. Initial investigations suggested a diagnosis of primary hyperparathyroidism. Subsequent investigations revealed that, in fact, she had familial hypocalciuric hypercalcaemia. Direct DNA sequencing of the calcium-sensing receptor (CASR) gene confirmed that the patient was heterozygous for c.2501delC, a novel frame shift mutation predicted to cause loss of function of the CASR gene. Several other family members were subsequently found to carry the same mutation. Suspected cases of hypocalciuric hypercalcaemia should be confirmed by detection of mutations within the CASR gene. Establishing the correct diagnosis will enable the patient and family members to avoid unnecessary investigations or operations.

Development and validation of stroke risk equation for Hong Kong Chinese patients with type 2 diabetes: the Hong Kong Diabetes Registry.

OBJECTIVE: We sought to develop stroke risk equations for Chinese patients with type 2 diabetes in Hong Kong. RESEARCH DESIGN AND METHODS: A total of 7,209 Hong Kong Chinese type 2 diabetic patients without a history of stroke at baseline were analyzed. The data were randomly and evenly divided into the training subsample and the test subsample. In the training subsample, stepwise Cox models were used to develop the risk equation. Validation of the U.K. Prospective Diabetes Study (UKPDS) stroke risk engine and the current stroke equation was performed in the test dataset. The life-table method was used to check calibration, and the area under the receiver operating characteristic curve (aROC) was used to check discrimination. RESULTS: A total of 372 patients developed incident stroke during a median of 5.37 years (interquartile range 2.88-7.78) of follow-up. Age, A1C, spot urine albumin-to-creatinine ratio (ACR), and history of coronary heart disease (CHD) were independent predictors. The performance of the UKPDS stroke engine was suboptimal in our cohort. The newly developed risk equation defined by these four predictors had adequate performance in the test subsample. The predicted stroke-free probability by the current equation was within the 95% CI of the observed probability. The aROC was 0.77 for predicting stroke within 5 years. The risk score was computed as follows: 0.0634 x age (years) + 0.0897 x A1C + 0.5314 x log(10) (ACR) (mg/mmol) + 0.5636 x history of CHD (1 if yes). The 5-year stroke probability can be calculated by: 1 - 0.9707(EXP (Risk Score - 4.5674)). CONCLUSIONS: Although the risk equation performed reasonably well in Chinese type 2 diabetic patients, external validation is required in other populations.

Factors associated with early hospital discharge of adult influenza patients.

BACKGROUND: Understanding factors affecting length of hospital stay (LOS) in patients with severe influenza may improve their management. METHODS: A retrospective cohort study on laboratory-confirmed, adult influenza patients hospitalized in 2004 and 2005 was conducted. For all influenza cases during that period, immunofluorescence assay on nasopharyngeal aspirate was used for rapid diagnosis, and oseltamivir (75 mg twice daily for 5 days) prescribed if the patient presented within 2 days of symptom onset. Independent factors associated with time to discharge were identified using Cox proportional hazards models. An adjusted hazard ratio (aHR) >1 signifies a higher chance of early discharge. Viral shedding and influenza vaccination history were studied during one 'flu' season. RESULTS: A total of 356 patients (influenza A 93.5%) were studied. The majority of patients were old (70.2 +/- 8.4 years), had > or = 1 comorbid illness (69.1%) and developed respiratory or cardiovascular complications (69.4%). Oseltamivir initiated within 2 days of illness was associated with shorter total LOS (Kaplan-Meier estimated median 4 versus 6 days [-33%]; aHR for discharge 1.54, 95% confidence intervals [95% CI] 1.23-1.92, P < 0.0001). Older age (> or = 70 years), comorbidities and complications were associated with prolonged LOS. Prolonged viral RNA detection >day 4 of illness (23 out of 99 consecutive patients) was also independently associated with longer LOS (aHR 0.36 [95% CI 0.19-0.71], P = 0.003), whereas influenza vaccination within 6 months was associated with shorter LOS (aHR 2.14 [95% CI 1.18-3.85], P = 0.012). CONCLUSION: Our analyses suggest that timely oseltamivir treatment is independently associated with shorter LOS in patients hospitalized for severe influenza. Efforts to ensure early diagnosis and therapeutic intervention are warranted.

Impacts of chronic kidney disease and albuminuria on associations between coronary heart disease and its traditional risk factors in type 2 diabetic patients - the Hong Kong diabetes registry.

BACKGROUND: Glycated haemoglobin (HbA1c), blood pressure and body mass index (BMI) are risk factors for albuminuria, the latter in turn can lead to hyperlipidaemia. We used novel statistical analyses to examine how albuminuria and chronic kidney disease (CKD) may influence the effects of other risk factors on coronary heart disease (CHD). METHODS: A prospective cohort of 7067 Chinese type 2 diabetic patients without history of CHD enrolled since 1995 were censored on July 30th, 2005. Cox proportional hazard regression with restricted cubic spline was used to auto-select predictors. Hazard ratio plots were used to examine the risk of CHD. Based on these plots, non-linear risk factors were categorised and the categorised variables were refitted into various Cox models in a stepwise manner to confirm the findings. RESULTS: Age, male gender, duration of diabetes, spot urinary albumin: creatinine ratio, estimated glomerular filtration rate, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and current smoking status were risk factors of CHD. Linear association between TC and CHD was observed only in patients with albuminuria. Although in general, increased HDL-C was associated with decreased risk of CHD, full-range HDL-C was associated with CHD in an A-shaped manner with a zenith at 1.1 mmol/L. Albuminuria and CKD were the main contributors for the paradoxically positive association between HDL-C and CHD for HDL-C values less than 1.1 mmol/L. CONCLUSION: In type 2 diabetes, albuminuria plays a linking role between conventional risk factors and CHD. The onset of CKD changes risk associations between lipids and CHD.

Hematocrit, independent of chronic kidney disease, predicts adverse cardiovascular outcomes in chinese patients with type 2 diabetes.

OBJECTIVE: Anemia and chronic kidney disease (CKD) are risk factors for cardiovascular diseases in diabetes. We examined the association between hematocrit, stratified by the presence of CKD, and cardiovascular events in a cohort of Chinese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 3,983 patients who underwent assessment for diabetes complications were recruited. Subjects were categorized into five groups. Group I included subjects with hematocrit below the normal sex-specific range. The cutoff points for groups II-V were selected to represent the distribution of the hematocrit for each sex. CKD was defined by the estimated glomerular filtration rate <60 ml/min per 1.73 m(2). Cardiovascular events were defined as cardiovascular mortality and morbidity, including new onset of myocardial infarction, acute coronary syndrome, revascularization, heart failure, and stroke requiring hospitalization. RESULTS: A total of 294 subjects (7.4%) developed cardiovascular events during the median of 36.4 months. The rate of cardiovascular events was highest in subjects with low hematocrit (group I, 18.6%) compared with group V (3.4%, P < 0.001). The multivariate-adjusted hazard ratio for cardiovascular events diminished with increasing hematocrit (group I, 1.0; group II, 0.73 [95% CI 0.51-1.04]; group III, 0.57 [0.39-0.83]; group IV, 0.61 [0.39-0.95]; and group V, 0.36 [0.17-0.79]). After stratifying by the presence of CKD, the previously observed reduction in the risk of developing cardiovascular events with increasing hematocrit was abolished in the cohort with CKD but persisted in the non-CKD cohort. CONCLUSIONS: In Chinese subjects with type 2 diabetes, low levels of hematocrit and the presence of CKD are associated with increased risk of developing adverse cardiovascular events.

Glomerular filtration rate, cardiorenal end points, and all-cause mortality in type 2 diabetic patients.

OBJECTIVE: Chronic kidney disease (CKD) predicts cardiovascular disease (CVD) in the general population. We investigated the effects of stages of renal function using the estimated glomerular filtration rate (eGFR) on all-cause mortality and cardiovascular end points in a prospective cohort of Chinese type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Between 1995 and 2000, 4,421 patients without macrovascular disease or end-stage renal disease were recruited. Renal function was assessed by eGFR, as calculated by the abbreviated Modification of Diet in Renal Disease Study Group formula. Clinical end points included all-cause mortality, cardiovascular end point (cardiovascular death, new admissions due to angina, myocardial infarction, stroke, revascularization, or heart failure), and renal end point (reduction in eGFR by >50%, progression of eGFR to stage 5, or dialysis or renal death). RESULTS: After a median follow-up period of 39.4 months (interquartile range 20.3-55), all-cause mortality rate increased from 1.2% (95% CI 0.8-1.7) to 18.3% (9.1-27.5) (P for trend <0.001) as renal function deteriorated from stage 1 (eGFR > or =90 ml/min per 1.73 m(2)) to stage 4 (15-29 ml/min per 1.73 m(2)). The respective rate of new cardiovascular end points also increased from 2.6% (2.0-3.3) to 25.3% (15.0-35.7) (P for trend <0.001). After adjustment for covariates (age, sex, albuminuria, use of renin-angiotensin-aldosterone system [RAAS] inhibitors, lipids, blood pressure, and glycemic control), hazard ratios across different stages of eGFR (> or =90, 60-89, 30-59, and 15-29 ml/min per 1.73 m(2)) for all-cause mortality were 1.00, 1.27, 2.34, and 9.82 (P for trend <0.001), for cardiovascular end points were 1.00, 1.04, 1.05, and 3.23 (P for trend <0.001), and for renal end points were 1.00, 1.36, 3.34, and 27.3 (P for trend <0.001), respectively. CONCLUSIONS: Chinese type 2 diabetic patients with reduced eGFR were at high risk of developing cardiovascular end points and all-cause mortality, independent of albuminuria and metabolic control.

Prognostic effect of insertion/deletion polymorphism of the ace gene on renal and cardiovascular clinical outcomes in Chinese patients with type 2 diabetes.

OBJECTIVE: The insertion/deletion (I/D) polymorphism of the ACE gene has been reported to be associated with diabetic microvascular or macrovascular complications. The aim of the present study was to investigate the prognostic effect of I/D polymorphism on renal and cardiovascular clinical outcomes in Chinese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A consecutive cohort of 1,281 Chinese patients with type 2 diabetes were followed for 41.3 +/- 21.6 months. Renal end points were defined as renal death and events (need for dialysis, plasma creatinine >/=500 micromol/l, or doubling of plasma creatinine of baseline value >/=150 micromol/l). Cardiovascular end points were defined as cardiovascular death and events, which included ischemic heart disease, heart failure, cerebrovascular accident, and revascularization requiring hospital admission. The I/D polymorphism of the ACE gene was examined by PCR followed by agarose gel electrophoresis. RESULTS: The frequencies of ACE gene I/D polymorphisms were in Hardy-Weinberg equilibrium. Patients who developed a renal end point (n = 98) had higher frequencies of DD genotype (19.4 vs. 10.8%, P = 0.018) and D allele (41.3 vs. 31.8%, P = 0.006) compared with subjects who did not (n = 1,183). The cumulative rates of renal end points were 10.0, 19.2, and 24.4% in the II (n = 595), DI (n = 539), and DD genotype carriers (n = 147), respectively (log rank P = 0.004). In multiple Cox regression analysis, the occurrence of renal end points remained significantly influenced by I/D polymorphism with a dominant deleterious effect of the DD genotype (DD versus II, adjusted hazard ratio 2.80 [95% CI 1.49-5.29]). There was no prognostic effect of I/D polymorphism on cardiovascular end points. CONCLUSIONS: The DD genotype of the ACE I/D polymorphism was an independent risk factor for renal but not cardiovascular end points in Chinese patients with type 2 diabetes.

Genome-wide scan for metabolic syndrome and related quantitative traits in Hong Kong Chinese and confirmation of a susceptibility locus on chromosome 1q21-q25.

We conducted autosomal genome scans to map loci for metabolic syndrome (MES) and related traits in the Hong Kong Family Diabetes Study. We selected 55 families with 137 affected members (121 affected relative pairs) for nonparametric linkage analysis on MES. We also selected 179 families with 897 members (2,127 relative pairs) for variance component-based linkage analyses on seven MES-related traits: waist circumference, systolic and diastolic blood pressure (BP), triglyceride, HDL cholesterol, fasting plasma glucose, and insulin resistance index (insulin resistance index by homeostasis model assessment [HOMA%IR]). Analyses revealed three regions that showed suggestive linkage for MES and also showed overlapping signals for metabolic traits: chromosome 1 at 169.5-181.5 cM (logarithm of odds [LOD] = 4.50 for MES, 3.71 for waist circumference, and 1.24 for diastolic BP), chromosome 2 at 44.1-57.3 cM (LOD = 2.22 for MES, 2.07 for fasting plasma glucose, and 1.29 for diastolic BP), and chromosome 16 at 45.2-65.4 cM (LOD = 1.75 for MES, 1.61 for HOMA%IR, and 1.25 for HDL cholesterol). Other regions that showed suggestive linkages included chromosome 5q for diastolic BP; 2q, 3q, 6q, 9q, 10q, and 17q for triglyceride; 12p, 12q, and 22q for HDL-C; and 6q for HOMA%IR. Simulation studies demonstrated genome-wide significant linkage of the chromosome 1 region to both MES and waist circumference (P(genome-wide) = 0.002 and 0.019, respectively). In summary, we have found a susceptibility locus on chromosome 1q21-q25 involved in the pathogenesis of multiple metabolic abnormalities, in particular obesity. Our results confirm the findings of previous studies on diabetes and related phenotypes. We also suggest the locations of other loci that may contribute to the development of MES in Hong Kong Chinese.

Genome-wide scan for type 2 diabetes loci in Hong Kong Chinese and confirmation of a susceptibility locus on chromosome 1q21-q25.

We conducted an autosomal genome scan to map loci for type 2 diabetes in a Hong Kong Chinese population. We studied 64 families, segregating type 2 diabetes, of which 57 had at least one member with an age at diagnosis of 0.59, P(pointwise) < 0.05): chromosome 1 at 173.9 cM (LOD = 3.09), chromosome 3 at 26.3 cM (LOD = 1.27), chromosome 4 at 135.3 cM (LOD = 2.63), chromosome 5 at 139.3 cM (LOD = 0.84), chromosome 6 at 178.9 cM (LOD = 1.91), chromosome 12 at 48.7 cM (LOD = 1.99), and chromosome 18 at 28.1 cM (LOD = 1.00). Simulation studies showed genome-wide significant evidence for linkage of the chromosome 1 region (P(genome-wide) = 0.036). We have confirmed the results of previous studies for the presence of a susceptibility locus on chromosome 1q21-q25 (173.9 cM) and suggest the locations of other loci that may contribute to the development of type 2 diabetes in Hong Kong Chinese.