High prevalence of NIDDM and impaired glucose tolerance in Indian, Creole, and Chinese Mauritians. Mauritius Noncommunicable Disease Study Group

Mauritius, a multiethnic island nation in the southwestern Indian Ocean, has one of the world's highest diabetes mortality rates. The prevalence of both impaired glucose tolerance (IGT) and non-insulin-dependent diabetes mellitus (NIDDM) was investigated in 5080 Muslim and Hindu Indian, Creole (mixed African, European, and Indian origin), and Chinese Mauritian adults aged 25-74 yr who were selected by random cluster sampling. Based on a 75-g oral glucose tolerance test and World Health Organization criteria, the age-standardized prevalence of IGT was significantly greater in women (19.7%, 95% confidence interval [CI] 18.1-21.2) than in men (11.7%, CI 10.5-12.8). By contrast, the prevalence of NIDDM was similar in men (12.1%, CI 10.9-13.4) and women (11.7%, CI 10.5-12.8) for all ethnic groups combined. The sex difference in IGT prevalence was seen in all ethnic groups, but for NIDDM, the sex difference was not consistent across ethnic groups. However, age- and sex-standardized prevalence of IGT and NIDDM was remarkably similar across ethnic groups (16.2 and 12.4% in Hindu Indians, 15.3 and 13.3% in Muslim Indians, 17.5 and 10.4% in Creoles, and 16.6 and 11.9% in Chinese, respectively). Three new cases of diabetes were diagnosed for every two known cases. The high prevalence of abnormal glucose tolerance in Indian subjects is consistent with studies of other migrant Indian communities, but the findings in Creole and, in particular, Chinese subjects are unexpected. Potent environmental factors shared between ethnic groups in Mauritius may be responsible for the epidemic of glucose intolerance.     

Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. Systolic Hypertension in Europe Trial Investigators

BACKGROUND: Recent reports suggest that calcium-channel blockers may be harmful in patients with diabetes and hypertension. We previously reported that antihypertensive treatment with the calcium-channel blocker nitrendipine reduced the risk of cardiovascular events. In this post hoc analysis, we compared the outcome of treatment with nitrendipine in diabetic and nondiabetic patients. METHODS: After stratification according to center, sex, and presence or absence of previous cardiovascular complications, 4695 patients (age, > or =60 years) with systolic blood pressure of 160 to 219 mm Hg and diastolic pressure below 95 mm Hg were randomly assigned to receive active treatment or placebo. Active treatment consisted of nitrendipine (10 to 40 mg per day) with the possible addition or substitution of enalapril (5 to 20 mg per day) or hydrochlorothiazide (12.5 to 25 mg per day) or both, titrated to reduce the systolic blood pressure by at least 20 mm Hg and to less than 150 mm Hg. In the control group, matching placebo tablets were administered similarly. RESULTS: At randomization, 492 patients (10.5 percent) had diabetes. After a median follow-up of two years, the systolic and diastolic blood pressures in the placebo and active-treatment groups differed by 8.6 and 3.9 mm Hg, respectively, among the diabetic patients. Among the 4203 patients without diabetes, systolic and diastolic pressures differed by 10.3 and 4.5 mm Hg, respectively, in the two groups. After adjustment for possible confounders, active treatment was found to have reduced overall mortality by 55 percent (from 45.1 deaths per 1000 patients to 26.4 deaths per 1000 patients), mortality from cardiovascular disease by 76 percent, all cardiovascular events combined by 69 percent, fatal and nonfatal strokes by 73 percent, and all cardiac events combined by 63 percent in the group of patients with diabetes. Among the nondiabetic patients, active treatment decreased all cardiovascular events combined by 26 percent and fatal and nonfatal strokes by 38 percent. In the group of patients receiving active treatment, reductions in overall mortality, mortality from cardiovascular disease, and all cardiovascular events were significantly larger among the diabetic patients than among the nondiabetic patients (P=0.04, P=0.02, and P=0.01, respectively). CONCLUSIONS: Nitrendipine-based antihypertensive therapy is particularly beneficial in older patients with diabetes and isolated systolic hypertension. Thus, our findings do not support the hypothesis that the use of long-acting calcium-channel blockers may be harmful in diabetic patients.     

A novel human leucocyte antigen-DRB1 genotyping method based on multiplex primer extension reactions

We have developed and validated a semi-automated fluorescent method of genotyping human leucocyte antigen (HLA)-DRB1 alleles, HLA-DRB1*01-16, by multiplex primer extension reactions. This method is based on the extension of a primer that anneals immediately adjacent to the single-nucleotide polymorphism with fluorescent dideoxynucleotide triphosphates (minisequencing), followed by analysis on an ABI Prism 3700 capillary electrophoresis instrument. The validity of the method was confirmed by genotyping 261 individuals using both this method and polymerase chain reaction with sequence-specific primer (PCR-SSP) or sequencing and by demonstrating Mendelian inheritance of HLA-DRB1 alleles in families. Our method provides a rapid means of performing high-throughput HLA-DRB1 genotyping using only two PCR reactions followed by four multiplex primer extension reactions and PCR-SSP for some allele groups. In this article, we describe the method and discuss its advantages and limitations.     

Cost-effective analysis of candidate genes using htSNPs: a staged approach

We have previously shown that the selection of haplotype tag single nucleotide polymorphisms (htSNPs) and their statistical analysis in a multi-locus transmission/disequilibrium test (TDT) results in a more cost-effective genotyping strategy in disease association studies of genes by minimising redundancy due to linkage disequilibrium between SNPs. Further savings can be achieved by the use of a two-stage genotyping strategy. This approach is illustrated here in conjunction with the multi-locus TDT in determining whether common alleles of the immune regulatory genes RANK and its ligand TRANCE (RANKL) are associated with type 1 diabetes (T1D). A saving of approximately 75% of potential genotyping reactions could be made with minimal loss of power. There was little evidence from our analysis for association between the TRANCE and RANK genes and T1D in the populations tested.     

Dominant negative mutations in the C-propeptide of COL2A1 cause platyspondylic lethal skeletal dysplasia, torrance type, and define a novel subfamily within the type 2 collagenopathies

Platyspondylic lethal skeletal dysplasia (PLSD) Torrance type (PLSD-T) is a rare skeletal dysplasia characterized by platyspondyly, brachydactyly, and metaphyseal changes. Generally a perinatally lethal disease, a few long-term survivors have been reported. Recently, mutations in the carboxy-propeptide of type II collagen have been identified in two patients with PLSD-T, indicating that PLSD-T is a type 2 collagen-associated disorder. We studied eight additional cases of PLSD-T and found that all had mutations in the C-propeptide domain of COL2A1. The mutational spectrum includes missense, stop codon and frameshift mutations. All non-sense mutations were located in the last exon, where they would escape non-sense-mediated RNA-decay. We conclude that PLSD-T is caused by mutations in the C-propeptide domain of COL2A1, which lead to biosynthesis of an altered collagen chain (as opposed to a null allele). Similar mutations have recently been found to be the cause of spondyloperipheral dysplasia, a non-lethal dominant disorder whose clinical and radiographical features overlap those of the rare long-term survivors with PLSD-T. Thus, spondyloperipheral dysplasia and PLSD-T constitute a novel subfamily within the type II collagenopathies, associated with specific mutations in the C-propeptide domain and characterized by distinctive radiological features including metaphyseal changes and brachydactyly that set them apart from other type 2 collagenopathies associated with mutations in the triple-helical domain of COL2A1. The specific phenotype of C-propeptide mutations could result from a combination of diminished collagen fibril formation, toxic effects through the accumulation of unfolded collagen chains inside the chondrocytes, and alteration of a putative signaling function of the carboxy-propeptide of type 2 collagen.     

Quality assessment of blood pressure measurements in epidemiological surveys. The impact of last digit preference and the proportions of identical duplicate measurements. WHO Monica Project [corrected

In the WHO MONICA Project, cardiovascular risk factor surveys including measurements of arterial blood pressure (BP) were conducted in more than 50 different populations. In the course of a retrospective BP measurement quality assessment effort, two indicators of "prejudiced" blood pressure reading, last digit preference and high proportions of identical results in duplicate measurements, are used in addition to other items to evaluate blood pressure measurement quality. We used fictitious blood pressure distributions and applied to them Last Digit Preference scores and Proportions of Identical Duplicate Measurements actually found in the MONICA surveys. The analysis showed that Last Digit Preference affects predominantly the shape of the BP distribution curve, whereas high Proportions of Identical Duplicate Measurements may cause a shift of the entire BP distribution curve. Although the two items are partly interrelated, a clear distinction between them and their effects is advocated.     

The relation of physical activity to cardiovascular disease risk factors in Mauritians. Mauritius Noncommunicable Disease Study Group

The authors investigated the relation between physical activity and cardiovascular disease risk factors in a random sample of 4,658 Asian Indian, Creole, and Chinese adults aged 25-74 years from the island nation of Mauritius. Subjects known to have diabetes were excluded from analyses. Subjects were divided into "active" and "inactive" groups on the basis of a combined leisure and occupational physical activity score determined at interview (April 1987). Two-hour plasma glucose concentration and fasting and 2-hour serum insulin concentrations were significantly lower and high density lipoprotein (HDL) cholesterol was significantly higher in active subjects of both sexes. Plasma uric acid and fasting triglyceride levels were also lower among active subjects, but significantly so only in females. Systolic and diastolic blood pressure levels, body mass index (weight (kg)/height (m)2), and waist:hip ratio varied little between the two activity groups. In multiple linear regression analyses, physical activity made an independent negative contribution to the models for 2-hour glucose and insulin in both males and females, as well as for fasting insulin in males. When glucose and insulin were not included, physical activity also made an independent contribution to the models for plasma triglycerides (inversely) in females and HDL cholesterol and HDL cholesterol as a proportion of total cholesterol (positively) in males. The authors have demonstrated improved cardiovascular disease profiles associated with physical activity in Mauritians. The data suggest that much of the effect is modulated via an effect on insulin-glucose metabolism. Promotion of exercise should become an important strategy in the prevention of cardiovascular disease and glucose intolerance in this population.