Multiple genetic variants explain measurable variance in type 2 diabetes-related traits in Pakistanis.

AIMS/HYPOTHESIS: Multiple genetic variants are associated with type 2 diabetes-related traits in Europeans, but their role in South Asian populations needs further study. We hypothesised that genetic variants associated with diabetes-related traits in Europeans would explain a similar proportion of phenotypic variance in a Pakistani population and could be used in Mendelian randomisation analyses. METHODS: We used data from 2,131 individuals from the Control of Blood Pressure and Risk Attenuation Trial (COBRA) in Karachi, Pakistan. Individuals were aged 40 years or older. RESULTS: Combining information from multiple genetic variants showed that fasting glucose, BMI, triacylglycerol, and systolic and diastolic blood pressure variants explained 2.9%, 0.7%, 5.5%, 1.2% and 1.8% of the variance in those traits respectively. Genetic risk scores of fasting glucose, triacylglycerol, BMI, systolic blood pressure and diastolic blood pressure variants were associated with these traits, with per allele SD effects of 0.057 (95% CI 0.041, 0.074), p=3.44 × 10(-12), 0.130 (95% CI 0.105, 0.155), p=2.9 × 10(-21), 0.04 (95% CI 0.014, 0.072), p=0.004, 0.031 (95% CI 0.016, 0.047), p=7.9 × 10(-5), 0.028 (95% CI 0.015, 0.042), p = 5.5 × 10(-5), respectively. These effects are consistent with those observed in Europeans, except that the effect of triacylglycerol variants in South Asians was slightly lower. Mendelian randomisation provided evidence that genetically influenced, raised triacylglycerol levels do not causally affect type 2 diabetes risk to the extent predicted from observational data (p=0.0003 for difference between observed and instrumental variables correlations). CONCLUSIONS/INTERPRETATION: Genetic variants identified in Europeans are associated with type 2 diabetes-related traits in Pakistanis, with comparable effect sizes. Larger studies are needed to perform adequately powered Mendelian randomisation and help dissect the relationships between type 2 diabetes-related traits in diverse South Asian subgroups.

An FTO variant is associated with Type 2 diabetes in South Asian populations after accounting for body mass index and waist circumference.

AIMS: A common variant, rs9939609, in the FTO (fat mass and obesity) gene is associated with adiposity in Europeans, explaining its relationship with diabetes. However, data are inconsistent in South Asians. Our aim was to investigate the association of the FTO rs9939609 variant with obesity, obesity-related traits and Type 2 diabetes in South Asian individuals, and to use meta-analyses to attempt to clarify to what extent BMI influences the association of FTO variants with diabetes in South Asians. METHODS: We analysed rs9939609 in two studies of Pakistani individuals: 1666 adults aged ≥40 years from the Karachi population-based Control of Blood Pressure and Risk Attenuation (COBRA) study and 2745 individuals of Punjabi ancestry who were part of a Type 2 diabetes case-control study (UK Asian Diabetes Study/Diabetes Genetics in Pakistan; UKADS/DGP). The main outcomes were BMI, waist circumference and diabetes. Regression analyses were performed to determine associations between FTO alleles and outcomes. Summary estimates were combined in a meta-analysis of 8091 South Asian individuals (3919 patients with Type 2 diabetes and 4172 control subjects), including those from two previous studies. RESULTS: In the 4411 Pakistani individuals from this study, the age-, sex- and diabetes-adjusted association of FTO variant rs9939609 with BMI was 0.45 (95%CI 0.24-0.67) kg/m(2) per A-allele (P=3.0 × 10(-5) ) and with waist circumference was 0.88 (95% CI 0.36-1.41) cm per A-allele (P=0.001). The A-allele (30% frequency) was also significantly associated with Type 2 diabetes [per A-allele odds ratio (95%CI) 1.18 (1.07-1.30); P=0.0009]. A meta-analysis of four South Asian studies with 8091 subjects showed that the FTO A-allele predisposes to Type 2 diabetes [1.22 (95%CI 1.14-1.31); P=1.07 × 10(-8) ] even after adjusting for BMI [1.18 (95%CI 1.10-1.27); P=1.02 × 10(-5) ] or waist circumference [1.18 (95%CI 1.10-1.27); P=3.97 × 10(-5) ]. CONCLUSIONS: The strong association between FTO genotype and BMI and waist circumference in South Asians is similar to that observed in Europeans. In contrast, the strong association of FTO genotype with diabetes is only partly accounted for by BMI.

Public health law in India: a framework for its application as a tool for social change.

Public health law focuses on the nexus between law, public health and the legal tools applicable to public health issues. Though there have been consistent interventions to address public health concerns in the past, there exists a need for a contemporary framework to appropriately use modern legal tools for complex health challenges. We identify a checklist of imperative indicators to assess whether public health legislations would be an effective form of intervention to bring about the desired social change.

Coronary artery disease epidemic in Pakistan: more electrocardiographic evidence of ischaemia in women than in men.

UNLABELLED: Indo-Pakistani populations have one of the highest risks of coronary artery disease (CAD) in the world. A population-based, cross-sectional survey was conducted on 3143 adults aged >or=40 years from 12 randomly selected communities in Karachi, Pakistan. Apart from smoking, women had more CAD risk factors (diabetes, hypertension, obesity, dyslipidaemia) than men. Definite CAD (history and Q waves on ECG) was more prevalent in men than in women (6.1% vs 4.0%; p = 0.009). In contrast, ischaemic and major ECG changes were twice as prevalent in women as in men (29.4% vs 15.6%, and 21.0% vs 10.5%; p<0.001 for each, respectively). All measures of CAD were strongly predicted by the metabolic syndrome, but that failed to account for the greater prevalence of ECG abnormalities in women than in men. The findings indicate that one in five middle-aged adults in urban Pakistan may have underlying CAD. Women are at greater risk than men. TRIAL REGISTRATION NUMBER: NCT00327574.

Rise in childhood obesity with persistently high rates of undernutrition among urban school-aged Indo-Asian children.

BACKGROUND: Childhood obesity is an emerging global public health challenge. Evidence for the transition in nutrition in Indo-Asian developing countries is lacking. We conducted these analyses to determine the trends in nutritional status of school-aged children in urban Pakistan. METHODS: Data on the nutritional status of children aged 5 to 14 years from two independent population-based representative surveys, the urban component of the National Health Survey of Pakistan (NHSP; 1990-1994) and the Karachi survey (2004-2005), were analysed. Using normative data from children in the United States as the reference, trends for age- and gender-standardised prevalence (95% CI) of underweight (more than 2 SD below the weight-for-age reference), stunted (more than 2 SD below the height-for-age reference) and overweight and obese (body mass index (BMI) 85(th) percentile or greater) children were compared for the two surveys. The association between physical activity and being overweight or obese was analysed in the Karachi survey using logistical regression analysis. RESULTS: 2074 children were included in the urban NHSP and 1675 in the Karachi survey. The prevalence of underweight children was 29.7% versus 27.3% (p = 0.12), stunting was 16.7% versus 14.3% (p = 0.05), and prevalence of overweight and obese children was 3.0 versus 5.7 (p<0.001) in the NHSP and Karachi surveys, respectively. Physical activity was inversely correlated with being overweight or obese (odds ratio, 95% CI, 0.51, 0.32-0.80 for those who engaged in more than 30 minutes of physical activity versus those engaged in less than 30 minutes' activity). CONCLUSIONS: Our study highlights the challenge faced by Pakistani school-aged children. There has been a rapid rise in the number of overweight and obese children despite a persistently high burden of undernutrition. Focus on prevention of obesity in children must include strategies for promoting physical activity.

Systemic hypertension and nondiabetic chronic kidney disease: the best evidence-based therapeutic approach today.

Despite the high prevalence and significant morbidity and mortality associated with high chronic kidney disease (CKD) in patients with hypertension, it remains vastly under-diagnosed and under-treated. Consequently, many patients develop kidney failure requiring dialysis or kidney transplant. Moreover, patients with CKD represent the group at highest risk from cardiovascular complications, even greater than patients with diabetes mellitus. Therefore, management of hypertension in such patients needs to be more aggressive compared to those with normal kidney function. This review provides guidelines for treatment of hypertension in patients with non-diabetic CKD based on updated evidence from clinical trials data. Following these recommendations is likely to minimize the risk of development of kidney failure and cardiovascular disease.

Ethnic differences and determinants of diabetes and central obesity among South Asians of Pakistan.

AIMS: To study the within ethnic subgroup variations in diabetes and central obesity among South Asians. METHODS: Data from 9442 individuals age > or = 15 years from the National Health Survey of Pakistan (NHSP) (1990-1994) were analysed. Diabetes was defined as non-fasting blood glucose > or = 7.8 mmol/l, or known history of diabetes. Central obesity was measured at the waist circumference. Distinct ethnic subgroups Muhajir, Punjabi, Sindhi, Pashtun, and Baluchi were defined by mother tongue. RESULTS: The age-standardized prevalence of diabetes varied among ethnic subgroups (P = 0.002), being highest among the Muhajirs (men 5.7%, women 7.9%), then Punjabis (men 4.6%, women 7.2%), Sindhis (men 5.1%, women 4.8%), Pashtuns (men 3.0%, women 3.8%), and lowest among the Baluchis (men 2.9%, women 2.6%). While diabetes was more prevalent in urban vs. rural dwellers [odds ratio (OR) 1.50, 95% confidence interval (CI) 1.24, 1.82], this difference was no longer significant after adjusting for central obesity (OR 1.15, 95% CI 0.95, 1.42). However, the ethnic differences persisted after adjusting for major sociodemographic risk factors (unadjusted OR for Pashtun vs. Punjabi 0.59, 95% CI 0.42, 0.84, adjusted OR 0.54, 95% CI 0.37, 0.78). Ethnic variation was also observed in central obesity, which varied with gender, and did not necessarily track with ethnic differences in diabetes. CONCLUSIONS: Unmeasured environmental or genetic factors account for ethnic variations in diabetes and central obesity, and deserve further study.

Risk factors for non-fatal myocardial infarction in young South Asian adults.

OBJECTIVE: To determine the risk factors for premature myocardial infarction among young South Asians. DESIGN AND SETTING: Case-control study in a hospital admitting unselected patients with non-fatal acute myocardial infarction. METHODS AND SUBJECTS: Risk factor assessment was done in 193 subjects aged 15-45 years with a first acute myocardial infarct, and in 193 age, sex, and neighbourhood matched population based controls. RESULTS: The mean (SD) age of the subjects was 39 (4.9) years and 326 (84.5%) were male. Current smoking (odds ratio (OR) 3.82, 95% confidence interval (CI) 1.47 to 9.94), use of ghee (hydrogenated vegetable oil) in cooking (OR 3.91, 95% CI 1.52 to 10.03), raised fasting blood glucose (OR 3.32, 95% CI 1.21 to 8.62), raised serum cholesterol (OR 1.67, 95% CI 1.14 to 2.45 for each 1.0 mmol/l increase), low income (OR 5.05, 95% CI 1.71 to 14.96), paternal history of cardiovascular disease (OR 4.84, 95% CI 1.42 to 16.53), and parental consanguinity (OR 3.80, 95% CI 1.13 to 1.75) were all independent risk factors for acute myocardial infarction in young adults. Formal education versus no education had an independently protective effect on acute myocardial infarction (OR 0.04, 95% CI 0.01 to 0.35). CONCLUSIONS: Tobacco use, ghee intake, raised fasting glucose, high cholesterol, paternal history of cardiovascular disease, low income, and low level of education are associated with premature acute myocardial infarction in South Asians. The association of parental consanguinity with acute myocardial infarction is reported for the first time and deserves further study.

Proteinuria as a modifiable risk factor for the progression of non-diabetic renal disease.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors reduce urine protein excretion and slow the progression of renal disease. The beneficial effect in slowing the progression of renal disease is greater in patients with higher urine protein excretion at the onset of treatment. We hypothesized that the greater beneficial effect of ACE inhibitors on the progression of renal disease in patients with higher baseline levels of proteinuria is due to their greater antiproteinuric effect in these patients. METHODS: Data were analyzed from 1860 patients enrolled in 11 randomized controlled trials comparing the effect of antihypertensive regimens, including ACE inhibitors to regimens not including ACE inhibitors on the progression of non-diabetic renal disease. Multivariable linear regression analysis was used to assess the relationship between the level of proteinuria at baseline and changes in urine protein excretion during follow-up. The Cox proportional hazards analysis was used to assess the relationship between changes in urine protein excretion during follow-up and the effect of ACE inhibitors on the time to doubling of baseline serum creatinine values or onset of end-stage renal disease. RESULTS: Mean (median) baseline urine protein excretion was 1.8 (0.94) g/day. Patients with higher baseline urine protein excretion values had a greater reduction in proteinuria during the follow-up in association with treatment with ACE inhibitors and in association with lowering systolic and diastolic blood pressures (interaction P < 0.001 for all). A higher level of urine protein excretion during follow-up (baseline minus change) was associated with a greater risk of progression [relative risk 5.56 (3.87 to 7.98) for each 1.0 g/day higher protein excretion]. After controlling for the current level of urine protein excretion, the beneficial effect of ACE inhibitors remained significant [relative risk for ACE inhibitors vs. control was 0.66 (0.52 to 0.83)], but there was no significant interaction between the beneficial effect of ACE inhibitors and the baseline level of urine protein excretion. CONCLUSIONS: The antiproteinuric effects of ACE inhibitors and lowering blood pressure are greater in patients with a higher baseline urine protein excretion. The greater beneficial effect of ACE inhibitors on renal disease progression in patients with higher baseline proteinuria can be explained by their greater antiproteinuric effects in these patients. The current level of urine protein excretion is a modifiable risk factor for the progression of non-diabetic renal disease. ACE inhibitors provide greater beneficial effect at all levels of current urine protein excretion.

Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data.

PURPOSE: To examine the efficacy of ACE inhibitors for treatment of nondiabetic renal disease. DATA SOURCES: 11 randomized, controlled trials comparing the efficacy of antihypertensive regimens including ACE inhibitors to the efficacy of regimens without ACE inhibitors in predominantly nondiabetic renal disease. STUDY SELECTION: Studies were identified by searching the MEDLINE database for English-language studies evaluating the effects of ACE inhibitors on renal disease in humans between May 1977 (when ACE inhibitors were approved for trials in humans) and September 1997. DATA EXTRACTION: Data on 1860 nondiabetic patients were analyzed. DATA SYNTHESIS: Mean duration of follow-up was 2.2 years. Patients in the ACE inhibitor group had a greater mean decrease in systolic and diastolic blood pressure (4.5 mm Hg [95% CI, 3.0 to 6.1 mm Hg]) and 2.3 mm Hg [CI, 1.4 to 3.2 mm Hg], respectively) and urinary protein excretion (0.46 g/d [CI, 0.33 to 0.59 g/d]). After adjustment for patient and study characteristics at baseline and changes in systolic blood pressure and urinary protein excretion during follow-up, relative risks in the ACE inhibitor group were 0.69 (CI, 0.51 to 0.94) for end-stage renal disease and 0.70 (CI, 0.55 to 0.88) for the combined outcome of doubling of the baseline serum creatinine concentration or end-stage renal disease. Patients with greater urinary protein excretion at baseline benefited more from ACE inhibitor therapy (P = 0.03 and P = 0.001, respectively), but the data were inconclusive as to whether the benefit extended to patients with baseline urinary protein excretion less than 0.5 g/d. CONCLUSION: Antihypertensive regimens that include ACE inhibitors are more effective than regimens without ACE inhibitors in slowing the progression of nondiabetic renal disease. The beneficial effect of ACE inhibitors is mediated by factors in addition to decreasing blood pressure and urinary protein excretion and is greater in patients with proteinuria. Angiotensin-converting inhibitors are indicated for treatment of nondiabetic patients with chronic renal disease and proteinuria and, possibly, those without proteinuria.

The role of systemic hypertension in the progression of nondiabetic renal disease.

BACKGROUND: A role for hypertension in the progression of renal disease has been convincingly shown in experimental animals only. In human studies, the relation between hypertension and progression is difficult to demonstrate due to several confounding factors: age, gender, race; the difficult choice of blood pressure (BP) parameters that correlate with progression; the abnormal circadian BP pattern; and the many non-hemodynamic factors of progression. An important role for hypertension in progressive nondiabetic renal disease has been suggested by observational studies and clinical trials originally intended to evaluate the effect of dietary protein restriction on progression. In addition, several studies, summarized by a recent meta-analysis, have shown that pharmacological agents which lower both BP and proteinuria, mainly the angiotensin-converting enzyme inhibitors (ACEI), significantly slow the rate of progression in these diseases. METHODS: In this article we review the effect of lowering BP on the progression of nondiabetic chronic renal disease, the patient characteristics that are associated with a greater or lesser benefit of blood pressure reduction, and the choice of antihypertensive regimens associated with better outcomes in patients with renal disease. RESULTS: Lower levels of achieved BP are associated with a slower decline in renal function, both in patients with and without proteinuria. ACEI are effective BP lowering agents and are associated with better preservation of renal function as opposed to antihypertensive regimens without ACEI. This protective effect of ACEI is in addition to their BP and urine protein lowering effects. The protective effect of ACEI on renal function is more pronounced in patients with proteinuria. CONCLUSION: In patients with nondiabetic renal disease and proteinuria, the risk of progression can be minimized by lowering both BP and proteinuria. ACEI have an additional beneficial effect.