Fine-scale human genetic structure in Western France

The difficulties arising from association analysis with rare variants underline the importance of suitable reference population cohorts, which integrate detailed spatial information. We analyzed a sample of 1684 individuals from Western France, who were genotyped at genome-wide level, from two cohorts D.E.S.I.R and CavsGen. We found that fine-scale population structure occurs at the scale of Western France, with distinct admixture proportions for individuals originating from the Brittany Region and the Vendée Department. Genetic differentiation increases with distance at a high rate in these two parts of Northwestern France and linkage disequilibrium is higher in Brittany suggesting a lower effective population size. When looking for genomic regions informative about Breton origin, we found two prominent associated regions that include the lactase region and the HLA complex. For both the lactase and the HLA regions, there is a low differentiation between Bretons and Irish, and this is also found at the genome-wide level. At a more refined scale, and within the Pays de la Loire Region, we also found evidence of fine-scale population structure, although principal component analysis showed that individuals from different departments cannot be confidently discriminated. Because of the evidence for fine-scale genetic structure in Western France, we anticipate that rare and geographically localized variants will be identified in future full-sequence analyses.     

Strong association of common variants in the <Emphasis Type="Italic">CDKN2A/CDKN2B</Emphasis> region with type 2 diabetes in French Europids

Aims/hypothesis Genome-wide association studies (GWASs) recently identified common variants in the CDKN2A/CDKN2B region on chromosome 9p as being strongly associated with type 2 diabetes. Since these association signals were not picked up by the French-Canadian GWAS, we sought to replicate these findings in the French Europid population and to further characterise the susceptibility variants at this novel locus. Methods We genotyped 20 single nucleotide polymorphisms (SNPs) spanning the CDKN2A/CDKN2B locus in our type 2 diabetes case-control cohort. The association between CDKN2A/CDKN2B SNPs and quantitative metabolic traits was also examined in the normoglycaemic participants comprising the control cohort. Results We report replication of the strong association of rs10811661 with type 2 diabetes found in the GWASs (; OR 1.43 [95% CI 1.24–1.64]). The other CDKN2A/CDKN2B susceptibility variant, rs564398, did not attain statistical significance (p = 0.053; OR 1.11 [95% CI 1.00–1.24]) in the present study. We also obtained several additional nominal association signals (p < 0.05) at the CDKN2A/CDKN2B locus; however, only the rs3218018 result (p = 0.002) survived Bonferroni correction for multiple testing (adjusted p = 0.04). Conclusions/interpretation Our comprehensive association study of common variation spanning the CDKN2A/CDKN2B locus confirms the strong association between the distal susceptibility variant rs10811661 and type 2 diabetes in the French population. Further genetic and functional studies are required to identify the aetiological variants at this locus and determine the cellular and physiological mechanisms by which they act to modulate type 2 diabetes susceptibility. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. K. Duesing and G. Fatemifar contributed equally to this work.     

Microalbuminuria and markers of the atherosclerotic process: the D.E. S.I.R. study

The relationship between microalbuminuria and tissue-type plasminogen activator antigen (tPA-ag) and fibrinogen was evaluated in non-diabetic subjects. Subjects were participants of the D.E.S.I. R. (Data from an Epidemiological Study on the Insulin Resistance syndrome) Study. Analyses were carried out on 2248 women and 2402 men for fibrinogen and on 272 women and 284 men for tPA-ag. Microalbuminuria was defined as urinary albumin concentration greater than 20 mg/l. Men with microalbuminuria had a 6% higher fibrinogen concentration than those without (3.07 g/l (95% confidence interval: 2.99,3.15) vs. 2.89 g/l (2.87,2.91), adjusted for age and smoking). This relationship existed in hypertensive as well as non-hypertensive subjects. The association between microalbuminuria and tPA-ag existed only in hypertensive men, those with microalbuminuria having a 21% higher tPA-ag than those without (4.39 ng/ml (3.70,5.08) vs. 3.63 ng/ml (3.32,3.94), adjusted for age and smoking). Adjustment for other risk markers for cardiovascular disease did not change the results. There was no relationship between microalbuminuria and these haemostatic factors in women. The results of this study suggest that in non-diabetic men, microalbuminuria is associated with fibrinogen, but with tPA-ag only when concomitant with hypertension.     

Hypertension in four African-origin populations: current 'Rule of Halves', quality of blood pressure control and attributable risk of cardiovascular disease

OBJECTIVE: To assess the public health burden from high blood pressure and the current status of its detection and management in four African-origin populations at emerging or high cardiovascular risk. DESIGN: Cross-site comparison using standardized measurement and techniques. SETTING: Rural and urban Cameroon; Jamaica; Manchester, Britain. SUBJECTS: Representative population samples in each setting. African-Caribbeans (80% of Jamaican origin) and a local European sample in Manchester. MAIN OUTCOME MEASURES: Cross-site age-adjusted prevalence; population attributable risk. RESULTS: Among 1,587 men and 2,087 women, age-adjusted rates of blood pressure > or =160 or 95 mmHg or its treatment rose from 5% in rural to 17% in urban Cameroon, despite young mean ages, to 21% in Jamaica and 29% in Caribbeans in Britain. Treatment rates reached 34% in urban Cameroon, and 69% in Jamaican- and British-Caribbean-origin women. Sub-optimal blood pressure control (> 140 and 90 mmHg) on treatment reached 88% in European women. Population attributable risks (or fractions) indicated that up to 22% of premature all-cause, and 45% of stroke mortality could be reduced by appropriate detection and treatment. Additional benefit on just strokes occurring on treatment could be up to 47% (e.g. in both urban Cameroon men and European women) from tighter blood pressure control on therapy. Cheap, effective therapy is available. CONCLUSION: With mortality risk now higher from non-communicable than communicable diseases in sub-Saharan Africa and elsewhere, systematic measurement, detection and genuine control of hypertension once treated can go hand-in-hand with other adult health programmes in primary care. Cost implications are not great. The data from this collaborative study suggest that such efforts should be well rewarded.     

The EGIR-RISC STUDY (The European group for the study of insulin resistance: relationship between insulin sensitivity and cardiovascular disease risk): I. Methodology and Objectives

Aims/hypotheses Insulin resistance is thought to be a key predictor for the development of Type 2 diabetes mellitus and cardiovascular disease (CVD), a leading cause of morbidity and premature mortality in Europe. Insulin resistance is influenced by both genetic and lifestyle factors (e.g. obesity and physical inactivity). The RISC (Relationship between Insulin Sensitivity and Cardiovascular disease) Study is using the infrastructure of an extended European collaborative research group to study insulin resistance and CVD risk in 1500 healthy people aged 30 to 60 years from 20 centres in 13 countries.Methods Baseline measurements of glucose tolerance and insulin sensitivity are made by the oral glucose tolerance test and the euglycaemic insulin clamp, respectively; carotid artery intima-medial thickness (by ultrasound), ankle/brachial pressure index and electrocardiography will enable evaluation of subclinical CVD at baseline and at follow-up. Classic CVD risk factors, as well as socioeconomic and lifestyle factors will be recorded at baseline; samples for measurement of biochemical and genetic markers will be collected and stored for future analyses. Investigations will be repeated after 3 and 10 years to evaluate the relationship between insulin resistance and the development of atherosclerosis as measured by carotid artery intima-media thickness. Development of Type 2 diabetes, dyslipidaemia, obesity, hypertension and cardiovascular events are additional endpoints.Conclusions This study will evaluate the importance of insulin resistance in the development of CVD and diabetes, and has implications for the development of prevention and treatment strategies.Abbreviations CVD Cardiovascular disease - cIMT carotid intima-medial thickness - CCA common carotid arteries - CB carotid bifurcation - ICA internal carotid arterySee the Acknowledgements for the full list of members of the EGIR-RISC Study Group     

Clinical and biochemical expression of the histopathological lesions of primary biliary cirrhosis. UDCA-PBC Group

BACKGROUND/AIMS: This study aimed to assess the relationships which may link elementary histological lesions with symptoms and biochemistries in primary biliary cirrhosis. METHODS: We studied 103 patients with primary biliary cirrhosis who participated in a double-blind, placebo-controlled trial of UDCA treatment and in whom liver biopsy specimens obtained at entry were reassessed. Relationships between histological features, fatigue, pruritus and biochemistries were calculated by using exact tests for 2 ordinal variables. RESULTS: The degrees of severity of fatigue and pruritus were significantly and exclusively related to the presence of florid interlobular bile duct lesions (p<0.01 and p<0.02, respectively). The only laboratory parameter associated with the presence of interlobular bile duct florid lesion was IgM level. The most discriminant biochemical test for interlobular bile duct paucity was gamma glutamyltranspeptidase activity. The degree of severity of both lymphocytic hepatocellular piecemeal necrosis and lobular inflammation and necrosis was mainly associated with increased gammaglobulin and IgG levels and to a lesser extent with increased IgM and aspartate aminotransferase levels. The extent of fibrosis was mainly associated with gammaglobulin levels and to a lesser degree with serum albumin, bilirubin and IgG levels. CONCLUSIONS: Symptoms and biochemistries classically used to assess primary biliary cirrhosis reflect in part the degree of severity of the main elementary histological lesions. We propose that the picture of primary biliary cirrhosis results from the clinical and biochemical expression of three distinct processes, e.g., bile duct inflammation and destruction, parenchymal inflammation and necrosis, and fibrosis. The various combinations of these processes may explain why the spectrum of primary biliary cirrhosis varies from typical primary biliary cirrhosis to mixed type of primary biliary cirrhosis and autoimmune hepatitis and suggests that the response to therapies may depend on the predominance of each process in a given patient.     

Preventive therapy of first gastrointestinal bleeding in patients with cirrhosis: results of a controlled trial comparing propranolol, endoscopic sclerotherapy and placebo

Propranolol and endoscopic sclerosis of esophageal varices are the two approaches currently used in prophylaxis of the first gastrointestinal hemorrhage in the cirrhotic patient. One hundred twenty-six cirrhotic patients with esophageal varices and no histories of bleeding were included in the trial regardless of the gravity of the cirrhosis or the size of the esophageal varices. Patients with hepatocarcinomas or other cancers, clearly impossible follow-up, previous treatment for portal hypertension or contraindication to beta-blockers were excluded. After randomization, 43 patients received propranolol twice daily at a dose reducing the heart rate by 25%; 42 patients were treated with intravariceal and extravariceal injections of Polidocanol; 41 control patients received vitamin K orally as placebo. The patients were seen at 3-mo intervals for 2 yr. On entry to the trial the three groups were comparable in terms of clinical and biological parameters, including size of esophageal varices (grade I = 51, grade II = 54, grade III = 17), Child-Pugh classification (A = 29, B = 61, C = 32) and the origin of cirrhosis (alcoholic in 79% of cases). Twenty-four patients bled (two bled in the propranolol group, nine bled in the endoscopic sclerosis of esophageal varices group and 13 bled in the placebo group). Actuarial estimates (Kaplan-Meier) of the time of onset of first bleeding showed that the differences were significant between propranolol and placebo (p less than 0.004) and between propranolol and sclerotherapy (p less than 0.03) but not between sclerotherapy and placebo.(ABSTRACT TRUNCATED AT 250 WORDS)     

Two hour plasma glucose is not unequivocally predictive for early death in men with impaired fasting glucose: more results from the Paris Prospective Study

AIMS/HYPOTHESIS: We examined whether the 2-h plasma glucose (2 hPG) concentration after a 75 g OGTT is predictive of death in men with a diabetic, an impaired or a normal fasting plasma glucose concentration (DM-FPG: > or =7.0 mmol/l; IFG: 6.1-6.9 mmol/l; normal-FPG: <6.1 mmol/l). METHODS: The 17-year mortality of 7018 men, aged 44 to 55 years, from the Paris Prospective Study, who were not known to be diabetic at baseline was studied. RESULTS: The 2 hPG was not associated with early mortality in men with a DM-FPG in contrast to men with an IFG or a normal-FPG; for an increase from 10 to 11 mmol/l in the 2 hPG, the age-adjusted hazards ratios were 1.01 (95% CI 0.95-1.08), 1.15 (1.03-1.28) and 1.24 (1.18-1.31) respectively. Coronary heart disease mortality and within this category sudden death but not ischaemic heart disease death, were related with 2 hPG but only in the men with normal FPG. However, the prediction by 2 hPG did not differ between the men with DM-FPG, an IFG or a normal-FPG: the overall age-adjusted hazards ratios for these three causes of death were 1.09 (1.00-1.18), 1.13 (1.02-1.26) and 1.13 (0.99-1.29), respectively. CONCLUSION/INTERPRETATION: 2 hPG is unequivocally prognostic for all-cause mortality only in men with normal FPG. Screening men with an IFG by using a 75 g OGTT is of limited benefit.     

Histopathological study of primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment on histology progression

The semiquantitative histopathological analysis of the liver biopsies obtained before and after 4 years of ursodeoxycholic acid (UDCA) therapy in a cohort of primary biliary cirrhosis (PBC) patients is reported. The relationships between elementary histological lesions before treatment and their progression under therapy were assessed. At baseline, two independent groups of lesions, each of which participate in the development of fibrosis, were individualized, i.e., florid bile duct lesions and ductopenia on one hand and lymphocytic piecemeal necrosis, ductular proliferation, and lobular necroinflammatory changes on the other hand. Four years of UDCA therapy were associated with a significant decrease in the prevalence of florid interlobular bile duct (ILBD) lesions, of epithelioid granuloma (P <.001) without any aggravation in the severity of bile duct paucity. Lobular inflammation and necrosis markedly improved (P <.001) whereas the degree of severity of the lymphocytic piecemeal necrosis and ductular proliferation at entry and at 4 years were similar. Worsening of fibrosis was observed in 14 patients (12 of them had a one grade progression) whereas stabilization was noted in 30 of the remaining patients. Severity of both the lymphocytic piecemeal necrosis and lobular inflammation and necrosis at entry was significantly associated with the progression of fibrosis. The results suggest that UDCA therapy influences the process leading to bile duct destruction. Patients with severe lymphocytic piecemeal necrosis and lobular inflammation may need additional therapeutic intervention because they have increased risk of fibrosis progression.     

Dietary antioxidant capacity and risk of type 2 diabetes in the large prospective E3N-EPIC cohort

Aims/hypothesis

Recent evidence suggests that oxidative stress may contribute to the pathogenesis of type 2 diabetes. The diet, and especially fruit and vegetables, contains a variety of compounds with antioxidant activity, which may have cumulative/synergistic antioxidant effects. The total antioxidant capacity, an index derived from dietary intake, is a single estimate of antioxidant capacity from all dietary antioxidants. The main aim of this study was to investigate the relationship between total antioxidant capacity and risk of type 2 diabetes.

Methods

Among 64,223 women (mean age 52 ± 7 years) from the French E3N-European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, 1751 women had validated type 2 diabetes during 15 years of follow-up. The total antioxidant capacity was estimated with the ferric ion-reducing antioxidant power (FRAP) method. Adjusted Cox proportional hazards regression models were used to calculate HRs and 95% CIs for the associations between total antioxidant capacity and type 2 diabetes risk, adjusted for potential confounders.

Results

In multivariable models, higher levels of total antioxidant capacity were associated with a lower risk of type 2 diabetes. Compared with women in the lowest quintile, women in the third, fourth and fifth quintiles for total antioxidant capacity had HRs of 0.74 (95% CI 0.63, 0.86), 0.70 (95% CI 0.59, 0.83) and 0.73 (95% CI 0.60, 0.89), respectively. The inverse association between total antioxidant capacity and risk of type 2 diabetes was linear up to values of 15 mmol/day, after which the effect reached a plateau.

Conclusions/interpretation

Our findings suggest that the total antioxidant capacity may play an important role in reducing the risk of type 2 diabetes in middle-aged women. More studies are warranted to better understand the biological mechanisms underlying this inverse association.