The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.

BACKGROUND: A high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular inflammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown. METHODS: Applying the mendelian randomisation principle, we used single nucleotide polymorphisms (SNPs) in the gene IL6R to evaluate the likely efficacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic findings with the effects of tocilizumab reported in randomised trials in patients with rheumatoid arthritis. FINDINGS: In 40 studies including up to 133,449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log interleukin-6 concentration (increase per allele 9·45%, 95% CI 8·34-10·57) as well as reduced C-reactive protein (decrease per allele 8·35%, 95% CI 7·31-9·38) and fibrinogen concentrations (decrease per allele 0·85%, 95% CI 0·60-1·10). This pattern of effects was consistent with IL6R blockade from infusions of tocilizumab (4-8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials. In 25,458 coronary heart disease cases and 100,740 controls, the IL6R rs7529229 SNP was associated with a decreased odds of coronary heart disease events (per allele odds ratio 0·95, 95% CI 0·93-0·97, p=1·53×10(-5)). INTERPRETATION: On the basis of genetic evidence in human beings, IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials. Genetic studies in populations could be used more widely to help to validate and prioritise novel drug targets or to repurpose existing agents and targets for new therapeutic uses. FUNDING: UK Medical Research Council; British Heart Foundation; Rosetrees Trust; US National Heart, Lung, and Blood Institute; Du Pont Pharma; Chest, Heart and Stroke Scotland; Wellcome Trust; Coronary Thrombosis Trust; Northwick Park Institute for Medical Research; UCLH/UCL Comprehensive Medical Research Centre; US National Institute on Aging; Academy of Finland; Netherlands Organisation for Health Research and Development; SANCO; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Agentschap NL; European Commission; Swedish Heart-Lung Foundation; Swedish Research Council; Strategic Cardiovascular Programme of the Karolinska Institutet; Stockholm County Council; US National Institute of Neurological Disorders and Stroke; MedStar Health Research Institute; GlaxoSmithKline; Dutch Kidney Foundation; US National Institutes of Health; Netherlands Interuniversity Cardiology Institute of the Netherlands; Diabetes UK; European Union Seventh Framework Programme; National Institute for Healthy Ageing; Cancer Research UK; MacArthur Foundation.

Comparative analysis of genome-wide association studies signals for lipids, diabetes, and coronary heart disease: Cardiovascular Biomarker Genetics Collaboration.

AIMS: To evaluate the associations of emergent genome-wide-association study-derived coronary heart disease (CHD)-associated single nucleotide polymorphisms (SNPs) with established and emerging risk factors, and the association of genome-wide-association study-derived lipid-associated SNPs with other risk factors and CHD events. METHODS AND RESULTS: Using two case-control studies, three cross-sectional, and seven prospective studies with up to 25 000 individuals and 5794 CHD events we evaluated associations of 34 genome-wide-association study-identified SNPs with CHD risk and 16 CHD-associated risk factors or biomarkers. The Ch9p21 SNPs rs1333049 (OR 1.17; 95% confidence limits 1.11-1.24) and rs10757274 (OR 1.17; 1.09-1.26), MIA3 rs17465637 (OR 1.10; 1.04-1.15), Ch2q36 rs2943634 (OR 1.08; 1.03-1.14), APC rs383830 (OR 1.10; 1.02, 1.18), MTHFD1L rs6922269 (OR 1.10; 1.03, 1.16), CXCL12 rs501120 (OR 1.12; 1.04, 1.20), and SMAD3 rs17228212 (OR 1.11; 1.05, 1.17) were all associated with CHD risk, but not with the CHD biomarkers and risk factors measured. Among the 20 blood lipid-related SNPs, LPL rs17411031 was associated with a lower risk of CHD (OR 0.91; 0.84-0.97), an increase in Apolipoprotein AI and HDL-cholesterol, and reduced triglycerides. SORT1 rs599839 was associated with CHD risk (OR 1.20; 1.15-1.26) as well as total- and LDL-cholesterol, and apolipoprotein B. ANGPTL3 rs12042319 was associated with CHD risk (OR 1.11; 1.03, 1.19), total- and LDL-cholesterol, triglycerides, and interleukin-6. CONCLUSION: Several SNPs predicting CHD events appear to involve pathways not currently indexed by the established or emerging risk factors; others involved changes in blood lipids including triglycerides or HDL-cholesterol as well as LDL-cholesterol. The overlapping association of SNPs with multiple risk factors and biomarkers supports the existence of shared points of regulation for these phenotypes.

Professionalism development and assessment in the pre-registration pharmacist placement in England: transformative moments and maturation periods.

OBJECTIVES: Development of new patient-facing roles for pharmacists and reports of poor patient care in the UK has led to questions concerning how pharmacists develop professionalism. This study explored how professionalism is developed and assessed during the post-graduation year in practice or pre-registration placement. The perspectives of two staff at the professional regulator UK (General Pharmaceutical Council), eight service users, seven pre-registration trainees, and 12 pre-registration tutors were recruited. METHODS: An interpretative paradigm was adopted. Data collection involved a semi-structured group interview, focus groups and a qualitative e-questionnaire. An inductive reasoning approach informed data analysis and interpretation. KEY FINDINGS: All groups provided insights into examples of transformative moments which potentiated professionalism development, the first being awarding the 'pre-registration trainee' title. All groups reported that contact with patients and trainee reflection aided professionalism maturation from a 'self-centred student' to becoming a 'responsible professional' where more than 'doing' is demanded. Furthermore, tutors stated the rate of professionalism development was affected by the sector of training and its opportunities for patient contact. Tutors felt they alone, not the registration exam, assessed professionalism using a variety of assessment approaches. Importantly, no tutors reported patient involvement in the assessment of trainees' professionalism, yet service users expected to be involved. CONCLUSIONS: Transformative moments and maturation periods during pre-registration training develop professionalism and enable trainees to 'become' a pharmacist. Careful planning of placements to optimise professionalism development across pharmacy sectors and consistent patient involvement in assessing trainee professionalism is recommended.

Free protein S level as a risk factor for coronary heart disease and stroke in a prospective cohort study of healthy United Kingdom men.

Plasma protein S (PS) levels are reportedly low in patients with venous thrombosis but high in coronary heart disease (CHD) patients. The authors examined the association between free PS concentration and CHD or stroke risk and assessed risk in combination with C-reactive protein (CRP) levels. Free PS concentration was determined in 6 annual visits among 3,052 middle-aged (49-64 years) United Kingdom men from the Second Northwick Park Heart Study, with 297 CHD events from 1989 to 2005. The highest (vs. first) quintile was associated with a significantly increased CHD risk after adjustment for all other risk factors and correction for regression dilution bias (hazard ratio = 1.85, 95% confidence interval: 1.08, 3.16; P = 0.024). Models that included all well-known risk factors plus PS quintiles improved prediction of CHD (net reclassification improvement (NRI) = 7.0% (P = 0.007), category-less NRI (>0) = 22.1% (P < 0.001)), and the likelihood ratio statistic increased significantly (P = 0.018). The increase in CHD risk was particularly strong when subjects also had high CRP levels. There was no association between free PS level and stroke risk. This study confirms the independent association of elevated free PS levels with future risk of CHD, although elevated PS levels added only modestly to prediction metrics. The novel finding of increased CHD risk, particularly when CRP and PS levels are high, requires further study.

FVII, FVIIa, and downstream markers of extrinsic pathway activation differ by EPCR Ser219Gly variant in healthy men.

OBJECTIVE: The purpose of this study was to determine the effect of a variant in EPCR (Ser219Gly), previously shown to affect EPCR shedding, on plasma FVII, FVIIa, and downstream markers of activated coagulation. METHODS AND RESULTS: Statistical analysis was undertaken in approximately 2000 healthy middle aged men (NPHSII). Higher soluble EPCR levels were confirmed for Gly allele carriers (P<0.0001). Significantly higher levels of FVII, FVIIa, and downstream markers of activated coagulation in the extrinsic pathway (FIX activation pep [FIXpep]; FX activation pep [FXpep]), and prothrombin F1+2 (F1+2) were identified in baseline samples, in Gly carriers compared to Ser/Ser (P

F9 Malmö, factor IX and deep vein thrombosis.

BACKGROUND: We recently reported the association between the Malmö sequence variant in F9 (rs6048) and deep vein thrombosis. DESIGN AND METHODS: We aimed to study whether the association between F9 Malmö and deep vein thrombosis is explained by linkage disequilibrium with nearby single-nucleotide polymorphisms, and whether the association is explained biologically by F9 Malmö affecting factor IX antigen levels or activation of factor IX. We investigated the association of F9 Malmö and 28 nearby single-nucleotide polymorphisms with deep vein thrombosis in men from two case-control studies, LETS (n=380) and MEGA (n=1,469). We assessed the association of F9 Malmö with factor IX antigen level in male control subjects from LETS (n=191) and two subsets of MEGA (n=823 and n=484) and the association with endogenous thrombin potential in LETS control men. We studied the association between F9 Malmö and factor IX activation peptide in 1,199 healthy middle-aged men from the NPHS-II cohort. RESULTS: In the combined LETS and MEGA studies, the odds ratio (95% confidence interval) for the G allele of F9 Malmö, compared with the A allele, was 0.80 (0.69-0.93). One single-nucleotide polymorphism in F9, rs422187, was strongly linked to F9 Malmö (r(2)=0.94) and was similarly associated with deep vein thrombosis. No other single-nucleotide polymorphism or haplotype tested was more strongly associated. Factor IX antigen level, factor IX activation peptide levels and endogenous thrombin potential did not differ between F9 Malmö genotypes. CONCLUSIONS: The F9 Malmö sequence variant was the most strongly associated with deep vein thrombosis among common single-nucleotide polymorphisms in the region. However, the biological mechanism by which F9 Malmö affects risk remains unknown.

The effect of WNT5B IVS3C>G on the susceptibility to type 2 diabetes in UK Caucasian subjects.

BACKGROUND AND AIMS: The wnt signaling pathway regulates adipogenesis and insulin secretion. The WNT5B gene has been reported to confer susceptibility to type 2 diabetes (T2D) in the Japanese population, and we therefore evaluated this in Caucasian subjects with respect to obesity status. METHODS AND RESULTS: Two thousand seven hundred and one Caucasian middle-aged men from the prospective Northwick Park Heart Study II (NPHSII) of whom 153 developed T2D over 15 years and 1268 Caucasian middle-aged patients with T2D (60% male) were genotyped using a TaqMan assay for the IVS3C>G variant (rs2270031) in the WNT5B gene. The frequency of the G allele was 0.026 (0.022-0.031) in controls and 0.031 (0.025-0.039) in patients with diabetes, p=0.24. In the prospective analysis, G allele carriers with BMI below 26 kg/m(2) had significantly higher T2D hazard risk [3.46 (1.34-8.96), p=0.01]. Comparing T2D cases with NPHSII controls, the G allele was associated with a significantly higher T2D odds ratio (OR) of 1.50 (1.06-2.12), p=0.02 in subjects with BMI lower than 30 kg/m(2). Increasing BMI had a smaller effect on risk in G allele carriers. The effect on risk was not explained by genotype being associated with any classical T2D risk factor. When the combined effect of this SNP and the TCF7L2 IVS3C>T SNP (rs7903146) was evaluated, a 2.07 (1.40-3.07), p<0.0001 fold higher OR was observed in carriers of both the rare alleles. CONCLUSION: Variation in WNT5B predisposes to T2D in the absence of obesity. The increase in risk conferred by the presence of both WNT5B and TCF7L2 variants strengthens the role of wnt signaling in T2D.

The effect of APOA5 and APOC3 variants on lipid parameters in European Whites, Indian Asians and Afro-Caribbeans with type 2 diabetes.

Common variants in APOA5 and APOC3 have been associated with differences in plasma triglyceride (TG) levels in healthy individuals. The aim of this study was to examine the association of APOA5 (-1131T>C, S19W) and APOC3 (-482C>T, 1100C>T) polymorphisms in patients with type 2 diabetes (T2D) of European White (EW) (n=931), Indian Asian (IA) (n=610) and Afro-Caribbean (AC) (n=167) origin, with lipid and T2D parameters. Rare allele frequencies and linkage disequilibrium differed significantly amongst ethnic groups. Compared to APOA5 -1131T and 19S homozygotes, -1131C and 19W carriers had higher TGs in all groups, but this effect was only statistically significant for the -1131C in the EWs (P=0.04) and 19W in the IAs (P<0.001). APOC3 SNPs showed no significant association with lipid levels in any ethnic group. While haplotypes carrying -1131C allele showed significant TG-raising in the EWs only, the 19W defined haplotype showed significant TG-raising in both IAs and EWs. Comparing all four SNPs in EW T2D subjects with healthy EWs (n=2579), the APOC3 1100C>T frequency was significantly higher in T2D [0.26 (0.24, 0.28)] vs. healthy EWs [0.22 (0.20, 0.23)], P=0.001. While the variable size effects of the two APOA5 SNPs on TG levels may result from ethnically different gene-gene or gene-environment interactions, APOA5 and APOC3 variants did not affect parameters of T2D. However, comparison between EWs with T2D and healthy EWs suggest APOC3 1100C>T is associated with increased risk of diabetes probably through mechanisms other than direct effects on TG.

IL6 gene promoter polymorphisms and type 2 diabetes: joint analysis of individual participants' data from 21 studies.

Several lines of evidence indicate a causal role of the cytokine interleukin (IL)-6 in the development of type 2 diabetes in humans. Two common polymorphisms in the promoter of the IL-6 encoding gene IL6, -174G>C (rs1800795) and -573G>C (rs1800796), have been investigated for association with type 2 diabetes in numerous studies but with results that have been largely equivocal. To clarify the relationship between the two IL6 variants and type 2 diabetes, we analyzed individual data on >20,000 participants from 21 published and unpublished studies. Collected data represent eight different countries, making this the largest association analysis for type 2 diabetes reported to date. The GC and CC genotypes of IL6 -174G>C were associated with a decreased risk of type 2 diabetes (odds ratio 0.91, P = 0.037), corresponding to a risk modification of nearly 9%. No evidence for association was found between IL6 -573G>C and type 2 diabetes. The observed association of the IL6 -174 C-allele with a reduced risk of type 2 diabetes provides further evidence for the hypothesis that immune mediators are causally related to type 2 diabetes; however, because the association is borderline significant, additional data are still needed to confirm this finding.

Common variants in the TCF7L2 gene and predisposition to type 2 diabetes in UK European Whites, Indian Asians and Afro-Caribbean men and women.

Common variants of TCF7L2, encoding a beta-cell-expressed transcription factor, are strongly associated with increased risk of type 2 diabetes (T2D). We examined this association using both prospective and case-control designs. A total of 2,676 healthy European white middle-aged men from the prospective NPHSII (158 developed T2D over 15 years surveillance) were genotyped for two intronic SNPs [rs 7903146 (IVS3C>T) and rs12255372 (IVS4G>T)] which showed strong linkage disequilibrium (D' = 0.88, p<0.001; R(2)=0.76, p<0.001). The IVS5T allele frequency was 0.28 (95% CI 0.27-0.29) and 0.33 (0.28-0.39) in healthy and T2D, respectively (p=0.04). Compared to CC men, CT and TT men had an adjusted [for age, body mass index, systolic blood pressure, triglyceride and C-reactive protein levels] hazard ratio for T2D of 1.65 (1.13-2.41) and 1.87 (0.99-3.53), respectively, p<0.01. The population attributable fraction for diabetes risk was 17%. In 1459, European white T2D men and women (60% male), T allele frequency was 0.36 (0.34-0.38), and compared to NPHSII healthy men the OR for T2D for the CT and TT subjects was 1.43 (1.24-1.65) and 2.11 (1.69-2.63), respectively p=<0.0001. A similar effect was observed in 919 T2D Indian Asians [OR=1.50 (1.14-1.99) and 1.64 (1.03-2.63) p=0.003] and 385 Afro-Caribbean subjects [OR=1.25 (0.90-1.75) and 1.32 (0.74-2.33) p=0.17] compared to non-diabetic ethnically matched subjects from South London. Weaker associations were found for the IVS4G>T in all studies. Linkage disequilibrium between the two SNPs was high in Indian Asians (D'=0.94), but much weaker in Afro-Caribbeans (D'=0.17) and haplotype frequencies differed markedly in this group. These results extend previous observations to other ethnic groups, and strongly confirm that TCF7L2 genotype is a major risk factor for development of T2D.

Peroxisome proliferator-activated receptor alpha gene variation influences age of onset and progression of type 2 diabetes.

Dysregulation of fatty acid metabolism is important in the pathogenesis of type 2 diabetes. Peroxisome proliferator-activated receptor (PPAR)alpha is a master regulator of fatty acid catabolism, and PPARalpha activators delay the onset of type 2 diabetes. We examined association between three PPARalpha gene polymorphisms (an A-->C variant in intron 1, the L162V variant, and the intron 7 G-->C variant) and age at diagnosis of type 2 diabetes in 912 Caucasian type 2 diabetic subjects. Individually, PPARalpha gene variants did not influence age at diagnosis, but in combination, the rare alleles of both the intron 1 A-->C (P < 0.001) and intron 7 G-->C (P = 0.025) variants synergistically lowered age at diagnosis (interaction P < 0.001). Overall, the PPARalpha haplotype signficantly influenced age at diagnosis (P = 0.027), with the C-L-C and C-V-C haplotypes (intron 1-L162V-intron 7) accelerating onset of diabetes by 5.9 (P = 0.02) and 10 (P = 0.03) years, respectively, as compared with the common A-L-G haplotype, and was associated with an odds ratio for early-onset diabetes (age at diagnosis

The factor VII activating protease G511E (Marburg) variant and cardiovascular risk.

A previous study had shown a strong relationship between a variant in factor VII activating protease (FSAP G511E) and advanced carotid atheroma. In-vitro, the variant has reduced fibrinolytic but normal pro-coagulant activity, which may constitute a prothrombotic state. The current study has addressed risk for coronary heart disease in a prospective study of cardiovascular disorders (Northwick Park Heart Study II). An interactive effect upon risk was found between the 511E allele and elevated levels of cholesterol and triglyceride. Fibrinogen could substitute for triglyceride levels in this risk-interaction analysis. The findings support the proposal that the FSAP 511E allele exacerbates atherosclerosis or its clinical sequelae.

Non-protein amino acids of Bocoa (Leguminosae; Papilionoideae).

The non-protein amino acids of the legume genus Bocoa (Papilionoideae; Swartzieae) were surveyed by LC-MS and GC-MS using extracts of herbarium leaf fragments. Bocoa alterna (Benth.) R.S. Cowan, B. decipiens R.S. Cowan, B. limae R.S. Cowan, B. mollis (Benth.) R.S. Cowan and B. racemulosa (Huber) R.S. Cowan were found to contain 2,4-methanoproline, 2,4-methanoglutamic acid, cis-1-amino-3-hydroxymethyl-cyclobutane-1-carboxylic acid and delta-N-acetylornithine. The former three compounds have otherwise only been reported from Ateleia and Cyathostegia and, therefore, the results support the relationship with these genera found in recent phylogenetic analysis of DNA sequence data. In contrast, Bocoa viridiflora (Ducke) R.S. Cowan was found to contain trans-5-hydroxypipecolic acid and trans-4-cis-5-dihydroxypipecolic acid, while trans-4-hydroxypipecolic acid and an unidentified compound were the major non-protein amino acids in B. prouacensis Aublet. The non-protein amino acid chemistry of these two species was therefore more similar to a representative of Swartzia examined, S. macrosema Harms, which also contained mono- and dihydroxypipecolic acids. The monotypic Candolleodendron brachystachyum (DC.) R.S. Cowan, considered related to Bocoa, accumulated trans-5-hydroxypipecolic acid. LC-MS data on flavonoids obtained from four of the extracts revealed the presence of flavone C-glycosides in B. viridiflora and B. prouacensis but only flavonoid O-glycosides in B. alterna and B. mollis. The chemical division of Bocoa concurs with studies of other character types and recent molecular phylogenies.

Association of TLL1 gene polymorphism (rs1503298, T > C) with coronary heart disease in PREDICT, UDACS and ED cohorts.

OBJECTIVE: To determine the sequence variant of TLL1 gene (rs1503298, T > C) in three British cohorts (PREDICT, UDACS and ED) of patients with type-2 Diabetes mellitus (T2DM) in order to assess its association with coronary heart disease (CHD). STUDY DESIGN: Analytical study. PLACE AND DURATION OF STUDY: UCL, London, UK. Participants were genotyped in 2011-2012 for TLL1 SNP. Samples and related information were previously collected in 2001-2003 for PREDICT, and in 2001-2002 for UDACS and ED groups. METHODOLOGY: Patients included in PREDICT (n=600), UDACS (n=1020) and ED (n=1240) had Diabetes. TLL1 SNP (rs1503298, T > C) was genotyped using TaqMan technology. Allele frequencies were compared using c2 test, and tested for Hardy-Weinberg equilibrium. The risk of disease was assessed from Odds ratios (OR) with 95% Confidence Intervals (95% CI). Moreover, for the PREDICT cohort, the SNP association was tested with Coronary Artery Calcification (CAC) scores. RESULTS: No significant association was found for this SNP with CHD or CAC scores in these cohorts. CONCLUSION: This SNP could not be confirmed as a risk factor for CHD in T2DM patients. However, the low power of thesmall sample size available is a limitation to the modest effect on risk. Further studies in larger samples would be useful.

Genetic variation in complement factor H and risk of coronary heart disease: eight new studies and a meta-analysis of around 48,000 individuals.

OBJECTIVES: To investigate the association of polymorphisms in complement factor H (CFH) and coronary heart disease (CHD) using meta-analysis. BACKGROUND: Age-related macular degeneration (AMD) and CHD may share partially overlapping pathogenesis. A non-synonymous SNP (rs1061170/Y402H) in CFH encoding complement factor H (fH) is robustly associated with increased AMD risk but associations with CHD risk have been inconsistent. METHODS: We conducted de novo genotyping and genetic association analyses of incident and prevalent CHD in four studies, and in silico analysis of the same association in a further four cohorts. We pooled these data with information from all published studies using random effects meta-analysis, including a total of 48,646 participants of which 9097 were CHD cases. We also evaluated the association of Y402H with known risk factors for CHD by pooling results from new and in silico studies providing relevant data. RESULTS: CFH genotype was not associated with CHD. Compared to the reference TT homozygote group the pooled odds ratio (OR) for individuals homozygous for the C allele was 1.02, 95% CI (0.91, 1.13) and that for heterozygote TC individuals was 1.04 (0.98, 1.10). There was no association of CFH with systolic and diastolic blood pressure, total-, LDL- and HDL-cholesterol, or body mass index. Individuals who were CC compared to TT had higher triglyceride levels: pooled mean difference 0.06 (0.02, 0.10) mmol/L, p=0.005. CONCLUSIONS: The AMD-associated CFH genotype is not associated with CHD. With the possible exception of triglycerides, this CFH SNP was not associated with a wide range of other CHD risk factors.

Joint analysis of individual participants' data from 17 studies on the association of the IL6 variant -174G>C with circulating glucose levels, interleukin-6 levels, and body mass index.

BACKGROUND: Several studies have investigated associations between the -174G>C single nucleotide polymorphism (rs1800795) of the IL6 gene and phenotypes related to type 2 diabetes mellitus (T2DM) but presented inconsistent results. AIMS: This joint analysis aimed to clarify whether IL6 -174G>C was associated with glucose and circulating interleukin-6 concentrations as well as body mass index (BMI). METHODS: Individual-level data from all studies of the IL6-T2DM consortium on Caucasian subjects with available BMI were collected. As study-specific estimates did not show heterogeneity (P>0.1), they were combined by using the inverse-variance fixed-effect model. RESULTS: The main analysis included 9440, 7398, 24,117, or 5659 non-diabetic and manifest T2DM subjects for fasting glucose, 2-hour glucose, BMI, or circulating interleukin-6 levels, respectively. IL6 -174 C-allele carriers had significantly lower fasting glucose (-0.091 mmol/L, P=0.014). There was no evidence for association between IL6 -174G>C and BMI or interleukin-6 levels, except in some subgroups. CONCLUSIONS: Our data suggest that C-allele carriers of the IL6 -174G>C polymorphism have lower fasting glucose levels on average, which substantiates previous findings of decreased T2DM risk of these subjects.

Population decline despite high genetic diversity in the new allopolyploid species Senecio cambrensis (Asteraceae).

Senecio cambrensis (Welsh groundsel) is a new allohexaploid species, which originated in Wales, UK, in the early part of the 20th century following hybridization between the native tetraploid groundsel (Senecio vulgaris) and the introduced diploid Oxford ragwort (Senecio squalidus). A survey of the number of populations and flowering individuals per population of S. cambrensis in Wales was conducted at peak flowering time in June 2002, 2003 and 2004. The results show a dramatic decrease in both population number and population size of the species since the 1980s when the last population census was conducted. A survey of amplified fragment length polymorphism (AFLP) variation showed that this decline has occurred despite the fact that S. cambrensis contains a high level of genetic diversity with each individual screened possessing a unique multilocus phenotype. The level of variance within the species was similar to that found in one parent (S. vulgaris) and slightly greater than that among samples of the other parent (S. squalidus). Only a small proportion (5%) of AFLP diversity was partitioned among populations indicating a lack of population structure and possibly high levels of gene flow via seed dispersal in what is predominantly a selfing species. Senecio cambrensis showed closer similarity in AFLP phenotype to S. vulgaris than to S. squalidus. Possible causes of this and also the high level of AFLP diversity found in S. cambrensis are discussed. It is suggested that intergenomic recombination following occasional multivalent formation during meiosis in S. cambrensis is likely to be an important cause of both phenomena, although other causes are not ruled out.

Six new isoflavones and a 5-deoxyflavonol glycoside from the leaves of Ateleiaherbert-smithii.

Six new isoflavones, 5-methoxy-6,7:3',4'-bis(methylenedioxy)isoflavone (1), 3'-methoxy-6,7:4',5'-bis(methylenedioxy)isoflavone (2), 5,2'-dimethoxy-6,7:4',5'-bis(methylenedioxy)isoflavone (3), 5,3'-dimethoxy-6,7:4',5'-bis(methylenedioxy)isoflavone (4), 5-hydroxy-7,3',4'-trimethoxyisoflavone (5), and 5,6,7,3',4'-pentamethoxyisoflavone (6), were obtained from diethyl ether extracts of the leaves of Ateleia herbert-smithii together with 11 known isoflavones and two chalcones. Four of the isoflavones (1-4) are characterized by a unique bis-methylenedioxyl substitution pattern. A new flavonol glycoside, 5-deoxyisorhamnetin 3-O-alpha-l-rhamnopyranosyl(1' " --> 6' ')-beta-d-glucopyranoside (20), and three known flavonol 3-O-glycosides were obtained from aqueous methanol extracts of leaves of the same species. Spectroscopic methods were used to determine the structures of the compounds. The significance of their occurrence in A. herbert-smithii is discussed from both biosynthetic and taxonomic viewpoints.