Publications by authors named "Cristina Maglio"

22 Publications

  • Page 1 of 1

Body fat composition and risk of rheumatoid arthritis: Mendelian randomisation study.

Arthritis Rheumatol 2021 Apr 12. Epub 2021 Apr 12.

Department of Health Data Science, University of Liverpool, Liverpool.

Observational studies showed obesity (defined using BMI) to be associated with rheumatoid arthritis (RA) risk, but its causal role remains unclear. Dramatic weight loss following bariatric surgery did not reduce RA risk [1]. Obesity is also paradoxically associated with reduced mortality among RA patients [2]. These inconsistencies may be due to challenges from confounding, reverse causation (chronic inflammation can induce changes to body composition), or limitations of BMI, which cannot distinguish fat from fat-free (lean) mass.
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http://dx.doi.org/10.1002/art.41766DOI Listing
April 2021

Adipocytokines in Untreated Newly Diagnosed Rheumatoid Arthritis: Association with Circulating Chemokines and Markers of Inflammation.

Biomolecules 2021 Feb 21;11(2). Epub 2021 Feb 21.

Department of Rheumatology and Inflammation Research, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, 413 46 Gothenburg, Sweden.

Adiponectin, leptin, and resistin are adipocytokines whose levels are elevated in blood and synovial fluid from patients with rheumatoid arthritis (RA). However, their role in RA pathogenesis is unclear. Here, we examined whether adipocytokines are associated with circulating chemokines, markers of inflammation and RA disease activity in patients with untreated newly diagnosed RA. Plasma levels of 15 chemokines, adiponectin, leptin, and resistin were measured using flow cytometry bead-based immunoassay or enzyme-linked immunosorbent assay (ELISA) in a cohort of 70 patients with untreated newly diagnosed RA. Markers of inflammation and disease activity were also assessed in all patients. Positive association was found between total adiponectin and CXCL10 (β = 0.344, = 0.021), CCL2 (β = 0.342, = 0.012), and CXCL9 (β = 0.308, = 0.044), whereas high-molecular weight (HMW) adiponectin associated only with CXCL9 (β = 0.308, = 0.033). Furthermore, both total and HMW adiponectin were associated with C-reactive protein (β = 0.485, = 0.001; β = 0.463, = 0.001) and erythrocyte sedimentation rate (β = 0.442, = 0.001; β = 0.507, < 0.001). Leptin and resistin were not associated with plasma chemokines, markers of inflammation, or disease activity scores. Our study shows an association between circulating adiponectin and pro-inflammatory chemokines involved in RA pathogenesis as well as markers of inflammation in a well-characterized cohort of patients with untreated newly diagnosed RA.
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http://dx.doi.org/10.3390/biom11020325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924659PMC
February 2021

Recombinant Adiponectin Induces the Production of Pro-Inflammatory Chemokines and Cytokines in Circulating Mononuclear Cells and Fibroblast-Like Synoviocytes From Non-Inflamed Subjects.

Front Immunol 2020 1;11:569883. Epub 2021 Feb 1.

Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Adiponectin is an adipokine with a modulatory role in metabolism and exerting both anti- and pro-inflammatory effects. Levels of adiponectin are increased in serum and synovial fluid from patients with rheumatoid arthritis (RA). Adiponectin is able to stimulate the production of different pro-inflammatory factors from peripheral blood mononuclear cells (PBMCs) and fibroblast-like synoviocytes (FLS) from subjects with established RA. As increased circulating adiponectin levels are a risk factor for future development of RA in subjects with obesity, we hypothesize that adiponectin is implicated in the development of RA at an early stage by initiating the pro-inflammatory processes associated with the disease pathogenesis. Therefore, we aimed to determine if adiponectin is able to induce pro-inflammatory responses in cells involved in the pathogenesis of RA, but collected from subjects without any known inflammatory disease. PBMCs and FLS were obtained from non-inflamed subjects and stimulated with 5 μg/ml human recombinant adiponectin. Supernatants collected after 48 h were analyzed for the production of 13 chemokines and 12 cytokines using multiplex assay and ELISA. Adiponectin significantly stimulated the production of CXCL1, CXCL5, and interleukin (IL)-6 in both PBMCs and FLS, whereas it induced CCL20, CCL4, CCL3, CCL17, tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor and IL-10 only in PBMCs, and CXCL8, CXCL10, CCL5, CCL11, and CCL2 only in FLS. Pre-stimulation with TNF of FLS from non-inflamed subjects did not significantly enhance the release of most pro-inflammatory factors compared to adiponectin alone. Our findings indicate that PBMCs and FLS from non-inflamed subjects react to adiponectin stimulation with the secretion of several pro-inflammatory chemokines and cytokines. These results suggest that adiponectin is able to initiate pro-inflammatory responses in cells from non-inflamed subjects and support the hypothesis that adiponectin is implicated in the early phases of RA pathogenesis.
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http://dx.doi.org/10.3389/fimmu.2020.569883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882698PMC
February 2021

Neonatal gut colonization by is associated with higher childhood cytokine responses.

Gut Microbes 2020 11;12(1):1-14

Institute of Medicine, Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

The gut microbiota is a major stimulus for the immune system, and late acquisition of bacteria and/or reduced complexity of the gut flora may delay adaptive immune maturation. However, it is unknown how the gut bacterial colonization pattern in human infants is related to T cell activation during early childhood. We followed 65 Swedish children in the FARMFLORA cohort, from birth up to 3 years of age. In fecal samples collected at several time points during the first year of life, the gut colonization pattern was investigated with the use of both 16S rRNA next generation sequencing (NGS) and culture-based techniques. This was related to production of IL-13, IL-5, IL-6, TNF, IL-1β and IFN-γ by PHA-stimulated fresh mononuclear cells and to proportions of CD4 T cells that expressed CD45RO at 36 months of age. Both NGS and culture-based techniques showed that colonization by at 1 week of age associated with higher production of IL-5, IL-6, IL-13, TNF and IL-1β at 36 months of age. By contrast, gut colonization by or in early infancy related inversely to induced IL-13, IL-5 and TNF at 3 years of age. Infants with elder siblings produced more cytokines and had a larger fraction of CD45RO T cells compared to single children. However, controlling for these factors did not abolish the effect of colonization by on immune maturation. Thus, gut colonization in early infancy affects T cell maturation and may be especially prone to induce infantile immune maturation.
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http://dx.doi.org/10.1080/19490976.2020.1847628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747801PMC
November 2020

Bariatric surgery and the incidence of rheumatoid arthritis - a Swedish Obese Subjects study.

Rheumatology (Oxford) 2020 02;59(2):303-309

Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Objective: The aim of this study was to determine the effect of bariatric surgery on the incidence of RA in participants of the Swedish Obese Subjects (SOS) study.

Methods: The SOS is a longitudinal study aiming to assess the effect of bariatric surgery on mortality and obesity-related diseases. This report includes 2002 subjects with obesity who underwent bariatric surgery and 2034 matched controls; none of them had RA at baseline. Cases of incident RA were identified through the Swedish National Patient Register by searching for International Classification of Diseases codes. Both intention-to-treat analyses and per-protocol analyses are reported. In the per-protocol analysis, participants from the control group who underwent bariatric surgery later on during follow-up were censored at the time of surgery.

Results: During follow-up, 92 study participants developed RA. The median follow-up was 21 years (range 0-29). Bariatric surgery was neither associated with the incidence of RA in the intention-to-treat analysis [hazard ratio (HR) 0.92 (95% CI 0.59, 1.46), P = 0.74], nor in the per-protocol analysis [HR 0.86 (95% CI 0.54, 1.38), P = 0.53]. Weight change at the 2 year follow-up, expressed as the change in BMI compared with baseline, did not associate with the development of RA. Higher serum CRP levels and smoking associated with the future development of RA independent of other factors.

Conclusions: We did not detect any association between bariatric surgery and the incidence of RA in subjects affected by obesity followed up for up to 29 years.

Clinicaltrials.gov: (http://clinicaltrials.gov): NCT01479452.
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http://dx.doi.org/10.1093/rheumatology/kez275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571486PMC
February 2020

Long-term incidence of serious fall-related injuries after bariatric surgery in Swedish obese subjects.

Int J Obes (Lond) 2019 04 24;43(4):933-937. Epub 2018 May 24.

National Institute for Health and Welfare, Helsinki, Finland.

Obesity increases risk of falling, but the effect of bariatric surgery on fall-related injuries is unknown. The aim of this study was therefore to study the association between bariatric surgery and long-term incidence of fall-related injuries in the prospective, controlled Swedish Obese Subjects study. At inclusion, body mass index was ≥ 34 kg/m in men and ≥38 kg/m in women. The surgery per-protocol group (n = 2007) underwent gastric bypass (n = 266), banding (n = 376), or vertical banded gastroplasty (n = 1365), and controls (n = 2040) received usual care. At the time of analysis (31 December 2013), median follow-up was 19 years (maximal 26 years). Fall-related injuries requiring hospital treatment were captured using data from the Swedish National Patient Register. During follow-up, there were 617 first-time fall-related injuries in the surgery group and 513 in the control group (adjusted hazard ratio 1.21, 95% CI, 1.07-1.36; P = 0.002). The incidence differed between treatment groups (P < 0.001, log-rank test) and was higher after gastric bypass than after usual care, banding and vertical banded gastroplasty (adjusted hazard ratio 0.50-0.52, P < 0.001 for all three comparisons). In conclusion, gastric bypass surgery was associated with increased risk of serious fall-related injury requiring hospital treatment.
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http://dx.doi.org/10.1038/s41366-018-0097-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252168PMC
April 2019

Bariatric Surgery and the Incidence of Psoriasis and Psoriatic Arthritis in the Swedish Obese Subjects Study.

Obesity (Silver Spring) 2017 12;25(12):2068-2073

Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

Objective: The aim of this study was to assess the effect of bariatric surgery (vertical gastroplasty, gastric banding, or gastric bypass) compared with usual care on the incidence of psoriasis and psoriatic arthritis (PsA) in the Swedish Obese Subjects study.

Methods: This report includes 1,991 subjects who underwent bariatric surgery and 2,018 controls with obesity from the SOS study; none of them had psoriasis or PsA at baseline. Information about psoriasis and PsA diagnosis was retrieved through the Swedish National Patient Register and questionnaires.

Results: During follow-up for up to 26 years, bariatric surgery was associated with a lower incidence of psoriasis compared with usual care (number of events = 174; hazard ratio 0.65; 95% CI: 0.47-0.89; P = 0.008). Both smoking and a longer duration of obesity were independently associated with a higher risk for psoriasis. No significant difference was detected among the three surgical procedures in terms of lowering the risk of developing psoriasis. The association between bariatric surgery and psoriasis incidence was not influenced by baseline confounders. No significant difference in the risk of developing PsA (number of events = 46) was detected when comparing the surgery and the control groups.

Conclusions: This study shows that bariatric surgery is associated with a lower risk of developing psoriasis compared with usual care.
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http://dx.doi.org/10.1002/oby.21955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725727PMC
December 2017

Effects of bariatric surgery on gout incidence in the Swedish Obese Subjects study: a non-randomised, prospective, controlled intervention trial.

Ann Rheum Dis 2017 04 8;76(4):688-693. Epub 2016 Oct 8.

Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

Objectives: To assess the long-term effect of bariatric surgery on the incidence of gout and hyperuricaemia in participants of the Swedish Obese Subjects (SOS) study.

Methods: This report includes 1982 subjects who underwent bariatric surgery and 1999 obese controls from the SOS study, a prospective intervention trial designed to assess the effect of bariatric surgery compared with conventional treatment. None of the subjects had gout at baseline. An endpoint on gout incidence was created based on information on gout diagnosis and use of gout medications through national registers and questionnaires. Median follow-up for the incidence of gout was about 19 years for both groups. Moreover, the incidence of hyperuricaemia over up to 20 years was examined in a subgroup of participants having baseline uric acid levels <6.8 mg/dL.

Results: Bariatric surgery was associated with a reduced incidence of gout compared with usual care (adjusted HR 0.60, 95% CI 0.48 to 0.75, p<0.001). The difference in absolute risk between groups was 3 percentage points at 15 years, and the number of subjects needed to be treated by bariatric surgery to prevent one incident gout event was 32 (95% CI 22 to 59). The effect of bariatric surgery on gout incidence was not influenced by baseline risk factors, including body mass index. During follow-up, the surgery group had a lower incidence of hyperuricaemia (adjusted HR 0.47, 95% CI 0.39 to 0.58, p<0.001). The difference in absolute risk between groups was 12 percentage points at 15 years, and the number of participants needed to be treated by bariatric surgery to prevent hyperuricaemia was 8 (95% CI 6 to 13).

Conclusions: Bariatric surgery prevents gout and hyperuricaemia in obese subjects.

Trial Registration Number: NCT01479452; Results.
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http://dx.doi.org/10.1136/annrheumdis-2016-209958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530073PMC
April 2017

Paradoxical dissociation between hepatic fat content and de novo lipogenesis due to PNPLA3 sequence variant.

J Clin Endocrinol Metab 2015 May 12;100(5):E821-5. Epub 2015 Mar 12.

Department of Molecular and Clinical Medicine (R.M.M, C.M, S.R., J.B.), University of Gothenburg, S-413 45 Gothenburg, Sweden; Department of Medicine, Cardiovascular Research Unit, Diabetes and Obesity Research Program (N.M., S.S., M.-R.T.), Heart and Lung Centre and Division of Endocrinology and Helsinki University Central Hospital, University of Helsinki, 00100 Helsinki, Finland; Department of Radiology, HUS Medical Imaging Center (N.L., A.H.), Helsinki University Central Hospital, University of Helsinki, 00100 Helsinki, Finland; Departments of Internal Medicine (R.R, S.F., L.V.), and General Surgery (E.M.), Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Policlinico, and Department of Pathophysiology and Transplantation Università degli Studi di Milano, 20122 Milano, Italy; and Department of Medical and Surgical Sciences (S.R.), Clinical Nutrition Unit, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy.

Context: Nonalcoholic fatty liver disease (NAFLD) is an emerging epidemic disease characterized by increased hepatic fat, due to an imbalance between synthesis and removal of hepatic lipids. In particular, increased hepatic de novo lipogenesis (DNL) is a key feature associated with NAFLD. The genetic variations I148M in PNPLA3 and E167K in TM6SF2 confer susceptibility to NAFLD.

Objective: Here we aimed to investigate the contribution of DNL to liver fat accumulation in the PNPLA3 I148M or TM6SF2 E167K genetic determinants of NAFLD.

Patients And Methods: The PNPLA3 I148M and TM6SF2 E167K were genotyped in two well-characterized cohorts of Europeans. In the first cohort (Helsinki cohort; n = 88), we directly quantified hepatic DNL using deuterated water. In the second cohort (Milan cohort; n = 63), we quantified the hepatic expression of SREBP1c that we have found previously associated with increased fat content. Liver fat was measured by magnetic resonance proton spectroscopy in the Helsinki cohort, and by histological assessment of liver biopsies in the Milan cohort.

Results: PNPLA3 148M was associated with lower DNL and expression of the lipogenic transcription factor SREBP1c despite substantial increased hepatic fat content.

Conclusions: Our data show a paradoxical dissociation between hepatic DNL and hepatic fat content due to the PNPLA3 148M allele indicating that increased DNL is not a key feature in all individuals with hepatic steatosis, and reinforces the contribution of decreased mobilization of hepatic triglycerides for hepatic lipid accumulation in subject with the PNPLA3 148M allele.
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http://dx.doi.org/10.1210/jc.2014-4464DOI Listing
May 2015

Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease.

Hepatology 2015 Feb;61(2):506-14

Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy.

Unlabelled: Excess hepatic storage of triglycerides is considered a benign condition, but nonalcoholic steatohepatitis (NASH) may progress to fibrosis and promote atherosclerosis. Carriers of the TM6SF2 E167K variant have fatty liver as a result of reduced secretion of very-low-density lipoproteins (VLDLs). As a result, they have lower circulating lipids and reduced risk of myocardial infarction. In this study, we aimed to assess whether TM6SF2 E167K affects liver damage and cardiovascular outcomes in subjects at risk of NASH. Liver damage was evaluated in 1,201 patients who underwent liver biopsy for suspected NASH; 427 were evaluated for carotid atherosclerosis. Cardiovascular outcomes were assessed in 1,819 controls from the Swedish Obese Subjects (SOS) cohort. Presence of the inherited TM6SF2 E167K variant was determined by TaqMan assays. In the liver biopsy cohort, 188 subjects (13%) were carriers of the E167K variant. They had lower serum lipid levels than noncarriers (P < 0.05), had more-severe steatosis, necroinflammation, ballooning, and fibrosis (P < 0.05), and were more likely to have NASH (odds ratio [OR]: 1.84; 95% confidence interval [CI]: 1.23-2.79) and advanced fibrosis (OR, 2.08; 95% CI: 1.20-3.55), after adjustment for age, sex, body mass index, fasting hyperglycemia, and the I148M PNPLA3 risk variant. However, E167K carriers had lower risk of developing carotid plaques (OR, 0.49; 95% CI: 0.25-0.94). In the SOS cohort, E167K carriers had higher alanine aminotransferase ALT and lower lipid levels (P < 0.05), as well as a lower incidence of cardiovascular events (hazard ratio: 0.61; 95% CI: 0.39-0.95).

Conclusions: Carriers of the TM6SF2 E167K variant are more susceptible to progressive NASH, but are protected against cardiovascular disease. Our findings suggest that reduced ability to export VLDLs is deleterious for the liver.
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http://dx.doi.org/10.1002/hep.27490DOI Listing
February 2015

PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells.

Hum Mol Genet 2014 Aug 25;23(15):4077-85. Epub 2014 Mar 25.

Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Center for Cardiovascular and Metabolic Research, Wallenberg Laboratory and Department of Medical and Surgical Sciences, Clinical Nutrition Unit, University Magna Graecia of Catanzaro, Catanzaro, Italy

Retinoids are micronutrients that are stored as retinyl esters in the retina and hepatic stellate cells (HSCs). HSCs are key players in fibrogenesis in chronic liver diseases. The enzyme responsible for hydrolysis and release of retinyl esters from HSCs is unknown and the relationship between retinoid metabolism and liver disease remains unclear. We hypothesize that the patatin-like phospholipase domain-containing 3 (PNPLA3) protein is involved in retinol metabolism in HSCs. We tested our hypothesis both in primary human HSCs and in a human cohort of subjects with non-alcoholic fatty liver disease (N = 146). Here we show that PNPLA3 is highly expressed in human HSCs. Its expression is regulated by retinol availability and insulin, and increased PNPLA3 expression results in reduced lipid droplet content. PNPLA3 promotes extracellular release of retinol from HSCs in response to insulin. We also show that purified wild-type PNPLA3 hydrolyzes retinyl palmitate into retinol and palmitic acid. Conversely, this enzymatic activity is markedly reduced with purified PNPLA3 148M, a common mutation robustly associated with liver fibrosis and hepatocellular carcinoma development. We also find the PNPLA3 I148M genotype to be an independent (P = 0.009 in a multivariate analysis) determinant of circulating retinol-binding protein 4, a reliable proxy for retinol levels in humans. This study identifies PNPLA3 as a lipase responsible for retinyl-palmitate hydrolysis in HSCs in humans. Importantly, this indicates a potential novel link between HSCs, retinoid metabolism and PNPLA3 in determining the susceptibility to chronic liver disease.
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http://dx.doi.org/10.1093/hmg/ddu121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082369PMC
August 2014

Effect of a basic Chinese traditional diet in overweight patients.

J Tradit Chin Med 2013 Jun;33(3):322-4

Department of Anatomic, Histologic, Forensic Medicine and Locomotor System Sciences, Sapienza University, Rome, Italy.

Objective: To evaluate the effect of a basic Chinese traditional diet (BTCD) in overweight patients on body mass index (BMI), lean mass, sense of hunger, and eating behaviour.

Methods: A total of 694 enrolled subjects (218 male and 476 female) were divided into two groups: group A undergoing a 1200-Kcal BTCD, and group B undergoing a 1200-Kcal standard western diet.

Results: From T0 (before treatment) to T1 (6 weeks after treatment), BMI was lowered in group A from (32.33 +/- 5.51) to (31.96 +/- 5.56) kg/m2, and in group B from (31.62 +/- 6.29) to (31.36 +/- 6.47) kg/m2. After treatment, patients in group A lost more weight (0.37 +/- 0.52) kg than group B (0.26 +/- 0.79) kg (P = 0.0044). From T0 to T1, the mean lean mass of group A decreased from (16.48 +/- 5.50) to (16.27 +/- 5.45) kg. In group B, mean lean mass decreased from (16.93 +/- 6.49) to (16.44 +/- 6.29) kg. The difference was significant (P = 0.0078).

Conclusion: The two diets could lead to lower BMI, improve lean mass as well as eating behaviour and sense of hunger. However, the BTCD was significantly better than the western standard diet.
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http://dx.doi.org/10.1016/s0254-6272(13)60173-9DOI Listing
June 2013

Alcohol consumption and alcohol problems after bariatric surgery in the Swedish obese subjects study.

Obesity (Silver Spring) 2013 Dec 31;21(12):2444-51. Epub 2013 May 31.

Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at Gothenburg University, SE-41345 Gothenburg, Sweden.

Objective: Increased sensitivity to alcohol after gastric bypass has been described. The aim of this study was to investigate whether bariatric surgery is associated with alcohol problems.

Design And Methods: The prospective, controlled Swedish Obese Subjects (SOS) study enrolled 2,010 obese patients who underwent bariatric surgery (68% vertical banded gastroplasty (VBG), 19% banding, and 13% gastric bypass) and 2,037 matched controls. Patients were recruited between 1987 and 2001. Data on alcohol abuse diagnoses, self-reported alcohol consumption, and alcohol problems were obtained from the National Patient Register and questionnaires. Follow-up time was 8-22 years.

Results: During follow-up, 93.1% of the surgery patients and 96.0% of the controls reported alcohol consumption classified as low risk by the World Health Organization (WHO). However, compared to controls, the gastric bypass group had increased risk of alcohol abuse diagnoses (adjusted hazard ratio [adjHR] = 4.97), alcohol consumption at least at the WHO medium risk level (adjHR = 2.69), and alcohol problems (adjHR = 5.91). VBG increased the risk of these conditions with adjHRs of 2.23, 1.52, and 2.30, respectively, while banding was not different from controls.

Conclusions: Alcohol consumption, alcohol problems, and alcohol abuse are increased after gastric bypass and VBG.
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http://dx.doi.org/10.1002/oby.20397DOI Listing
December 2013

The COBLL1 C allele is associated with lower serum insulin levels and lower insulin resistance in overweight and obese children.

Diabetes Metab Res Rev 2013 Jul;29(5):413-6

Institute of Medicine, Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Wallenberg Laboratory, University of Gothenburg, Bruna Stråket 16, Göteborg, Sweden.

Background: Childhood obesity is a growing epidemic worldwide, and it is associated with metabolic complications, such as insulin resistance. Recently, a genetic variation (rs7607980) in the COBLL1 gene has been associated with lower insulin resistance in adults. The aim of the study was to investigate if the association between COBLL1 rs7607980 genetic variant and lower insulin resistance was present early in life.

Methods: This sequence variant was genotyped in 878 overweight and obese children (mean age: 10 years) from Sardinia, Italy, from the outpatient clinic of the Pediatric Endocrine Unit, at the Regional Hospital for Microcitaemia in Cagliari. Insulin resistance was assessed by measurement of fasting circulating insulin levels before and after an oral glucose tolerance test and by HOMA-IR.

Results: The COBLL1 rs7607980 C allele was associated with lower fasting insulin and HOMA-IR levels (p = 0.002 and p = 0.035, respectively) in overweight and obese children. Importantly, lower insulin levels were also observed 2 h after oral glucose tolerance test in C allele carriers (p = 0.009).

Conclusions: The present study shows for the first time, the association between COBLL1 rs7607980 C allele, lower serum insulin levels and lower insulin resistance in overweight and obese children.
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http://dx.doi.org/10.1002/dmrr.2408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799017PMC
July 2013

The IRS1 rs2943641 variant and risk of future cancer among morbidly obese individuals.

J Clin Endocrinol Metab 2013 Apr 15;98(4):E785-9. Epub 2013 Feb 15.

Department of Molecular and Clinical Medicine and Center for Cardiovascular and Metabolic Research, the Sahlgrenska Academy, University of Gothenburg, S-413 45 Gothenburg, Sweden.

Context: Obesity and insulin resistance are risk factors for cancer development. The IRS1 rs2943641 genetic variant has been widely associated with insulin resistance.

Objective: The aim of the study was to examine whether the IRS1 rs2943641 associates with cancer incidence in obese individuals.

Design, Setting And Patients: The IRS1 rs2943641 was genotyped in participants from the Swedish Obese Subjects (SOS) study, an intervention trial on the effect of bariatric surgery on mortality and morbidity compared with usual care and in the population-based Malmö Diet and Cancer (MDC) cohort. In both studies, the median follow-up for cancer incidence was about 15 years.

Intervention And Main Outcome Measure: Cancer incidence was assessed in both the SOS and the MDC cohorts through national and local registers.

Results: The IRS1 T allele was associated with lower insulin resistance in both the SOS and the MDC studies. A lower cancer incidence was found in T allele carriers from the SOS control group (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.62-0.96; P = .021) and was restricted to morbidly obese individuals (HR 0.67, 95% CI 0.50-0.91; P = .011). No evidence of such association was detected in the surgery group (interaction P = .005). In the MDC cohort, a nonsignificant tendency for lower cancer incidence in T allele carriers was observed only in morbidly obese individuals. A meta-analysis of morbidly obese individuals (body mass index > 40 kg/m(2)) from the two cohorts strengthened the evidence for the association (HR 0.66, 95% CI 0.50-0.87; P = .004).

Conclusions: Our results suggest that the T allele of rs2943641 near IRS1 may associate with lower cancer incidence in morbidly obese individuals.
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http://dx.doi.org/10.1210/jc.2012-2831DOI Listing
April 2013

PNPLA 3 I148M genetic variant associates with insulin resistance and baseline viral load in HCV genotype 2 but not in genotype 3 infection.

BMC Med Genet 2012 Sep 14;13:82. Epub 2012 Sep 14.

Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.

Background: Hepatic steatosis in HCV patients has been postulated as a risk factor associated with a higher frequency of fibrosis and cirrhosis. A single genetic variant, PNPLA3 I148M, has been widely associated with increased hepatic steatosis. Previous studies of the PNPLA3 I148M sequence variant in HCV infected individuals have reported an association between this variant and prevalence of steatosis, fibrosis, and cirrhosis. To evaluate the impact of PNPLA3 I148M variant on metabolic traits and treatment response in HCV genotype 2 and 3 infected patients.

Methods: Three hundred and eighty-two treatment naïve HCV genotype 2 or 3 infected patients were included in a phase III, open label, randomized, multicenter, investigator-initiated trial (the NORDynamIC study), in which pretreatment liver biopsies were mandatory. PNPLA3I148M genotyping was performed in a total of 359 Caucasian patients.

Results: In HCV genotype 2 infected patients carrying the PNPLA3 148M allele, there was significantly increased insulin resistance (P = 0.023) and lower viral load (P = 0.005) at baseline as well as the first seven days of antiviral treatment. These results were not observed in HCV genotype 3 infected patients.

Conclusions: Our results suggest a possible association between the PNPLA3 148M allele and insulin resistance as well as baseline viral load in HCV genotype 2, but not in genotype 3.
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http://dx.doi.org/10.1186/1471-2350-13-82DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495049PMC
September 2012

Bariatric surgery and prevention of type 2 diabetes in Swedish obese subjects.

N Engl J Med 2012 Aug;367(8):695-704

Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

Background: Weight loss protects against type 2 diabetes but is hard to maintain with behavioral modification alone. In an analysis of data from a nonrandomized, prospective, controlled study, we examined the effects of bariatric surgery on the prevention of type 2 diabetes.

Methods: In this analysis, we included 1658 patients who underwent bariatric surgery and 1771 obese matched controls (with matching performed on a group, rather than individual, level). None of the participants had diabetes at baseline. Patients in the bariatric-surgery cohort underwent banding (19%), vertical banded gastroplasty (69%), or gastric bypass (12%); nonrandomized, matched, prospective controls received usual care. Participants were 37 to 60 years of age, and the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) was 34 or more in men and 38 or more in women. This analysis focused on the rate of incident type 2 diabetes, which was a prespecified secondary end point in the main study. At the time of this analysis (January 1, 2012), participants had been followed for up to 15 years. Despite matching, some baseline characteristics differed significantly between the groups; the baseline body weight was higher and risk factors were more pronounced in the bariatric-surgery group than in the control group. At 15 years, 36.2% of the original participants had dropped out of the study, and 30.9% had not yet reached the time for their 15-year follow-up examination.

Results: During the follow-up period, type 2 diabetes developed in 392 participants in the control group and in 110 in the bariatric-surgery group, corresponding to incidence rates of 28.4 cases per 1000 person-years and 6.8 cases per 1000 person-years, respectively (adjusted hazard ratio with bariatric surgery, 0.17; 95% confidence interval, 0.13 to 0.21; P<0.001). The effect of bariatric surgery was influenced by the presence or absence of impaired fasting glucose (P=0.002 for the interaction) but not by BMI (P=0.54). Sensitivity analyses, including end-point imputations, did not change the overall conclusions. The postoperative mortality was 0.2%, and 2.8% of patients who underwent bariatric surgery required reoperation within 90 days owing to complications.

Conclusions: Bariatric surgery appears to be markedly more efficient than usual care in the prevention of type 2 diabetes in obese persons. (Funded by the Swedish Research Council and others; ClinicalTrials.gov number, NCT01479452.).
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http://dx.doi.org/10.1056/NEJMoa1112082DOI Listing
August 2012

Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro.

J Hepatol 2012 Dec 6;57(6):1276-82. Epub 2012 Aug 6.

Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.

Background & Aims: The robust association between non-alcoholic fatty liver disease (NAFLD) and the genetic variant I148M (rs738409) in PNPLA3 has been widely replicated. The aim of this study was to investigate the effect of the PNPLA3 I148M mutation on: (1) hepatic secretion of very low density lipoproteins (VLDL) in humans; and (2) secretion of apolipoprotein B (apoB) from McA-RH 7777 cells, which secrete VLDL-sized apoB-containing lipoproteins.

Methods: VLDL kinetics was analyzed after a bolus infusion of stable isotopes in 55 overweight/obese men genotyped for the PNPLA3 I148M variant. Intracellular lipid content, apoB secretion and glycerolipid metabolism were studied in McA-RH 7777 cells overexpressing the human 148I wild type or 148M mutant PNPLA3 protein.

Results: In humans, carriers of the PNPLA3 148M allele had increased liver fat compared to 148I homozygotes, and kinetic analysis showed a relatively lower secretion of the large, triglyceride-rich VLDL (VLDL(1)) in 148M carriers vs. 148I homozygotes for the same amount of liver fat. McA-RH 7777 cells overexpressing the 148M mutant protein showed a higher intracellular triglyceride content with a lower apoB secretion and fatty acid efflux, compared to cells overexpressing the 148I wild type protein. The responses with 148M matched those observed in cells expressing the empty vector, indicating that the mutation results in loss of function.

Conclusions: We have shown that PNPLA3 affects the secretion of apoB-containing lipoproteins both in humans and in vitro and that the 148M protein is a loss-of-function mutation. We propose that PNPLA3 148M promotes intracellular lipid accumulation in the liver by reducing the lipidation of VLDL.
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http://dx.doi.org/10.1016/j.jhep.2012.07.030DOI Listing
December 2012

Cardiovascular events after bariatric surgery in obese subjects with type 2 diabetes.

Diabetes Care 2012 Dec 1;35(12):2613-7. Epub 2012 Aug 1.

Department of Molecular and Clinical Medicine and Center for Cardiovascular and Metabolic Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Objective: Obese individuals with type 2 diabetes have an increased risk of cardiovascular disease. The effect of bariatric surgery on cardiovascular events in obese individuals with type 2 diabetes remains to be determined. The Swedish Obese Subjects (SOS) study is a prospective, controlled intervention study that examines the effects of bariatric surgery on hard end points. The aim of the present study was to examine the effect of bariatric surgery on cardiovascular events in the SOS study participants with type 2 diabetes.

Research Design And Methods: All SOS study participants with type 2 diabetes at baseline were included in the analyses (n = 345 in the surgery group and n = 262 in the control group). Mean follow-up was 13.3 years (interquartile range 10.2-16.4) for all cardiovascular events.

Results: Bariatric surgery was associated with a reduced myocardial infarction incidence (38 events among the 345 subjects in the surgery group vs. 43 events among the 262 subjects in the control group; log-rank P = 0.017; adjusted hazard ratio [HR] 0.56 [95% CI 0.34-0.93]; P = 0.025). No effect of bariatric surgery was observed on stroke incidence (34 events among the 345 subjects in the surgery group vs. 24 events among the 262 subjects in the control group; log-rank P = 0.852; adjusted HR 0.73 [0.41-1.30]; P = 0.29). The effect of surgery in reducing myocardial infarction incidence was stronger in individuals with higher serum total cholesterol and triglycerides at baseline (interaction P value = 0.02 for both traits). BMI (interaction P value = 0.12) was not related to the surgery outcome.

Conclusions: Bariatric surgery reduces the incidence of myocardial infarction in obese individuals with type 2 diabetes. Preoperative BMI should be integrated with metabolic parameters to maximize the benefits of bariatric surgery.
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http://dx.doi.org/10.2337/dc12-0193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507566PMC
December 2012

Paradoxical lower serum triglyceride levels and higher type 2 diabetes mellitus susceptibility in obese individuals with the PNPLA3 148M variant.

PLoS One 2012 18;7(6):e39362. Epub 2012 Jun 18.

Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.

Background: Obesity is highly associated with elevated serum triglycerides, hepatic steatosis and type 2 diabetes (T2D). The I148M (rs738409) genetic variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is known to modulate hepatic triglyceride accumulation, leading to steatosis. No association between PNPLA3 I148M genotype and T2D in Europeans has been reported. Aim of this study is to examine the relationship between PNPLA3 I148M genotypes and serum triglycerides, insulin resistance and T2D susceptibility by testing a gene-environment interaction model with severe obesity.

Methods And Findings: PNPLA3 I148M was genotyped in a large obese cohort, the SOS study (n = 3,473) and in the Go-DARTS (n = 15,448), a T2D case-control study. Metabolic parameters were examined across the PNPLA3 I148M genotypes in participants of the SOS study at baseline and at 2- and 10-year follow up after bariatric surgery or conventional therapy. The associations with metabolic parameters were validated in the Go-DARTS study. Serum triglycerides were found to be lower in the PNPLA3 148M carriers from the SOS study at baseline and from the Go-DARTS T2D cohort. An increased risk for T2D conferred by the 148M allele was found in the SOS study (O.R. 1.09, 95% C.I. 1.01-1.39, P = 0.040) and in severely obese individuals in the Go-DARTS study (O.R. 1.37, 95% C.I. 1.13-1.66, P = 0.001). The 148M allele was no longer associated with insulin resistance or T2D after bariatric surgery in the SOS study and no association with the 148M allele was observed in the less obese (BMI<35) individuals in the Go-DARTS study (P for interaction  = 0.002). This provides evidence for the obesity interaction with I48M allele and T2D risk in a large-scale cross-sectional and a prospective interventional study.

Conclusions: Severely obese individuals carrying the PNPLA3 148M allele have lower serum triglyceride levels, are more insulin resistant and more susceptible to T2D. This study supports the hypothesis that obesity-driven hepatic lipid accumulation may contribute to T2D susceptibility.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0039362PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3377675PMC
December 2012

PNPLA3 I148M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals.

Dig Liver Dis 2012 Dec 15;44(12):1037-41. Epub 2012 Jun 15.

Department of Molecular and Clinical Medicine and Center for Cardiovascular and Metabolic Research, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Obesity is a risk factor for cancer, including hepatocellular carcinoma. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) genetic variant has been associated with hepatocellular carcinoma (HCC) in individuals with chronic alcohol abuse or hepatic viral infection. In the present study we examined the association between the PNPLA3 I148M genetic variant and hepatocellular carcinoma in obese individuals from the Swedish Obese Subjects cohort (n = 4047).

Methods: We performed a matched, prospective, controlled, interventional trial, investigating the effect of bariatric surgery (surgery group) compared to conventional treatment (control group) for obesity.

Results: A total of 9 events were observed in the 15-year median follow up (5 in the control group and 4 in the surgery group). A significantly higher incidence of hepatocellular carcinoma in PNPLA3 148M allele carriers was found in obese individuals in the control group (log-rank P-value = 0.001), but not in the surgery group (log-rank P-value = 0.783). Consistently, an increased risk (for each PNPLA3 148M allele, hazard ratio: 5.9; 95% confidence interval 1.5-23.8; P-value = 0.013) of developing hepatocellular carcinoma was observed only in the control group.

Conclusion: The current study is the first prospective report showing the association of the PNPLA3 I148M genetic variant and hepatocellular carcinoma in severely obese individuals.
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http://dx.doi.org/10.1016/j.dld.2012.05.006DOI Listing
December 2012

Lack of effect of apolipoprotein C3 polymorphisms on indices of liver steatosis, lipid profile and insulin resistance in obese Southern Europeans.

Lipids Health Dis 2011 Jun 10;10:93. Epub 2011 Jun 10.

Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Italy.

Background: Apolipoprotein C3 (APOC3) is a component of triglyceride-rich lipoproteins, and APOC3 rs2854116 and rs2854117 polymorphisms have been associated with non-alcoholic fatty liver disease, hypertriglyceridaemia, and insulin-resistance.

Objective: To determine if the APOC3 variants alter the susceptibility of obese subjects to develop liver damage, hypertrigliceridaemia, and insulin-resistance.

Methods: The study was carried out on 585 unrelated obese Italians (median body mass index BMI = 41 kg/m2) who were genotyped for the rs2854116 and rs2854117 variants. All participants underwent oral glucose tolerance tests (OGTT), with measurement of glucose, insulin, lipid parameters. Indices of insulin-resistance (HOMA and ISI) were calculated. Alanine transaminase (ALT) and aspartate transaminase (AST) were used as markers of liver injury.

Results: The study subjects were divided into two groups: those homozygous for the wild-type alleles at both SNPs (-482C and -455T alleles) and those who were carriers of at least one variant allele or both (-482T, -455C or both). Also each SNP was analysed independently. No significant differences were found in ALT and AST levels and in the lipid profile between the two groups. Insulin concentrations, glucose tolerance and insulin sensitivity were similar in the two groups.

Conclusion: We did not identify any significant association between APOC3 polymorphisms and fatty liver disease, lipids, and insulin-resistance in obese subjects, thus not confirming the suggested role of these APOC3 gene sequence variants.
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http://dx.doi.org/10.1186/1476-511X-10-93DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135552PMC
June 2011