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  • Ahluwalia, Tarunveer S., et al. (författare)
  • A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes : results from an exome-wide association study of albuminuria
  • 2019
  • Ingår i: Diabetologia. - : Springer. - 0012-186X. ; 62:2, s. 292-305
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims/hypothesis: Identifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants. Methods: We performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included. Results: We identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, β = 0.27, p = 1.3 × 10−11) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (pinteraction = 7.0 × 10−4, β with diabetes = 0.69, β without diabetes = 0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (pBonferroni < 2.7 × 10−6). Conclusions/interpretation: The current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. The findings provide new insights into the genetic architecture of albuminuria and highlight target genes and pathways for the prevention of diabetes-related kidney disease.
  • Bao, Xue, et al. (författare)
  • Growth differentiation factor-15 and incident chronic kidney disease : a population-based cohort study
  • 2021
  • Ingår i: BMC Nephrology. - : BioMed Central (BMC). - 1471-2369. ; 22:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The relationship between growth differentiation factor 15 (GDF-15) and the development of chronic kidney disease (CKD) is still unclear. We sought to examine whether plasma GDF-15 was related to incident CKD and kidney function decline using a large prospective cohort study. Methods: 4318 participants of the Malmö Diet and Cancer Study-Cardiovascular Cohort were examined in 1991-1994. Incidence of CKD was followed prospectively by linkage with national patient registers. Estimated glomerular filtration rate (eGFR) was available for all participants at baseline, and was re-measured in a subgroup of 2744 subjects after 16.6 ± 1.49 years. Incidence of CKD was examined in relation to GDF-15 using Cox regression analysis. Logistic regression was used to examine the association of GDF-15 with eGFR change and eGFR-based CKD. Models were carefully corrected for potential confounders including baseline eGFR, N-terminal pro-B-type natriuretic peptide, and competing risk from death. Results: 165 patients developed CKD after 19.2 ± 4.04 years of follow-up. The adjusted hazard ratio (95% confidence interval, CI) for CKD in 4th versus 1st quartile of GDF-15 was 2.37 (1.33, 4.24) (p for trend < 0.01). Each per 1 standard deviation increase in GDF-15 was associated with a decline in eGFR of − 0.97 mL/min/1.73 m2 (95% CI, − 1.49 ~ − 0.45; p < 0.001). GDF-15 was also significantly associated eGFR-based CKD in 2713 subjects with baseline eGFR ≥60 mL/min/1.73 m2. Conclusions: GDF-15 predicted incidence of CKD and eGFR decline in the general population, independent of a wide range of potential risk factors and competing risk of death.
  • Bao, Xue, et al. (författare)
  • Growth differentiation factor-15 is a biomarker for all-cause mortality but less evident for cardiovascular outcomes : A prospective study
  • 2021
  • Ingår i: American Heart Journal. - : Mosby-Elsevier. - 0002-8703. ; 234, s. 81-89
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Previous studies have proposed growth differentiation factor-15 (GDF-15) as a predictor of adverse cardiovascular outcomes and mortality. The present study aimed to determine if such associations remain after accounting for death as a competing risk, and if GDF-15 provides superior prediction performance than other biomarkers. Methods: Plasma GDF-15 levels and cardiovascular risk factors were measured in individuals without cardiovascular diseases (n = 4,143, aged 57.4 ± 5.96 years, 38.6 % men) from Malmö Diet and Cancer-Cardiovascular Cohort and were followed up for more than 20 years. Incidence of coronary events, ischemic stroke, cardiovascular mortality, and all-cause mortality was studied in relation to GDF-15 using Cox proportional hazards regression, with adjustment for potential confounders. Confounding from death as competing risk was carefully checked using the Fine and Gray subdistribution hazard model. Predictive capabilities were further evaluated using C-statistics, continuous net reclassification improvement, and integrated discrimination improvement. Results: During follow-up, 424 coronary events, 327 ischemic stroke, 368 cardiovascular deaths, and 1,308 all-cause deaths occurred. After controlling for death from other causes as competing events, only all-cause mortality remained significantly related to GDF-15. The addition of GDF-15 significantly improved prediction for all-cause mortality in addition to the traditional risk factors, high-sensitive C-reactive protein and N-terminal prohormone of brain natriuretic peptide. Only N-terminal prohormone of brain natriuretic peptide improved prediction for CVD mortality. Conclusions: GDF-15 is a robust biomarker for all-cause mortality but less reliable for coronary event, ischemic stroke or cardiovascular mortality. Competing risk from death is an important consideration when interpreting the results.
  • Bao, Xue, et al. (författare)
  • Growth differentiation factor 15 is positively associated with incidence of diabetes mellitus : the Malmö Diet and Cancer–Cardiovascular Cohort
  • 2019
  • Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 62:1, s. 78-86
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims/hypothesis: Growth differentiation factor 15 (GDF-15) is an anti-inflammatory cytokine of the transforming growth factor-β superfamily. Circulating levels of GDF-15 are associated with hyperglycaemia among people with obesity or diabetes, but longitudinal evidence on the association between GDF-15 levels and diabetes risk is scarce. Our aim was to explore whether circulating levels of GDF-15 at baseline are positively associated with future diabetes incidence in a middle-aged urban population. Methods: Between 1991 and 1994, baseline fasting plasma GDF-15 levels were measured in 4360 individuals without diabetes (mean age 57.4 ± 5.96 years, 38.6% men) who were participants in the Malmö Diet and Cancer–Cardiovascular Cohort. After a follow-up of 19.0 ± 5.16 years (mean ± SD), Cox proportional hazards regression analysis was used for the study of the relationship between baseline GDF-15 and incident diabetes, with adjustment for established confounders. A sensitivity analysis included further adjustment for levels of C-reactive protein (CRP). Results: During the follow-up period, 621 individuals developed diabetes. The multivariate-adjusted HR for diabetes incidence was 1.43 (95% CI 1.11, 1.83; p for trend = 0.007) for the fourth compared with the first quartile of GDF-15, and was 1.17 (95% CI 1.07, 1.28; p < 0.001) per SD increase of GDF-15. If participants were grouped according to baseline fasting glucose, the association between GDF-15 and diabetes risk was only evident in the group without impaired fasting glucose (n = 3973). The association tended to be less significant with increasing age: multivariate-adjusted HRs for diabetes per SD increase of GDF-15 were 1.24 (95% CI 1.08, 1.42), 1.19 (95% CI 1.00, 1.41) and 1.04 (95% CI 0.89, 1.23) for participants aged ≤55, 56–60 (>55 and ≤60) and >60 years, respectively. With adjustment for levels of CRP, the HR per SD increase of GDF-15 (1.21, 95% CI 1.09, 1.35) was significant (p = 0.015), but the HR for the fourth compared with the first quartile of GDF-15 was not significant (HR 1.30; 95% CI 1.01, 1.67; p for trend = 0.061). Conclusions/interpretation: GDF-15 may be useful for identification of people with a risk of incident diabetes, especially if those people are ≤60 years old.
  • Bao, Xue, et al. (författare)
  • The associations of self-rated health with cardiovascular risk proteins : A proteomics approach
  • 2019
  • Ingår i: Clinical Proteomics. - : Humana Press. - 1542-6416. ; 16
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Though subjective, poor self-rated health (SRH) has consistently been shown to predict cardiovascular disease (CVD). The underlying mechanism is unclear. This study evaluates the associations of SRH with biomarkers for CVD, aiming to explore potential pathways between poor SRH and CVD. Methods: Based on the Malmö Diet and Cancer Cardiovascular Cohort study, a targeted proteomics approach was used to assess the associations of SRH with 88 cardiovascular risk proteins, measured in plasma from 4521 participants without CVD. The false discovery rate (FDR) was controlled using the Benjamini and Hochberg method. Covariates taken into consideration were age, sex, traditional CVD risk factors (low-density lipoprotein cholesterol, systolic blood pressure, anti-hypertensive medication, diabetes, body mass index, smoking), comorbidity, life-style and psycho-social factors (education level, living alone, alcohol consumption, low physical activity, psychiatric medication, sleep duration, and unemployment). Results: Age and sex-adjusted associations with SRH was found for 34 plasma proteins. Nine of them remained significant after adjustments for traditional CVD risk factors. After further adjustment for comorbidity, life-style and psycho-social factors, only leptin (β = - 0.035, corrected p = 0.016) and C-C motif chemokine 20 (CCL20; β = - 0.054, corrected p = 0.016) were significantly associated with SRH. Conclusions: Poor SRH was associated with raised concentrations of many plasma proteins. However, the relationships were largely attenuated by adjustments for CVD risk factors, comorbidity and psycho-social factors. Leptin and CCL20 were associated with poor SRH in the present study and could potentially be involved in the SRH-CVD link.
  • Barchetta, Ilaria, et al. (författare)
  • Neurotensin is a lipid-induced gastrointestinal peptide associated with visceral adipose tissue inflammation in obesity
  • 2018
  • Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 10:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Neurotensin (NT) is a 13-amino acid peptide localized in the neuroendocrine cells of the small intestine, which promotes fat absorption and fatty acids translocation in response to lipid ingestion. NT-knock-out mice fed with a high-fat diet are protected from obesity, fatty liver, and the development of insulin-resistance. In humans, higher plasma levels of pro-NT, which is the stable circulating precursor of NT, predict obesity, type 2 diabetes (T2D), and cardiovascular disease. In obesity, the presence of visceral adipose tissue (VAT) inflammation leads to unfavorable metabolic outcomes and is associated with the development of T2D and non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the relationship between plasma pro-NT levels and the presence of VAT inflammation in biopsies from 40 morbidly obese subjects undergoing bariatric surgery. We demonstrated that higher proNT levels are significantly associated with greater macrophages infiltration, HIF-1α, WISP-1, and UNC5B expression in VAT (all p < 0.01) due to the diagnosis of T2D and NAFLD. The overall results show that, in obesity, pro-NT is a biomarker of VAT inflammation and insulin-resistance. Additionally, NT may be involved in the development of dysmetabolic conditions likely mediated by increased gut fat absorption and the presence of a proinflammatory milieu in the adipose tissue.
  • Bengtsson Boström, Kristina, et al. (författare)
  • Polymorphism in the angiotensin converting enzyme but not in the angiotensinogen gene is associated with hypertension and type 2 diabetes: the Skaraborg Hypertension and diabetes project
  • 1999
  • Ingår i: Journal of Hypertension. - : Lippincott Williams & Wilkins. - 1473-5598. ; 17:11, s. 1569-1575
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: To study the association between polymorphisms in the angiotensin converting enzyme (ACE) gene and angiotensinogen (AGT) gene and hypertension and/or type 2 diabetes in a community population. PATIENTS AND METHODS: The insertion (I)/deletion (D) polymorphism of the ACE gene and the M235T polymorphism of the AGT gene were genotyped in 773 nondiabetic individuals with hypertension, 193 normotensive patients with type 2 diabetes, 243 patients with type 2 diabetes and hypertension, and in 820 normotensive control individuals identified in a community-based study. RESULTS: The DD genotype was associated with hypertension in individuals less than 70 years [odds ratio (OR) = 1.54, confidence interval (CI) = 1.09-2.18] and remained so when patients with type 2 diabetes were excluded from the analysis (OR = 1.45, CI = 1.01-2.09). The strongest association was with the combination of type 2 diabetes and hypertension (OR = 2.19, CI = 1.09-4.38). There was no association with type 2 diabetes without hypertension. No association was observed between the M235T variant or the 3'-microsatellite polymorphism of the AGT gene and hypertension. CONCLUSION: The D-allele of the ACE gene ID polymorphism increases susceptibility to hypertension, particularly when associated with type 2 diabetes. No association was observed between the M235T variant or 3'-microsatellite polymorphism of the AGT gene and hypertension.
  • Bengtsson, Eva, et al. (författare)
  • ADAMTS-7 is associated with a high-risk plaque phenotype in human atherosclerosis
  • 2017
  • Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 7:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Several large-scale genome-wide association studies have identified single-nucleotide polymorphisms in the genomic region of A Disintegrin And Metalloproteinase with ThromboSpondin type 1 repeats (ADAMTS)-7 and associations to coronary artery disease. Experimental studies have provided evidence for a functional role of ADAMTS-7 in both injury-induced vascular neointima formation and development of atherosclerotic lesions. However, whether ADAMTS-7 is associated with a specific plaque phenotype in humans has not been investigated. Carotid plaques (n = 206) from patients with and without cerebrovascular symptoms were analyzed for expression of ADAMTS-7 by immunohistochemistry and correlated to components associated with plaque vulnerability. Plaques from symptomatic patients showed increased levels of ADAMTS-7 compared with lesions from asymptomatic patients. High levels of ADAMTS-7 correlated with high levels of CD68-staining and lipid content, but with low smooth muscle cell and collagen content, which together are characteristics of a vulnerable plaque phenotype. ADAMTS-7 levels above median were associated with increased risk for postoperative cardiovascular events. Our data show that ADAMTS-7 is associated with a vulnerable plaque phenotype in human carotid lesions. These data support previous observations of a potential proatherogenic role of ADAMTS-7.
  • Bengtsson, Kristina, et al. (författare)
  • Beta(2)-adrenergic receptor gene variation and hypertension in subjects with type 2 diabetes
  • 2001
  • Ingår i: Hypertension. - : Lippincott Williams & Wilkins. - 1524-4563. ; 37:5, s. 1303-1308
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to investigate whether polymorphisms in the beta(2)-adrenergic receptor gene (5'LC-Arg19Cys, Arg16Gly, Gln27Glu) are associated with hypertension in patients with or without type 2 diabetes and with the blood pressure levels in normotensive sib pairs. The association study included 291 hypertensive patients without type 2 diabetes, 124 hypertensive patients with type 2 diabetes, and 265 healthy control subjects from SWEDEN: In addition, normotensive sib pairs that were discordant for the Arg16Gly (72 pairs) and Gln27Glu (40 pairs) polymorphisms were identified in type 2 diabetes families from FINLAND: Genotyping was performed using polymerase chain reaction-restriction fragment-length polymorphism analysis. Homozygous carriers of the Arg16 allele had a significantly increased odds ratio (OR) for hypertension in patients with type 2 diabetes (OR 2.14; 95% confidence interval [CI], 1.05 to 4.33), particularly among lean (body mass index<27 kg/m(2)) patients (OR 3.47; 95% CI, 1.06 to 11.33). The Gln27 allele showed a weaker association to hypertension (OR 1.55; 95% CI, 1.00 to 2.41) and was found to be in linkage disequilibrium with the Cys19 allele of the 5'LC-Arg19Cys polymorphism. In the paired-sibling analysis, siblings with at least 1 copy of the Arg16 allele had higher systolic blood pressure (P=0.049), and nondiabetic siblings had a higher body mass index (P=0.026) than siblings homozygous for the Gly16 allele. These results indicate that the Arg16 allele of the beta(2)-adrenergic receptor gene confers an increased risk for hypertension in subjects with type 2 diabetes and is associated with higher blood pressure levels and higher body mass index in sib pairs who are discordant for the polymorphism.
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