Waist circumference and a body shape index and prostate cancer risk and mortality.

We recently found a negative association between body mass index (BMI) and the risk of localised prostate cancer (PCa), no association with advanced PCa, and a positive association with PCa-specific mortality. In a 15% subpopulation of that study, we here investigated the measures of abdominal adiposity including waist circumference (WC) and A Body Shape Index (ABSI) in relation to PCa risk and mortality. We used data from 58,457 men from four Swedish cohorts to assess WC and ABSI in relation to PCa risk according to cancer risk category, including localised asymptomatic and symptomatic PCa and advanced PCa, and PCa-specific mortality. Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). During, on average, 10 years of follow-up, 3290 men were diagnosed with PCa and 387 died of PCa. WC was negatively associated with the risk of total PCa (HR per 10 cm, 0.95; 95% CI 0.92-0.99), localised PCa (HR per 10 cm, 0.93, 95% CI 0.88-0.96) and localised asymptomatic PCa cases detected through a prostate-specific antigen (PSA) test (HR per 10 cm, 0.87, 95% CI 0.81-0.94). WC was not associated with the risk of advanced PCa (HR per 10 cm, 1.02, 95% CI 0.93-1.14) or with PCa-specific mortality (HR per 10 cm, 1.04, 95% CI 0.92-1.19). ABSI showed no associations with the risk of PCa or PCa-specific mortality. While the negative association between WC and the risk of localised PCa was partially driven by PSA-detected PCa cases, no association was found between abdominal adiposity and clinically manifest PCa in our population

Height, body mass index and prostate cancer risk and mortality by way of detection and cancer risk category.

Obesity is a risk factor for advanced, but not localised, prostate cancer (PCa), and for poor prognosis. However, the detection of localised PCa through asymptomatic screening might influence these associations. We investigated height and body mass index (BMI) among 431 902 men in five Swedish cohorts in relation to PCa risk, according to cancer risk category and detection mode, and PCa-specific mortality using Cox regression. Statistical tests were two-sided. Height was positively associated with localised intermediate-risk PCa (HR per 5 cm, 1.03, 95% CI 1.01-1.05), while overweight and obesity were negatively associated with localised low- and intermediate-risk PCa (HRs per 5 kg/m2 , 0.86, 95% CI 0.81-0.90, and 0.92, 95% CI 0.88-0.97). However, these associations were partially driven by PCa's detected by asymptomatic screening and, for height, also by symptoms unrelated to PCa. The HR of localised PCa's, per 5 kg/m2 , was 0.88, 95% CI 0.83 to 0.92 for screen-detected PCa's and 0.96, 95% CI 0.90 to 1.01 for PCa's detected through lower urinary tract symptoms. BMI was positively associated with PCa-specific mortality in the full population and in case-only analysis of each PCa risk category (HRs per 5 kg/m2 , 1.11-1.22, P for heterogeneity = .14). More active health-seeking behaviour among tall and normal-weight men may partially explain their higher risk of localised PCa. The higher PCa-specific mortality among obese men across all PCa risk categories in our study suggests obesity as a potential target to improve the prognosis of obese PCa patients

Plasma levels of the proprotein convertase furin and incidence of diabetes and mortality

Background. Diabetes mellitus is linked to premature mortality of virtually all causes. Furin is a proprotein convertase broadly involved in the maintenance of cellular homeostasis; however, little is known about its role in the development of diabetes mellitus and risk of premature mortality. Objectives. To test if fasting plasma concentration of furin is associated with the development of diabetes mellitus and mortality. Methods. Overnight fasted plasma furin levels were measured at baseline examination in 4678 individuals from the population-based prospective Malmo Diet and Cancer Study. We studied the relation of plasma furin levels with metabolic and hemodynamic traits. We used multivariable Cox proportional hazards models to investigate the association between baseline plasma furin levels and incidence of diabetes mellitus and mortality during 21.3-21.7 years follow-up. Results. An association was observed between quartiles of furin concentration at baseline and body mass index, blood pressure and plasma concentration of glucose, insulin, LDL and HDL cholesterol (vertical bar 0.11 vertical bar Conclusion. Individuals with high plasma furin concentration have a pronounced dysmetabolic phenotype and elevated risk of diabetes mellitus and premature mortality.Peer reviewe

Genetic risk of type 2 diabetes modifies the effects of a lifestyle intervention aimed at the prevention of gestational and postpartum diabetes

Aims/hypothesis The aim of this study was to assess the interaction between genetic risk and lifestyle intervention on the occurrence of gestational diabetes mellitus (GDM) and postpartum diabetes. Methods The RADIEL study is an RCT aimed at prevention of GDM and postpartum diabetes through lifestyle intervention. Participants with a BMI >= 30 kg/m(2) and/or prior GDM were allocated to intervention and control groups before pregnancy or in early pregnancy. The study visits took place every 3 months before pregnancy, once in each trimester, and at 6 weeks and 6 and 12 months postpartum. We calculated a polygenic risk score (PRS) based on 50 risk variants for type 2 diabetes. Results Altogether, 516 participants provided genetic and GDM data. The PRS was associated with higher glycaemic levels (fasting glucose and/or HbA(1c)) and a lower insulin secretion index in the second and third trimesters and at 12 months postpartum, as well as with a higher occurrence of GDM and glycaemic abnormalities at 12 months postpartum (n = 356). There was an interaction between the PRS and lifestyle intervention (p=0.016 during pregnancy and p=0.024 postpartum) when analysing participants who did not have GDM at the first study visit during pregnancy (n = 386). When analysing women in tertiles according to the PRS, the intervention was effective in reducing the age-adjusted occurrence of GDM only among those with the highest genetic risk (OR 0.37; 95% CI 0.17, 0.82). The risk of glycaemic abnormalities at 12 months postpartum was reduced in the same group after adjusting additionally for BMI, parity, smoking and education (OR 0.35; 95% CI 0.13, 0.97). Conclusions/interpretation Genetic predisposition to diabetes modifies the response to a lifestyle intervention aimed at prevention of GDM and postpartum diabetes. This suggests that lifestyle intervention may benefit from being tailored according to genetic risk.Peer reviewe

Obesity/insulin resistance rather than liver fat increases coagulation factor activities and expression in humans

Increased liver fat may be caused by insulin resistance and adipose tissue inflammation or by the common I148M variant in PNPLA3 at rs738409, which lacks both of these features. We hypothesised that obesity/insulin resistance rather than liver fat increases circulating coagulation factor activities. We measured plasma prothrombin time (PT, Owren method), activated partial thromboplastin time (APTT), activities of several coagulation factors, VWF:RCo and fibrinogen, and D-dimer concentration in 92 subjects divided into groups based on insulin sensitivity [insulin-resistant ('IR') versus insulin-sensitive ('IS')] and PNPLA3 genotype (PNPLA3(148MM/MI) vs PNPLA3(148II)). Liver fat content (H-1-MRS) was similarly increased in 'IR' (13 +/- 1%) and PNPLA3(148MM/MI) (12 +/- 2%) as compared to 'IS' (6 +/- 1%, pPeer reviewe

A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study

<p>Abstract</p> <p>Background</p> <p>Blood lipid levels including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are highly heritable. Genome-wide association is a promising approach to map genetic loci related to these heritable phenotypes.</p> <p>Methods</p> <p>In 1087 Framingham Heart Study Offspring cohort participants (mean age 47 years, 52% women), we conducted genome-wide analyses (Affymetrix 100K GeneChip) for fasting blood lipid traits. Total cholesterol, HDL-C, and TG were measured by standard enzymatic methods and LDL-C was calculated using the Friedewald formula. The long-term averages of up to seven measurements of LDL-C, HDL-C, and TG over a ~30 year span were the primary phenotypes. We used generalized estimating equations (GEE), family-based association tests (FBAT) and variance components linkage to investigate the relationships between SNPs (on autosomes, with minor allele frequency ≥10%, genotypic call rate ≥80%, and Hardy-Weinberg equilibrium p ≥ 0.001) and multivariable-adjusted residuals. We pursued a three-stage replication strategy of the GEE association results with 287 SNPs (P < 0.001 in Stage I) tested in Stage II (n ~1450 individuals) and 40 SNPs (P < 0.001 in joint analysis of Stages I and II) tested in Stage III (n~6650 individuals).</p> <p>Results</p> <p>Long-term averages of LDL-C, HDL-C, and TG were highly heritable (h²= 0.66, 0.69, 0.58, respectively; each P < 0.0001). Of 70,987 tests for each of the phenotypes, two SNPs had p < 10^-5in GEE results for LDL-C, four for HDL-C, and one for TG. For each multivariable-adjusted phenotype, the number of SNPs with association p < 10^-4ranged from 13 to 18 and with p < 10^-3, from 94 to 149. Some results confirmed previously reported associations with candidate genes including variation in the lipoprotein lipase gene (<it>LPL</it>) and HDL-C and TG (rs7007797; P = 0.0005 for HDL-C and 0.002 for TG). The full set of GEE, FBAT and linkage results are posted at the <b>d</b>ata<b>b</b>ase of <b>G</b>enotype <b>a</b>nd <b>P</b>henotype (dbGaP). After three stages of replication, there was no convincing statistical evidence for association (i.e., combined P < 10^-5across all three stages) between any of the tested SNPs and lipid phenotypes.</p> <p>Conclusion</p> <p>Using a 100K genome-wide scan, we have generated a set of putative associations for common sequence variants and lipid phenotypes. Validation of selected hypotheses in additional samples did not identify any new loci underlying variability in blood lipids. Lack of replication may be due to inadequate statistical power to detect modest quantitative trait locus effects (i.e., <1% of trait variance explained) or reduced genomic coverage of the 100K array. GWAS in FHS using a denser genome-wide genotyping platform and a better-powered replication strategy may identify novel loci underlying blood lipids.</p

Impaired hepatic lipid synthesis from polyunsaturated fatty acids in TM6SF2 E167K variant carriers with NAFLD

Background: Carriers of the transmembrane 6 superfamily member 2 E167K gene variant (TM6SF2(EK/KK)) have decreased expression of the TM6SF2 gene and increased risk of NAFLD and NASH. Unlike common 'obese/metabolic' NAFLD, these subjects lack hypertriglyceridemia and have lower risk of cardiovascular disease. In animals, phosphatidylcholine (PC) deficiency results in a similar phenotype. PCs surround the core of VLDL consisting of triglycerides (TGs) and cholesteryl-esters (CEs). We determined the effect of the TM6SF2 E167K on these lipids in the human liver and serum and on hepatic gene expression and studied the effect of TM6SF2 knockdown on hepatocyte handling of these lipids. Methods: Liver biopsies were taken from subjects characterized with respect to the TM6SF2 genotype, serum and liver lipidome, gene expression and histology. In vitro, after TM6SF2 knockdown in HuH-7 cells, we compared incorporation of different fatty acids into TGs, CEs, and PCs. Results: The TM6SF2(EK/KK) and TM6SF2EE groups had similar age, gender, BMI and HOMA-IR. Liver TGs and CEs were higher and liver PCs lower in the TM6SF2(EK/KK) than the TM6SF2EE group (p Conclusions: Hepatic lipid synthesis from PUFAs is impaired and could contribute to deficiency in PCs and increased intrahepatic TG in TM6SF2 E167K variant carriers. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.Peer reviewe

The PNPLA3-I148M variant increases polyunsaturated triglycerides in human adipose tissue

Background & Aims The I148M variant in PNPLA3 is the major genetic risk factor for non-alcoholic fatty liver disease (NAFLD). The liver is enriched with polyunsaturated triglycerides (PUFA-TGs) in PNPLA3-I148M carriers. Gene expression data indicate that PNPLA3 is liver-specific in humans, but whether it functions in adipose tissue (AT) is unknown. We investigated whether PNPLA3-I148M modifies AT metabolism in human NAFLD. Methods Profiling of the AT lipidome and fasting serum non-esterified fatty acid (NEFA) composition was conducted in 125 volunteers (PNPLA3(148MM/MI), n = 63; PNPLA3(148II), n = 62). AT fatty acid composition was determined in 50 volunteers homozygous for the variant (PNPLA3(148MM), n = 25) or lacking the variant (PNPLA3(148II), n = 25). Whole-body insulin sensitivity of lipolysis was determined using [H-2(5)]glycerol, and PNPLA3 mRNA and protein levels were measured in subcutaneous AT and liver biopsies in a subset of the volunteers. Results PUFA-TGs were significantly increased in AT in carriers versus non-carriers of PNPLA3-I148M. The variant did not alter the rate of lipolysis or the composition of fasting serum NEFAs. PNPLA3 mRNA was 33-fold higher in the liver than in AT (P <.0001). In contrast, PNPLA3 protein levels per tissue protein were three-fold higher in AT than the liver (P <.0001) and nine-fold higher when related to whole-body AT and liver tissue masses (P <.0001). Conclusions Contrary to previous assumptions, PNPLA3 is highly abundant in AT. PNPLA3-I148M locally remodels AT TGs to become polyunsaturated as it does in the liver, without affecting lipolysis or composition of serum NEFAs. Changes in AT metabolism do not contribute to NAFLD in PNPLA3-I148M carriers.Peer reviewe

Associations of common polymorphisms in GCKR with type 2 diabetes and related traits in a Han Chinese population: a case-control study

<p>Abstract</p> <p>Background</p> <p>Several studies have shown that variants in the glucokinase regulatory protein gene (<it>GCKR</it>) were associated with type 2 diabetes and dyslipidemia. The purpose of this study was to examine whether tag single nucleotide polymorphisms (SNPs) in the <it>GCKR </it>region were associated with type 2 diabetes and related traits in a Han Chinese population and to identify the potential mechanisms underlying these associations.</p> <p>Methods</p> <p>We investigated the association of polymorphisms in the <it>GCKR </it>gene with type 2 diabetes by employing a case-control study design (1118 cases and 1161 controls). Four tag SNPs (rs8179206, rs2293572, rs3817588 and rs780094) with pairwise r²> 0.8 and minor allele frequency > 0.05 across the <it>GCKR </it>gene and its flanking regions were studied and haplotypes were constructed. Genotyping was performed by matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy using a MassARRAY platform.</p> <p>Results</p> <p>The G alleles of <it>GCKR </it>rs3817588 and rs780094 were associated with an increased risk of type 2 diabetes after adjustment for year of birth, sex and BMI (OR = 1.24, 95% CI 1.08-1.43, p = 0.002 and OR = 1.22, 95% CI 1.07-1.38, p = 0.002, respectively). In the non-diabetic controls, the GG carriers of rs3817588 and rs780094 were nominally associated with a lower plasma triglyceride level compared to the AA carriers after adjustment for year of birth, sex and BMI (p for trend = 0.00004 and 0.03, respectively). Furthermore, the association of rs3817588 with plasma triglyceride level was still significant after correcting for multiple testing.</p> <p>Conclusions</p> <p>The rs3817588 A/G polymorphism of the <it>GCKR </it>gene was associated with type 2 diabetes and plasma triglyceride level in the Han Chinese population.</p