| 1. |
- Sarwar, Nadeem, et al.
(författare)
-
Interleukin-6 receptor pathways in coronary heart disease : a collaborative meta-analysis of 82 studies
- 2012
-
Ingår i: The Lancet. - New York, NY, USA : Elsevier. - 0140-6736 .- 1474-547X. ; 379:9822, s. 1205-1213
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings: The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele >= 0.04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34.3% (95% CI 30.4-38.2) and of interleukin 6 by 14.6% (10.7-18.4), and mean concentration of C-reactive protein was reduced by 7.5% (5.9-9.1) and of fibrinogen by 1.0% (0.7-1.3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3.4% (1.8-5.0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.
|
|
| 2. |
- Roos, Vendela, et al.
(författare)
-
Metabolic Syndrome Development during Aging with Special Reference to Obesity Without the Metabolic Syndrome
- 2017
-
Ingår i: Metabolic syndrome and related disorders. - : Mary Ann Liebert Inc. - 1540-4196 .- 1557-8518. ; 15:1, s. 36-43
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Obesity and its associated metabolic complications continue to increase worldwide. We investigated the development of metabolic syndrome (MetS) during aging in relation to body mass index (BMI) and exercise habits. We assigned special emphasis to the metabolic stability in individuals with obesity, but without MetS, a condition often referred to as metabolically healthy obesity. Materials and Methods: Cross-sectional analysis was carried out in a sample of 19,129 men and women aged 45-75 years from the EpiHealth study. In addition, longitudinal analyses were carried out in the ULSAM study (2322 men at baseline followed from age 50 to age 77) and in the PIVUS study (1016 men and women at baseline followed from age 70 to age 80). Participants were categorized into six groups according to BMI category (normal weight/BMI <25 kg/m2, overweight/BMI 25-30 kg/m2, and obesity/BMI >30 kg/m2) and MetS status (+/-, National Cholesterol Education Program criteria). Results: MetS prevalence and number of MetS components increased with age in all three samples. The PIVUS study showed that high baseline BMI, low baseline physical activity, and increasing BMI during follow-up were related to increasing MetS prevalence and increasing numbers of MetS components during follow-up. One-third to half of individuals initially belonging to the obesity without MetS category acquired MetS during aging. Conclusions: MetS prevalence increased during aging, especially in individuals with high BMI, low level of physical activity, and weight gain. Obesity without MetS was not a stable condition over time as many of those individuals gained metabolic disturbances during aging.
|
|
| 3. |
- Roos, Vendela, et al.
(författare)
-
Alterations in multiple lifestyle factors in subjects with the metabolic syndrome independently of obesity
- 2017
-
Ingår i: Metabolic Syndrome and Related Disorders. - : Mary Ann Liebert Inc. - 1540-4196 .- 1557-8518. ; 15:3, s. 118-123
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Many lifestyle factors have been associated with the metabolic syndrome (MetS). However, most of these studies have not considered the potential impact of obesity and have often only investigated one lifestyle factor at the time. We aimed to investigate the interplay between body mass index (BMI) and MetS with respect to multiple lifestyle factors.METHODS: BMI and MetS [National Cholesterol Education Program (NCEP)/Adult Treatment Panel III criteria] were assessed in a sample of 18,880 subjects aged 45-75 years from the population-based EpiHealth study. Participants were categorized into six groups according to BMI category (normal weight/BMI <25 kg/m(2), overweight/BMI 25-30 kg/m(2), and obesity/BMI >30 kg/m(2)) and MetS status (+/-, NCEP criteria). A wide range of lifestyle factors related to physical activity, smoking, alcohol, sleep quality, working conditions, quality of life and stress, and eating patterns were assessed using a questionnaire.RESULTS: Prevalent MetS (23% in the sample) was associated with less physical activity (P < 0.0001), more TV watching (P < 0.0001), more years of smoking (P < 0.0001), lower education level (P = 0.007), and experiencing a poor general quality of life (P < 0.0001). These lifestyle factors were all associated with MetS, independently of each other and independently of BMI. Similar results were generated when number of MetS components and presence/absence of individual MetS components were used as outcomes.CONCLUSIONS: This cross-sectional study identified alterations in a number of lifestyle factors associated with MetS independently of each other and independently of BMI. Future longitudinal studies are needed to assess causal and temporal relationships between lifestyle factors and MetS development.
|
|
| 4. |
- Lind, Lars, et al.
(författare)
-
Cardiometabolic Proteins Associated with Metabolic Syndrome
- 2019
-
Ingår i: Metabolic syndrome and related disorders. - : Mary Ann Liebert Inc. - 1557-8518 .- 1540-4196. ; 17:5, s. 272-279
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Although metabolic syndrome (MetS) was described in the late 80s, the molecular mechanisms underlying clustering of risk factors in certain individuals are not fully understood. The present study used targeted proteomics to establish cardiometabolic proteins related to all MetS components, thereby providing new hypotheses regarding pathways involved in the pathogenesis of MetS. Methods: In the EpiHealth study, 249 cardiometabolic proteins were measured by proximity extension assay (PEA) and related to the five MetS components [consensus-modified National Cholesterol Education Program (NCEP) criteria] in 2,444 participants aged 45-75 years (50% women). Results: Thirty-one proteins were associated with systolic blood pressure following adjustment for age and sex (P < 0.000040, taking multiple testing into account). The corresponding number of proteins significantly associated with fasting glucose, waist circumference, high-density lipoprotein cholesterol, and serum triglycerides were 58, 132, 127, and 148. Twenty-two proteins were significantly related to all 5 MetS components, and of those, 20 were with MetS as a binary outcome (n = 600, 24% of the sample) following adjustment for age, sex, fat mass, and lifestyle factors (alcohol intake, smoking, education, and exercise habits). Conclusion: Using targeted proteomics, we identified 20 proteins reflecting a range of pathways, such as immunomodulation at different levels; regulation of adipocyte differentiation; lipid, carbohydrate, and amino acid metabolism; or insulin-like growth factor signaling, to be strongly associated with MetS independently of fat mass and lifestyle factors. Whether some of these proteins are causally involved in the pathogenesis of clustering of multiple risk factors in the same individual remains to be investigated.
|
|
| 5. |
- Lind, Lars, et al.
(författare)
-
A detailed cardiovascular characterization of obesity without the metabolic syndrome
- 2011
-
Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : American Heart Association. - 1079-5642 .- 1524-4636. ; 31:8, s. e27-e34
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Although obesity without metabolic disturbances has been regarded as harmless, we have recently shown that obese subjects without the metabolic syndrome (MetS) has an increased risk of cardiovascular (CV) disorders and mortality during long-term follow-up. To investigate the basis for that increased risk, we studied the impact of obesity without MetS on multiple markers of subclinical CV disease.Methods and results: At age 70, 1016 subjects were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors study. According to body mass index (BMI)/MetS status, they were categorized as normal weight (BMI <25 kg/m2) without MetS (National Cholesterol Education Program criteria, n=319), normal weight with MetS (n=19), overweight (BMI 25 to 29.9 kg/m2) without MetS (n=333), overweight with MetS (n=94), obese (BMI =30 kg/m2) without MetS (n=102), and obese with MetS (n=118). Several different measurements of endothelial reactivity, arterial compliance (plethysmography and ultrasound), carotid artery atherosclerosis, and echocardiography were performed, and 7 markers of coagulation/fibrinolysis were measured. Subjects with obesity without MetS showed impaired vasoreactivity, a more echolucent carotid artery wall, increased left ventricular mass and function together with impaired coagulation/fibrinolysis compared with normal-weight subjects without the MetS (P<0.05 to 0.001). The majority of these disturbances were also seen in overweight subjects without the MetS.Conclusion: In contrast to some previous studies, our data do not support that obesity without MetS is a benign condition, because obesity without MetS was associated with impairments in multiple markers of subclinical CV disease. This was also the case for overweight subjects without the MetS.
|
|
| 6. |
- Lind, Lars, et al.
(författare)
-
Can the Plasma Concentration Ratio of Triglyceride/High-Density Lipoprotein Cholesterol Identify Individuals at High Risk of Cardiovascular Disease During 40-Year Follow-Up?
- 2018
-
Ingår i: Metabolic Syndrome and Related Disorders. - : Mary Ann Liebert Inc. - 1540-4196 .- 1557-8518. ; 16:8, s. 433-439
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The plasma concentration ratio of triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) is a simple way to estimate insulin resistance. We aimed to evaluate the TG/HDL-C ratio as a simple clinical way to identify apparently healthy individuals with insulin resistance and enhanced risk of future cardiovascular disease (CVD).METHODS: One thousand seven hundred twenty men, aged 50 years, free from diabetes and CVD when evaluated at baseline in 1970-1974 were followed for 40 years regarding incident CVD (myocardial infarction and/or ischemic stroke, n = 576).RESULTS: Participants with a high TG/HDL-C ratio (highest quartile >1.8) at baseline were more insulin resistant, with a significantly more adverse cardiometabolic risk profile (P < 0.001) at baseline, compared with those with a lower ratio. This group also showed an increased risk of CVD [hazard ratio, HR 1.47 (95% confidence interval 1.26-1.93) P < 0.001]. Fourteen percent of subjects with metabolic syndrome, in whom insulin resistance is increased, were also at enhanced CVD risk [HR 1.75 (1.42-2.16) P < 0.001].CONCLUSIONS: Twenty-five percent of apparently healthy 50-year-old men with the highest TG/HDL-C plasma concentration ratio had a significantly more adverse cardiometabolic profile at baseline, and developed more CVD over the next 40 years, compared with those not meeting this cut point. Determining the TG/HDL-C ratio in middle-aged men provided a simple and potentially clinically useful way to identify increased risk of developing CVD in persons free of diabetes or manifest CVD.
|
|
| 7. |
- Saxena, Richa, et al.
(författare)
-
Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge
- 2010
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:2, s. 142-148
-
Tidskriftsartikel (refereegranskat)abstract
- Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958–30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, β (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 × 10−15). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 × 10−17; ratio of insulin to glucose area under the curve, P = 1.3 × 10−16) and diminished incretin effect (n = 804; P = 4.3 × 10−4). We also identified variants at ADCY5 (rs2877716, P = 4.2 × 10−16), VPS13C (rs17271305, P = 4.1 × 10−8), GCKR (rs1260326, P = 7.1 × 10−11) and TCF7L2 (rs7903146, P = 4.2 × 10−10) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09–1.15, P = 4.8 × 10−18).
|
|
| 8. |
- Knowles, Joshua W., et al.
(författare)
-
Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene
- 2015
-
Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 125:4, s. 1739-1751
-
Tidskriftsartikel (refereegranskat)abstract
- Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.
|
|
| 9. |
- Carlsson, Axel C, et al.
(författare)
-
Growth differentiation factor 15 (GDF-15) is a potential biomarker of both diabetic kidney disease and future cardiovascular events in cohorts of individuals with type 2 diabetes : a proteomics approach
- 2020
-
Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 25:1, s. 37-43
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Diabetic kidney disease (DKD) is a leading risk factor for end-stage renal disease and is one of the most important risk factors for cardiovascular disease in patients with diabetes. It is possible that novel markers portraying the pathophysiological underpinning processes may be useful.Aim: To investigate the associations between 80 circulating proteins, measured by a proximity extension assay, and prevalent DKD and major adverse cardiovascular events (MACE) in type 2 diabetes.Methods: We randomly divided individuals with type 2 diabetes from three cohorts into a two-thirds discovery and one-third replication set (total n = 813, of whom 231 had DKD defined by estimated glomerular filtration rate <60 mg/mL/1.73 m2 and/or urinary albumin-creatinine ratio ≥3 g/mol). Proteins associated with DKD were also assessed as predictors for incident major adverse cardiovascular events (MACE) in persons with DKD at baseline.Results: Four proteins were positively associated with DKD in models adjusted for age, sex, cardiovascular risk factors, glucose control, and diabetes medication: kidney injury molecule-1 (KIM-1, odds ratio [OR] per standard deviation increment, 1.65, 95% confidence interval [CI] 1.27-2.14); growth differentiation factor 15 (GDF-15, OR 1.40, 95% CI 1.16-1.69); myoglobin (OR 1.57, 95% CI 1.30-1.91), and matrix metalloproteinase 10 (MMP-10, OR 1.43, 95% CI 1.17-1.74). In patients with DKD, GDF-15 was significantly associated with increased risk of MACE after adjustments for baseline age, sex, microalbuminuria, and kidney function and (59 MACE events during 7 years follow-up, hazard ratio per standard deviation increase 1.43 [95% CI 1.03-1.98]) but not after further adjustments for cardiovascular risk factors.Conclusion: Our proteomics approach confirms and extends previous associations of higher circulating levels of GDF-15 with both micro- and macrovascular disease in patients with type 2 diabetes. Our data encourage additional studies evaluating the clinical utility of our findings.
|
|
| 10. |
- Locke, Adam E, et al.
(författare)
-
Genetic studies of body mass index yield new insights for obesity biology.
- 2015
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
-
Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
|
|
