[Show abstract][Hide abstract] ABSTRACT: Background/objectives: To examine whether higher fasting plasma glucose (FPG) levels were independently associated with left ventricular (LV) mass and/or geometry in elderly, otherwise healthy subjects.
Methods: We tested cross-sectional associations between echocardiographically determined LV mass/geometric patterns, cardiovascular risk factors, and FPG categorized as normal fasting glucose (NFG), impaired fasting glucose (IFG), and untreated diabetes mellitus (DM), in 486 men and 207 women aged 56–79 years without overt cardiovascular disease, who received no cardiovascular, anti-diabetic, or lipid-lowering drugs and had a preserved LV ejection fraction >50%.
Results: Unadjusted mean LV mass index (LVMI) was significantly greater among subjects with DM than those without (90 +/− 26 g/m2 vs. 85 +/− 20 g/m2, p = 0.01), as were both relative wall thickness (RWT)
(0.43 +/− 0.09 vs. 0.40 +/− 0.08, p = 0.01) and prevalence of concentric LV hypertrophy (LVH) (11% vs. 6%,
p = 0.03). However, only RWT remained significantly associated with the presence of DM after multivariable adjustment (p = 0.04). Interaction analyses revealed that greater LVMI/LVH was predominantly associated with higher levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) among subjects with IFG orDM, but notNFG.
Conclusions: Subjects with untreated DMhad higher values of LVMI and a greater prevalence of concentric LVH, but the associations were not independent of other risk factors. NT-proBNP was primarily associated with greater LV size in subjects with IFG or DM.
IJC Metabolic and Endocrine 12/2015; 9:39-47. DOI:10.1016/j.ijcme.2015.10.005
[Show abstract][Hide abstract] ABSTRACT: We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
[Show abstract][Hide abstract] ABSTRACT: Objective:
The purpose of the study was to investigate the long-term associations between smoking habits, environmental tobacco smoke exposure (ETS), carotid intima-media thickness (IMT) progression rate, and rate of lumen diameter reduction in the carotid artery during a 16-year follow-up. Another objective was to investigate if an effect of smoking on progression rate could be explained by increased low grade inflammation.
The study population included 2992 middle-aged men and women in the 1991-1994 (baseline) and the 2007-2012 (re-examination) investigation of the Malmö Diet and Cancer Study cardiovascular cohort. Associations between smoking, progression of carotid IMT and lumen diameter reduction due to plaque protrusion were assessed by linear regression.
IMT progression rates and rate of lumen diameter reduction increased from never smokers with no ETS through former, moderate and heavy smokers, even after adjustment for traditional risk factors (e.g., differences in yearly progression rates (mm/year) of maximal IMT in the carotid bifurcation compared to never smokers; former smokers 0.0074 (95% CI: 0.0018-0.0129), moderate smokers 0.0106 (95% CI: 0.0038-0.0175), and heavy smokers 0.0146 (95% CI: 0.0061-0.0230)). Former smokers showed distinct lowering of progression rates after more than five years since smoking cessation. Smoking and former smoking was associated with increased low grade inflammation, however, the effect of smoking on atherosclerotic progression rate remained fairly unchanged after such adjustment.
The effect of smoking and former smoking on carotid IMT progression rates and change in lumen reduction due to plaque protrusion could not be explained by differences in traditional risk factors or low grade inflammation.
European Journal of Internal Medicine 11/2015; DOI:10.1016/j.ejim.2015.10.018 · 2.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
Recently, imbalance in the vasopressin (AVP) system, measured as elevated levels of copeptin (the c-terminal part of the AVP pro-hormone) in plasma, was linked to development of abdominal obesity and diabetes mellitus (DM). Here, we aim to investigate if genetic variation of the human AVP receptor 1b gene (AVPR1B) is associated with measures of obesity and DM.
Malmö Diet and Cancer study (MDC) is a population-based prospective cohort examined 1991-1996.
Four tag SNPs (rs35810727, rs28373064, rs35439639, rs35608965) of AVPR1B were genotyped in the cardiovascular cohort (n=6 103) of MDC (MDC-CC) and associated with measures of obesity and DM. Significant SNPs were replicated in another 24 344 MDC individuals (MDC replication cohort).
In MDC-CC, the major allele of rs35810727 was associated with elevated BMI (beta-coefficient ± SE; 0.30 ± 0.14, P=0.03) and waist (0.78 ± 0.36, P=0.03) after age and gender adjustment. The association with BMI was replicated in the MDC replication cohort (0.21 ± 0.07, P=0.003), whereas that with waist was not significant. In MDC-CC there was no association between the major allele of rs35810727 and DM, but in the complete MDC cohort (n=30 447) the major allele of rs35810727 was associated with DM (OR (95% CI); 1.10 (1.00-1.20), P=0.04).
Genetic variance of AVPR1B contributes to overweight. Furthermore, our data indicate a link between AVPR1B variance and DM development. Our data point at a relationship between disturbance of the pharmacologically modifiable AVP system and body weight regulation.
European Journal of Endocrinology 10/2015; 174(1). DOI:10.1530/EJE-15-0781 · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the pro-atherogenic cytokine osteopontin (OPN) in mouse arteries, via local release of endothelin-1 (ET-1) and activation of cAMP response element binding protein (CREB). Infusion of GIP increases plasma OPN levels in healthy individuals. Plasma ET-1 and OPN levels are positively correlated in patients with critical limb ischemia. Fasting GIP levels are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared to controls. GIP receptor (GIPR) and OPN mRNA levels are higher in carotid endarterectomies from patients with symptoms (stroke, transient ischemic attacks, amaurosis fugax) than in asymptomatic patients; and expression associates to parameters characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from human, mouse, rat and pig; remarkable up-regulation is observed in endothelial and smooth muscle cells upon culture conditions yielding a "vascular disease-like" phenotype. Moreover, a common variant rs10423928 in the GIPR gene associated with increased risk of stroke in type 2 diabetes patients.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND/OBJECTIVE:Genome-wide-association studies have identified numerous BMI-associated variants, but it is unclear how these relate to weight gain in adults at different ages.
METHODS: We examined the association of a genetic risk score (GRS), consisting of 31 BMI-associated variants, with an annual weight gain (AWG) and a substantial weight gain (SWG) of 10% by comparing self-reported weight at 20 years (y) with baseline weight (mean: 58 y; standard deviation (s.d.): 8y) in 21407 participants from the Malmö Diet and Cancer Study (MDCS), and comparing baseline weight to weight at follow-up (mean: 73y; s.d.: 6y) among 2673 participants. Association between GRS and AWG and SWG was replicated in 4327 GLACIER participants (mean: 45y; s.d.: 7y) with 10y follow-up. Cohort-specific results were pooled by fixed-effect meta-analyses.
RESULTS: In MDCS, the GRS was associated with increased AWG (β: 0.003; s.e: 0.01; P: 7 × 10-8) and increased odds for SWG (odds ratio (OR) 1.01 (95% confidence interval (CI): 1.00, 1.02); P: 0.013) per risk-allele from age 20y, but unexpectedly with decreased AWG (β: -0.006; s.e: 0.002; P: 0.009) and decreased odds for SWG OR 0.96 (95% CI: 0.93, 0.98); P: 0.001) between baseline and follow-up. Effect estimates from age 20y to baseline differed significantly from those from baseline to follow-up (P: 0.0002 for AWG and P: 0.0001 for SWG). Similar to MDCS, the GRS was associated with decreased odds for SWG OR 0.98 (95% CI: 0.96, 1.00); P: 0.029) from baseline to follow-up in GLACIER. In meta-analyses (n=7000), the GRS was associated with decreased AWG (β: -0.005; s.e: 0.002; P: 0.002) and decreased odds for SWG OR 0.97 (95% CI: 0.96, 0.99); P: 0.001) per risk-allele.
CONCLUSION: Our results provide convincing evidence for a paradoxical inversed relationship between a high number of BMI-associated risk-alleles and less weight gain during and after middle-age, in contrast to the expected increased weight gain seen in younger age.
International Journal of Obesity 09/2015; 10.1038/ijo.2015.180. DOI:10.1038/ijo.2015.180 · 5.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background/objective:
The present study tested the hypothesis that obesity-related changes in carotid intima-media thickness (IMT) might represent not only preclinical atherosclerosis but an adaptive remodeling meant to preserve circumferential wall stress (CWS) in altered hemodynamic conditions characterized by body size-dependent increase in stroke volume (SV) and blood pressure (BP).
Common carotid artery (CCA) luminal diameter (LD), IMT and CWS were measured in three different populations in order to study: (A) cross-sectional associations between SV, BP, anthropometric parameters and CCA LD (266 healthy subjects with wide range of body weight (24-159 kg)); (B) longitudinal associations between CCA LD and 3-year IMT progression rate (ΔIMT; 571 healthy non-obese subjects without increased cardiovascular (CV) risk); (C) the impact of obesity on CCA geometry and CWS (88 obese subjects without CV complications and 88 non-obese subjects matched for gender and age).
CCA LD was independently associated with SV that was determined by body size. In the longitudinal study, baseline LD was an independent determinant of ΔIMT, and ΔIMT of subjects in the highest LD quartile was significantly higher (28±3 μm) as compared with those in the lower quartiles (8±3, 16±4 and 16±3 μm, P=0.001, P<0.05 and P=0.01, respectively). In addition, CCA CWS decreased during the observational period in the highest LD quartile (from 54.2±8.6 to 51.6±7.4 kPa, P<0.0001). As compared with gender- and age-matched lean individuals, obese subjects had highly increased CCA LD and BP (P<0.0001 for both), but only slightly higher CWS (P=0.05) due to a significant increase in IMT (P=0.005 after adjustment for confounders).
Our findings suggest that in obese subjects, the CCA wall thickens to compensate the luminal enlargement caused by body size-induced increase in SV, and therefore, to normalize the wall stress. CCA diameter in obesity could represent an additional biomarker, depicting the impact of altered hemodynamics on arterial wall.
[Show abstract][Hide abstract] ABSTRACT: Arterial stiffness is an independent risk factor for cardiovascular morbidity and can be assessed by applanation tonometry by measuring pulse wave velocity (PWV) and augmentation index (AIX) by pressure pulse wave analysis (PWA). As an inexpensive and operator independent alternative, photoelectric plethysmography (PPG) has been introduced with analysis of the digital volume pulse wave (DPA) and its second derivatives of wave reflections.
The objective was to investigate the repeatability of arterial stiffness parameters measured by digital pulse wave analysis (DPA) and the associations to applanation tonometry parameters.
112 pregnant and non-pregnant individuals of different ages and genders were examined with SphygmoCor arterial wall tonometry and Meridian DPA finger photoplethysmography. Coefficients of repeatability, Bland-Altman plots, intraclass correlation coefficients and correlations to heart rate (HR) and body height were calculated for DPA variables, and the DPA variables were compared to tonometry variables left ventricular ejection time (LVET), PWV and AIX. No DPA variable showed any systematic measurement error or excellent repeatability, but dicrotic index (DI), dicrotic dilatation index (DDI), cardiac ejection elasticity index (EEI), aging index (AI) and second derivatives of the crude pulse wave curve, b/a and e/a, showed good repeatability. Overall, the correlations to AIX were better than to PWV, with correlations coefficients >0.70 for EEI, AI and b/a. Considering the level of repeatability and the correlations to tonometry, the overall best DPA parameters were EEI, AI and b/a. The two pansystolic time parameters, ejection time compensated (ETc) by DPA and LVET by tonometry, showed a significant but weak correlation.
For estimation of the LV function, ETc, EEI and b/a are suitable, for large artery stiffness EEI, and for small arteries DI and DDI. The only global parameter, AI, showed a high repeatability and the overall best correlations with AIX and PWV.
PLoS ONE 08/2015; 10(8):e0135659. DOI:10.1371/journal.pone.0135659 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Obesity is a disorder that develops from the interaction between genotype and environment involving social, behavioral, cultural, and physiological factors. Obesity increases the risk for type 2 diabetes mellitus, hypertension, cardiovascular disease, cancer, musculoskeletal disorders, chronic kidney and pulmonary disease. Although obesity is clearly associated with an increased prevalence of hypertension, many obese individuals may not develop hypertension. Protecting factors may exist and it is important to understand why obesity is not always related to hypertension. The aim of this review is to highlight the knowledge gap for the association between obesity, hypertension, and potential genetic and racial differences or environmental factors that may protect obese patients against the development of hypertension and other co-morbidities. Specific mutations in the leptin and the melaninocortin receptor genes in animal models of obesity without hypertension, the actions of α-melanocyte stimulating hormone, and SNS activity in obesity-related hypertension may promote recognition of protective and promoting factors for hypertension in obesity. Furthermore, gene-environment interactions may have the potential to modify gene expression and epigenetic mechanisms could also contribute to the heritability of obesity-induced hypertension. Finally, differences in nutrition, gut microbiota, exposure to sun light and exercise may play an important role in the presence or absence of hypertension in obesity.
Journal of Hypertension 06/2015; 33(8). DOI:10.1097/HJH.0000000000000645 · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
The observational relationship between obesity and periodontitis is widely known, yet causal evidence is lacking. Our objective was to investigate causal associations between periodontitis and body mass index (BMI).
We performed Mendelian randomization analyses with BMI-associated loci combined in a genetic risk score (GRS) as the instrument for BMI. All analyses were conducted within the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium in 13 studies from Europe and the USA, including 49,066 participants with clinically assessed (seven studies, 42.1% of participants) and self-reported (six studies, 57.9% of participants) periodontitis and genotype data (17,672/31,394 with/without periodontitis); 68,761 participants with BMI and genotype data; and 57,871 participants (18,881/38,990 with/without periodontitis) with data on BMI and periodontitis.
In the observational meta-analysis of all participants, the pooled crude observational odds ratio (OR) for periodontitis was 1.13 [95% confidence interval (CI): 1.03, 1.24] per standard deviation increase of BMI. Controlling for potential confounders attenuated this estimate (OR = 1.08; 95% CI:1.03, 1.12). For clinically assessed periodontitis, corresponding ORs were 1.25 (95% CI: 1.10, 1.42) and 1.13 (95% CI: 1.10, 1.17), respectively. In the genetic association meta-analysis, the OR for periodontitis was 1.01 (95% CI: 0.99, 1.03) per GRS unit (per one effect allele) in all participants and 1.00 (95% CI: 0.97, 1.03) in participants with clinically assessed periodontitis. The instrumental variable meta-analysis of all participants yielded an OR of 1.05 (95% CI: 0.80, 1.38) per BMI standard deviation, and 0.90 (95% CI: 0.56, 1.46) in participants with clinical data.
Our study does not support total adiposity as a causal risk factor for periodontitis, as the point estimate is very close to the null in the causal inference analysis, with wide confidence intervals.
International Journal of Epidemiology 06/2015; 44(2). DOI:10.1093/ije/dyv075 · 9.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: To determine whether baseline hemodynamic and/or glucometabolic risk factors could predict renal function at follow-up, independently of baseline serum creatinine, in survivors from a random population sample. Design and method: We examined associations between baseline serum creatinine, hemodynamic factors (systolic blood pressure (SBP), heart rate (HR)), glucometabolic factors (fasting plasma glucose and insulin, 2-hour plasma glucose and insulin during oral glucose tolerance test (OGTT), a modified 40 minute oral disposition index (DIo), and Homeostatic Model Assessment (HOMA) derived indices of beta-cell function (HOMA-2B), insulin sensitivity (HOMA-2S), and insulin resistance (HOMA-2IR)), traditional cardiovascular risk factors (age, sex, smoking status, body mass index, diabetes mellitus, total serum cholesterol), and later renal function determined as serum cystatin C in 238 men and 7 women aged 38 to 49 years at the time of inclusion, using multivariable linear regression analysis (p-entry 0.05, p-removal 0.20). Study subjects came from a random population based sample and were included 1974-1992, whilst the follow-up with cystatin C measurement was performed 2002-2006. Results: Mean (+/- s.d.) follow-up time, creatinine, and cystatin C were 28 +/- 1 years, 94 +/- 12 micromoles/L, and 1.220 +/- 0.298 mg/L. Mean estimated glomerular filtration rates at baseline and follow-up were 84 +/- 12 mL/min/1.73m2 and 68 +/- 18 mL/min/1.73m2. In univariate analyses, cystatin C was positively associated with age, female sex, SBP, HOMA-2B, creatinine, and the time elapsed between inclusion and follow-up. In multivariable analysis, age (beta = 0.013 (95% confidence interval (CI), 0.002 to 0.024); p < 0.02), female sex (beta = 0.271 (95% CI, 0.036 to 0.506); p = 0.02), creatinine (beta = 0.007 (95% CI, 0.004 to 0.010); p < 0.001), and time span (beta = 0.062 (95% CI, 0.018 to 0.106); p = 0.006) remained significantly associated with cystatin C. We did not detect any significant interactions between SBP, HOMA-2B, and the other risk factors. Conclusions: Although SBP and HOMA-2B were both associated with later renal function as assessed by serum cystatin C, none of them remained significant in a multivariable model adjusted for age, sex, serum creatinine, and time from inclusion to follow-up. Copyright
Journal of Hypertension 06/2015; 33:e352. DOI:10.1097/01.hjh.0000468464.05356.c6 · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: To explore possible hemodynamic and metabolic determinants of diastolic dysfunction in a random population sample. Design and method: We examined associations between hemodynamic factors (systolic blood pressure (SBP), heart rate (HR)), metabolic factors (fasting insulin, fasting plasma glucose, 2-hour glucose during oral glucose tolerance test (OGTT), oral disposition index (DIo), and Homeostatic Model Assessment (HOMA) derived indices of beta-cell function (HOMA-2B), insulin sensitivity (HOMA-2S), and insulin resistance (HOMA-2IR)), other traditional cardiovascular risk factors, and later detection of grade 2 or 3 diastolic dysfunction (DD) in 243 men and 22 women aged 28 to 57 years at the time of inclusion, using binary logistic regression analysis. Study subjects came from a random population based sample and were included 1974-1992, whilst the echocardiography was performed 2002-2006. Results: After a mean follow-up time of 27 years, grade 2 or 3 diastolic dysfunction was detected in 34% (n = 89) of subjects. In univariate analyses (significance level 0.05), diastolic dysfunction was associated with age, sex, heart rate, systolic blood pressure, fasting insulin levels, 2-hour glucose levels, HOMA-2B, HOMA-2S, HOMA-2IR, and the time elapsed between inclusion and echocardiography. In multivariable analysis (significance level 0.20), sex (odds ratio (OR) = 6.08 (95% confidence interval (CI), 1.26-29.25); p = 0.02), heart rate (OR = 1.02 (95% CI, 0.996-1.05); p = 0.1), HOMA-2B (OR = 1.01 (95% CI, 1.00-1.01); p = 0.051), and time span (OR = 1.84 (95% CI, 1.73-1.96); p = 0.01), remained significantly associated with diastolic dysfunction, whereas age was forced into the model (OR = 1.03 (95% CI, 0.96-1.11); p = 0.41). We did not detect any significant interactions between HOMA-2B and other variables in the prediction of diastolic dysfunction. Conclusions: In a binary logistic regression model adjusted for age, sex, and time, HOMA-2B was significantly associated with the development of grade 2 or 3 diastolic dysfunction. It is suggested that subjects with increased HOMA-2B values may be at greater cardiovascular risk. Copyright
Journal of Hypertension 06/2015; 33:e202. DOI:10.1097/01.hjh.0000467960.60608.5d · 4.72 Impact Factor