BACKGROUND:Obesity increases cancer risk, whereas surgery-induced weight loss is associated with reduced risk. Risk-based patient stratification may be needed to better understand and maximize benefits of weight loss interventions in individuals with obesity. To this end, comprehensive data from high-quality studies with extended follow-up are imperative. This study examines the link between bariatric surgery and long-term cancer outcomes, focusing on patient subgroups defined by previously suggested predictors of treatment benefit, such as sex and baseline insulin levels. METHODS AND FINDINGS:This post-hoc analysis used data from the Swedish Obese Subjects (SOS) study, a prospective, controlled intervention trial, designed to investigate the long-term effects of bariatric surgery-induced weight loss (ClinicalTrials.gov, NCT01479452). The study was conducted at 25 public surgical departments and 480 primary healthcare centers across Sweden. Between Sept 1, 1987, and Jan 31, 2001, 2,007 per-protocol patients with obesity who underwent bariatric surgery (gastric bypass, n = 266; gastric banding, n = 376; vertical banded gastroplasty, n = 1,365) and 2,040 matched controls, receiving standard nonsurgical obesity-related care, were recruited. Inclusion criteria were age 37-60 years and a body mass index (BMI) ≥34 kg/m2 for men and ≥38 kg/m2 for women. The primary outcome measures were cancer events and cancer-related deaths, captured through nearly complete data sourced from national Swedish health registries. Female-specific cancers were defined as gynecologic and breast cancers. Analyses were adjusted (adj) for baseline age, sagittal diameter, alcohol consumption, smoking, and serum insulin levels. The study was closed on December 31, 2022. Median follow-up was 26.8 years (interquartile range (IQR) [22.9, 29.6]) in the surgery group and 24.9 years (IQR [18.7, 28.8]) in the control group. Bariatric surgery was associated with a lower overall cancer incidence rate in women (adjusted hazard ratio (HRadj) = 0.78; 95% confidence interval (CI) [0.67, 0.90]; p = 0.001), but not in men (sex-treatment interaction p = 0.013). The HRadj for overall cancer mortality rate in women was 0.78 (95% CI [0.61, 1.00]; p = 0.050). In women, surgery was associated with a lower incidence rate of both obesity-related cancers (HRadj = 0.70; 95% CI [0.58, 0.85]; p < 0.001) and female-specific cancers (HRadj = 0.60; 95% CI [0.47, 0.75]; p < 0.001). Importantly, subgroup analyses showed that the associations between surgery and female-specific cancer incidence, as well as female-specific cancer-related mortality, were stronger in women with high baseline insulin levels (insulin-treatment interaction p = 0.021 and 0.039, respectively). The main limitation is that cancer was not a predefined study outcome. CONCLUSIONS:Bariatric surgery is associated with a lower risk of cancer and cancer-related mortality in women with obesity, with the strongest association observed for female-specific cancers in women with elevated baseline insulin levels. In men, bariatric surgery was not associated with overall cancer incidence or mortality. These findings support incorporating risk-based stratification to better tailor cancer prevention strategies in obesity care.

OBJECTIVE:Bariatric surgery has been suggested to improve obstructive sleep apnea (OSA) in short-term studies, but long-term evidence is limited. We evaluated remission and new onset of OSA over 20 years in participants from the Swedish Obese Subjects (SOS) study, comparing bariatric surgery with usual obesity care. METHODS:The SOS study is a nonrandomized, controlled intervention study including 4047 individuals who received bariatric surgery (n = 2010) or usual obesity care (n = 2037). OSA status was assessed via questionnaires at baseline and at 1, 2, 3, 4, 6, 8, 10, 15, and 20 years. We examined remission and new onset of OSA among participants with or without the condition at baseline, comparing surgery to usual care. RESULTS:On average over 20 years, bariatric surgery was associated with a 32.1 percentage points lower prevalence of OSA in participants with baseline OSA (95% CI: -36.9 to -27.2; p < 0.001) compared to usual care. Among those without baseline OSA, surgery patients had a 5.8 percentage points lower prevalence of new-onset OSA (95% CI: -7.1 to -4.6; p < 0.001). CONCLUSIONS:Bariatric surgery was associated with durable OSA benefits, including higher remission and lower long-term new onset of OSA compared to usual obesity care. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT01479452.

Abstract The FTO rs9939609 SNP has been linked to higher BMI, insulin resistance, and breast cancer risk. Weight loss by bariatric surgery lowers breast cancer risk, particularly in women with baseline hyperinsulinemia, but it is unclear whether this effect varies by FTO genotype. In the Swedish Obese Subjects (SOS) study, 2596 women with severe obesity were followed for a median of 23.9 years to examine breast cancer incidence after bariatric surgery compared with usual care. Genotyping for rs9939609 was performed, and breast cancer events were identified via the Swedish National Cancer Registry. Among 135 breast cancer cases (77 in the control group and 58 in the surgery group), surgery was associated with a lower breast cancer incidence in carriers of the risk allele (TA/AA) (adjusted HR = 0.53 [0.34–0.83], P = 0.005), but not in non-carriers (TT) (adjusted HR = 1.19 [0.65–2.15], P = 0.573; P for treatment-genotype interaction = 0.031). These findings suggest that the FTO rs9939609 genotype may modify the association between bariatric surgery and breast cancer incidence. Trial registration: ClinicalTrials.gov, identifier: NCT01479452.

BACKGROUND:A body of evidence supports a link between metabolic bariatric surgery (MBS) and alcohol use disorder (AUD), while the possible contribution to alcohol-related mortality remains unclear. The aim of this study was to examine the association between MBS and the risk of AUD and alcohol-related mortality over up to 35 years. METHODS:The Swedish Obese Subjects (SOS) study enrolled 2007 participants with severe obesity who underwent MBS and 2040 matched controls (median follow-up 25.2 years). Patients in the surgery group underwent gastric bypass (GBP; 266 patients), gastric banding (376 patients), or vertical banded gastroplasty (VBG; 1365 patients). The matched controls received the customary treatment for severe obesity at their primary healthcare centres. Data on AUD diagnoses and alcohol-related mortality were captured from the Swedish National Patient Register and the Swedish Cause of Death Register respectively. RESULTS:During long-term follow-up, a significant difference in the incidence of AUD was found across surgery groups (log rank P < 0.001). Patients who underwent GBP exhibited the highest AUD risk (adjusted HR (HRadj) 5.07 (95% c.i. 3.11 to 8.25); P < 0.001), followed by patients who underwent VBG (HRadj 2.28 (95% c.i. 1.56 to 3.34); P < 0.001) and patients who underwent gastric banding (HRadj 2.34 (95% c.i. 1.37 to 4.01); P = 0.002), compared with usual obesity care. Alcohol-related mortality was significantly elevated after GBP (adjusted sub-HR (sub-HRadj) 6.18 (95% c.i. 2.48 to 15.40); P < 0.001) and VBG (sub-HRadj 3.56 (95% c.i. 1.79 to 7.08); P < 0.001) compared with usual obesity care. Mortality after gastric banding was also elevated, but did not reach statistical significance (sub-HRadj 2.52 (95% c.i. 0.89 to 7.15); P = 0.082). CONCLUSION:Effective management of alcohol-related complications in MBS patients requires preoperative risk assessment, postoperative monitoring, and access to targeted interventions for AUD.

Background:The clinical implications of weight regain following weight loss remain uncertain. We analysed mortality, cardiovascular events, cancer, and microvascular disease in individuals with significant weight loss, comparing maintainers to regainers. Methods:Using a prospective cohort design, we analysed 1346 participants who underwent bariatric surgery in the Swedish Obese Subjects (SOS) study, aged 37-60 years with BMI ≥34 (men) or ≥38 (women), recruited 1987-2001. Individuals who regained ≥20% of their 1-year weight loss after 4 years (regain group) were compared to those who regained less (maintenance group). The study was closed on December 31, 2020 with median follow-up of 27 years and 99.9% mortality tracking (ClinicalTrials.govNCT01479452). Findings:Average weight loss after 1 year was 29.3 ± 11.7 kg and 31.9 ± 13.8 kg and average weight change from year 1 to year 4 was +12.7 ± 6.6 kg and -0.6 ± 7.3 kg in the regain and maintenance groups, respectively. During follow-up, regain and maintenance groups showed similar rates of total mortality and cancer, 12.4 (95% CI: 10.9-14.2) vs 12.4 (10.7-14.3), p = 0.740, and 11.3 (95% CI: 9.7-13.0) vs 10.4 (8.8-12.2) per 1000 person-years (p = 0.308), respectively. The regain group had, however, higher incidence of microvascular disease, 11.0 (95% CI: 9.5-12.8) vs 8.7 (7.3-10.4) per 1000 person-years (p = 0.024), and while not statistically significant, also higher incidence of major adverse cardiovascular events (myocardial infarction, stroke, and heart failure) 15.7 (95% CI: 13.8-17.8) vs 13.0 (11.2-15.1) per 1000 person-years (p = 0.055). Interpretation:Weight regain was linked to increased vascular disease risk but we could not demonstrate an association with life expectancy. Funding:The Swedish Research Council, the Swedish State under the agreement between the Swedish Government and the county councils, the Health & Medical Care Committee of the Region Västra Götaland, the Adlerbert Research Foundation, the Wilhelm and Martina Lundgren Foundation, the Royal Society of Arts and Sciences in Gothenburg, Academy of Finland, Finnish Medical Foundation, Gyllenberg Foundation, Novo Nordisk Foundation, Finnish Diabetes Research Foundation, Paulo Foundation and Sigrid Juselius Foundation.

Some studies of obesity treatments use control groups identified from real-world registers, which may differ from people with obesity in the general population. We evaluated whether such control groups affect the results. The SOS study examines long-term mortality post-bariatric surgery. Among volunteers with obesity, 2,007 individuals underwent surgery, while a control group of 2,040 individuals was matched using 18 variables. Age was 37–60 years and BMI was ≥ 34/≥38 kg/m2 for men and women, respectively. We subdivided the control group into those with an obesity diagnosis (n = 177) and those without an obesity diagnosis (n = 1,863) in the Swedish National Patient Register prior to study inclusion. Mortality was determined over a median follow-up period of 26 years. The controls with a prior obesity diagnosis had a higher mortality rate than the controls without a prior obesity diagnosis, with 19.7 (95

Purpose (the aim of the study): Musculoskeletal pain is more common among individuals with obesity compared to the general population. Excess mechanical load to joints in combination with endocrine and metabolic factors in the obese state may lead to an increased risk of osteoarthritis (OA) and OA-related pain in weight bearing joints. Obesity is also associated with chronic and widespread pain. Obesity treatment with bariatric surgery leads to long-term weight reduction and improves many of the co-morbidities associated with obesity.

AIMS:Life expectancy is reduced in people with obesity and is further reduced in those with concomitant type 2 diabetes. The aim of the study was to assess whether a 2-year delay in diabetes development influences life expectancy in people with obesity. MATERIALS AND METHODS:Participants from the Swedish Obese Subjects study without diabetes at baseline and known diabetes status at the 2-year follow-up were included: bariatric surgery (n = 1471) and usual obesity care (n = 1392). Median follow-up was 26.1 years (interquartile range: 22.7-28.7 years). The Swedish Cause of Death Register, case sheets and autopsy reports were assessed to determine the direct cause of death. Analyses were adjusted for preselected risk factors: inclusion year, sex, baseline age, body mass index (BMI) and smoking. RESULTS:Across both study arms, 146 participants were newly diagnosed with type 2 diabetes at the 2-year examination, whereas 2717 remained diabetes-free. Most participants diagnosed with diabetes (n = 140) were from the usual care control group. During the follow-up, there were 18.3 deaths per 1000 person-years (95% confidence interval [CI]:14.1-23.9) in the group with diagnosed diabetes at the 2-year follow-up and 10.9 deaths per 1000 person-years (95% CI:10.2-11.8) in the group that remained diabetes-free (adjusted hazard ratio [HRadj] 1.60, 95% CI: 1.19-2.15, p = 0.002). The adjusted median life expectancy in the diabetes group was 3.7 years (95% CI: 1.4-6.0, p = 0.002) shorter than in the diabetes-free group. Specifically, cardiovascular mortality was higher in the group with diabetes (adj sub-hazard ratio [sub-HR] 1.74 [95% CI: 1.09-2.77], p = 0.021). CONCLUSIONS:A 2-year delay in diabetes development may be linked to increased life expectancy, possibly due to a reduction in cardiovascular mortality. Future studies should confirm these findings.

BACKGROUND:People with obesity and type 2 diabetes (T2D) have reduced life expectancy, partly explained by increased risk of cardiovascular diseases and cancer. Here, we examined whether 2-year diabetes remission after bariatric surgery or usual care is associated with long-term mortality. MATERIALS AND METHODS:This report includes 586 participants with obesity and concomitant T2D from the prospective Swedish Obese Subjects (SOS) cohort study; 338 underwent bariatric surgery and 248 received usual obesity care. At inclusion, age was 37-60 years and BMI ≥34 kg/m 2 in men and ≥38 kg/m 2 in women. Median follow-up was 26.2 years (interquartile range 22.7-28.7). Diabetes status was determined using self-reported data on diabetes medication and in-study measures of blood glucose and HbA1c. The study was cross-linked to Swedish national registers for data on morbidity, death, and emigration. RESULTS:Overall, 284 participants, 71.9% of surgery and 16.5% of usual care patients were in remission at the 2-year examination. During follow-up, mortality rates were 16.6 deaths per 1000 person-years (95% CI: 13.7-20.1) in the remission subgroup and 26.0 deaths per 1000 person-years (95% CI:22.2-30.4) in the non-remission subgroup (adjusted hazard ratio (HR adj )=0.71, 95% CI:0.54-0.95, P =0.019). The adjusted median life expectancy in the remission subgroup was 2.5 years (95% CI:0.3-4.7) longer than in the non-remission subgroup. Specifically, remission was associated with decreased cardiovascular mortality (sub-HR adj =0.54, 95% CI: 0.35-0.85, P =0.008), but no detectable association with cancer mortality was found (sub-HR adj =1.06, 95% CI:0.60-1.86), P =0.841). CONCLUSION:In this post-hoc analysis of data from the SOS study, patients who achieved short-term diabetes remission had increased life expectancy and decreased cardiovascular death over up to 32 years of follow-up. Future studies should confirm these findings.

OBJECTIVE:The objective of this study was to study the recovery from, and incidence of, work-restricting musculoskeletal pain after bariatric surgery compared with usual obesity care. METHODS:Pain in different body regions was monitored using questionnaires in the nonrandomized, prospective, controlled Swedish Obese Subjects (SOS) study, which included 2007 participants treated with bariatric surgery and a matched control group of 2040 participants receiving usual obesity care at primary health care centers. Self-reported pain in the neck and shoulders, back, hips, knees, and ankles was captured from questionnaires administered at baseline and after 1, 2, 3, 4, 6, 8, 10, 15, and 20 years. RESULTS:Compared with matched controls, bariatric surgery was associated with better recovery from baseline work-restricting knee and ankle pain in both the short (1-4 years) and long term (up to 20 years), as well as from back and hip pain in the short term. In participants without pain at baseline, bariatric surgery was associated with a lower incidence of developing new pain in the knee and ankle in the short and long term. CONCLUSIONS:Bariatric surgery was associated with better recovery from pain, primarily in weight-bearing joints, as well as with prevention of pain development in the knee and ankle compared with matched controls receiving usual obesity care.

Importance:Obesity and insulin are risk factors for breast cancer, and retrospective studies suggest bariatric surgery reduces breast cancer risk in women. However, long-term prospective data on breast cancer risk after bariatric surgery and the role of baseline insulin levels are lacking. Objective:To examine if bariatric surgery is associated with breast cancer incidence in women and if treatment benefit is modified by baseline insulin levels. Design, Setting, and Participants:The Swedish Obese Subjects (SOS) study was a nonrandomized intervention trial designed to investigate the long-term effects of bariatric surgery on obesity-related mortality and morbidity. Study recruitment took place between 1987 and 2001, and median (IQR) follow-up time was 23.9 years (20.1-27.1) years. The study was conducted at 25 public surgical departments and 480 primary health care centers in Sweden and included 2867 women aged 37 to 60 years and with body mass index 38 or greater (calculated as weight in kilograms divided by height in meters squared). Intervention:In the surgery group (n = 1420), 260 women underwent gastric banding, 970 vertical banded gastroplasty, and 190 gastric bypass. The remaining contemporaneously matched control individuals (n = 1447) received usual obesity care. Main Outcome and Measures:Breast cancer, the main outcome of this secondary report, was not a predefined outcome in the SOS study. Breast cancer events were identified in the Swedish National Cancer Registry. Results:The study population comprised 2867 women with a mean (SD) age of 48.0 (6.2) years. During follow-up, there were 154 breast cancer events, 66 in the surgery group and 88 in the usual care group, and a decreased risk of breast cancer was observed in the bariatric surgery group (hazard ratio [HR], 0.68; 95% CI, 0.49-0.94; P = .019; adjusted HR, 0.72; 95% CI, 0.52-1.01; P = .06). The surgical treatment benefit on breast cancer risk was greater in women with baseline insulin levels above the median 15.8 μIU/L (HR, 0.48; 95% CI, 0.31-0.74; P = .001; adjusted HR, 0.55; 95% CI, 0.35-0.86; P = .008) compared to those below (HR, 0.95; 95% CI, 0.59-1.53; P = .84; adjusted HR, 1.01; 95% CI, 0.61-1.66; P = .97; interaction P = .02). Conclusions and Relevance:This prospective clinical trial indicated a reduced risk of breast cancer after bariatric surgery in women with obesity. The surgical treatment benefit was predominantly seen in women with hyperinsulinemia. Trial Registration:ClinicalTrials.gov Identifier: NCT01479452.

Objectives To determine life expectancy and causes of death after bariatric surgery in relation to baseline type 2 diabetes (T2D) in the prospective, Swedish Obese Subjects study. Methods The study included 2010 patients with obesity who underwent bariatric surgery and 2037 matched controls, eligible for surgery. The surgery group underwent gastric bypass ( n = 265), banding ( n = 376), or vertical banded gastroplasty ( n = 1369). The control group ( n = 2037) received usual obesity care. Causes of death were obtained from the Swedish Cause of Death Register, case sheets and autopsy reports, in patients with baseline T2D ( n = 392 surgery patients/ n = 305 controls) or non-T2D ( n = 1609 surgery patients/ n = 1726 controls) during a median follow-up 26 years. Results In T2D and non-T2D subgroups, bariatric surgery was associated with increased life expectancy (2.1, 95% confidence interval (95% CI) 0.2–4.0; and 1.6, 0.5–2.7 years, respectively) and reduced overall mortality (adjusted hazard ratio (adjHR) = 0.77, 95% CI: 0.61–0.97; and 0.82, 0.72–0.94, respectively), and the treatment benefit was similar (interaction p = 0.615). Bariatric surgery was associated with reduced cardiovascular mortality in both subgroups (adjHR = 0.65, 95% CI: 0.46–0.91; and 0.70, 0.55–0.88, respectively (interaction p = 0.516)). Conclusions Bariatric surgery is associated with similar reduction of overall and cardiovascular mortality and increased life expectancy regardless of baseline diabetes status.

The goal of this study was to investigate whether bariatric surgery is associated with substance use disorder (SUD) with substances other than alcohol.

Objective: To study the long-term effect of obesity and bariatric surgery on incidences of osteoarthritis and arthroplasty of hip and knee.Design: Hazard ratios (HR) and incidence rates (IR) of osteoarthritis and arthroplasty of hip and knee were studied in the prospective, controlled, non-randomized Swedish Obese Subjects (SOS) study (bariatric surgery group, n = 2007; matched controls given usual obesity care, n = 2040) and the SOS reference cohort (n = 1135, general population). Osteoarthritis diagnosis and arthroplasty for osteoarthritis were captured from the National Swedish Patient Register. Median follow-up time was 21.2 (IQR 16.4-24.8), 22.9 (IQR 19.1-25.7), and 20.1 years (IQR 18.7-20.9) for the control group, surgery group and reference cohort, respectively.Results: The surgery group displayed lower incidence of hip osteoarthritis (IR 5.3, 95% CI 4.7-6.1) compared to controls (IR 6.6, 95% CI 5.9-7.5, adjHR 0.83, 95% CI 0.69-1.00) but similar incidence of hip arthroplasty. Similar incidence of knee osteoarthritis was observed in the surgery group and controls, but knee arthroplasty was more common in the surgery group (IR 7.4, 95% CI 6.6-8.2 and 5.6, 95% CI 4.9-6.4, adjHR 1.45, 95% CI 1.22-1.74). The reference cohort displayed lower incidences of osteoarthritis and arthroplasty of hip and knee compared with the surgery group and controls.Conclusion: Bariatric surgery did not normalize the increased risk of knee and hip osteoarthritis in patients with obesity but was associated with an increased incidence of knee arthroplasty compared to the control group. With the limitations inherent to the present data, additional studies are needed to confirm these results. Trial registration: clinicaltrials.gov Identifier: NCT01479452.& COPY; 2023 The Author(s). Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).

Background Haematopoietic clones caused by somatic mutations with >= 2% variant allele frequency (VAF) increase with age and are linked to risk of haematological malignancies and cardiovascular disease. Recent observations suggest that smaller clones (VAF<2%) are also associated with adverse outcomes. Our aims were to determine the prevalence of clonal haematopoiesis driven by clones of variable sizes in individuals with obesity treated by usual care or bariatric surgery (a treatment that improves metabolic status), and to examine the expansion of clones in relation to age and metabolic dysregulation over up to 20 years.Methods Clonal haematopoiesis-driver mutations (CHDMs) were identified in blood samples from participants of the Swedish Obese Subjects intervention study. Using an ultrasensitive assay, we analysed single-timepoint samples from 1050 individuals treated by usual care and 841 individuals who had undergone bariatric surgery, and multiple-timepoint samples taken over 20 years from a subset (n = 40) of the individuals treated by usual care.Findings In this explorative study, prevalence of CHDMs was similar in the single-timepoint usual care and bariatric surgery groups (20.6% and 22.5%, respectively, P = 0.330), with VAF ranging from 0.01% to 31.15%. Clone sizes increased with age in individuals with obesity, but not in those who underwent bariatric surgery. In the multiple-timepoint analysis, VAF increased by on average 7% (range -4% to 24%) per year and rate of clone growth was negatively associated with HDL-cholesterol (R = -0.68, 1.74 E-04).Interpretation Low HDL-C was associated with growth of haematopoietic clones in individuals with obesity treated by usual care.

BACKGROUND:Bariatric surgery in people with obesity is associated with a reduced overall cancer risk. Retrospective studies indicate that bariatric surgery specifically might reduce the risk of haematological cancers, but there is an absence of data from long-term, prospective studies. We therefore studied the association between bariatric surgery and haematological cancer in the Swedish Obese Subjects study.METHODS:The prospective controlled Swedish Obese Subjects study was designed to compare overall mortality in people who underwent bariatric surgery (n=2007) and usual care (n=2040). Participants were recruited through campaigns in mass media and at 480 primary health-care centres all over Sweden. The inclusion criteria were an age of 37-60 years and a BMI of 34 kg/m2 or more in men and 38 kg/m2 or more in women before or at the time of the examination. Haematological cancer events, including malignant lymphoma, myeloma, myeloproliferative neoplasms, as well as acute and chronic leukaemias, were captured from the Swedish Cancer Registry. The main outcome of this study was haematological cancer incidence and mortality. This study is registered with ClinicalTrials.gov (NCT01479452) and is ongoing.FINDINGS:A total of 4047 individuals with obesity were enrolled between Sept 1, 1987, and Jan 31, 2001. Overall, 34 participants in the surgery group and 51 participants in the usual care control group were diagnosed with haematological cancer during follow-up (hazard ratio [HR] 0·60; 95% CI 0·39-0·92; p=0·020). Moreover, there were three deaths by haematological cancer in the surgery group and 13 deaths in the control group (0·22; 0·06-0·76; p=0·017). Surgery was also associated with a reduced incidence of lymphoma (0·45; 0·23-0·88; p=0·020). A significant difference in treatment effect between men and women was found; bariatric surgery was associated with reduced incidence of haematological cancer in women (0·44; 0·26-0·74; p=0·002), but not in men (1·35; 0·58-3·17; p=0·489; interaction p=0·031).INTERPRETATION:Bariatric surgery is associated with a reduced incidence of haematological cancer, specifically in women. Health-care providers and policy makers working in the field of cancer prevention should consider bariatric surgery a primary prevention resource for people with obesity.FUNDING:The Swedish Research Council, the Swedish State under the agreement between the Swedish Government and the county councils, the Avtal om Läkarutbildning och Forskning agreement, the Health & Medical Care Committee of the Region Västra Götaland, the Swedish Heart Lung Foundation, Gothenburg Medical Society, and the Adlerbert Research Foundation.TRANSLATION:For the Swedish translation of the abstract see Supplementary Material section.

Background Elevated serum levels of serum amyloid A (SAA) are associated with increased risk of cardiovascular disease. In this study, we examine associations between allelic variation in the rs11024595 single nucleotide polymorphism (SNP) in the 5’ flanking region of the SAA1 gene and adipose tissue gene expression, serum levels of SAA and cardiovascular risk factors. Methods DNA samples from 729 participants in the SibPair study, comprising weight discordant siblings and their biological parents, and 3542 participants (1783 patients treated with bariatric surgery and 1759 controls) from the Swedish Obese Subjects (SOS) study were used. The rs11024595 SNP was genotyped in both cohorts using Pyrosequencing or the Sequenom MassARRAY platform, respectively. Blood chemistry and anthropometry were assessed at study start. Adipose tissue SAA1 gene expression and serum levels of SAA in the SibPair study were analyzed with DNA microarray or immunoassay, respectively. Results In the SibPair study, the rs11024595 SNP was associated with serum levels of SAA ( P = 0.0050) where T allele carriers displayed lower levels of SAA ( P = 0.0025) but no association between genotype and adipose tissue SAA1 gene expression was found. In the SOS study, the rs11024595 SNP was associated with serum levels of HDL cholesterol ( P = 0.0045), triglycerides ( P = 0.025) and apolipoprotein E ( P = 0.026). Moreover, T allele carriers had lower levels of HDL cholesterol ( P = 0.0148), but higher levels of triglycerides ( P = 0.0418) and apolipoprotein E ( P = 0.028) compared to C allele homozygotes. The rs11024595 SNP was also associated with plasma glucose ( P = 0.044). Conclusions The rs11024595 SNP in the 5’ flanking region of the SAA1 gene is associated with both serum levels of SAA and other cardiovascular risk factors. Future studies are required to elucidate whether the rs11024595 SNP can affect the risk of cardiovascular events. Trial registration ClinicalTrials.gov Identifier: NCT01479452 Registered 24 November 2011 - retrospectively registered.

Elucidationof mechanisms that govern lipid storage, oxidative stress and insulinresistance may lead to improved therapeutic options for type 2 diabetes and otherobesity-related diseases. Here, we find that adipose expression of the small neutral amino acid transporterSLC7A10, also known as alanine-serine-cysteine transporter 1 (ASC-1), showsstrong inverse correlates with visceral adiposity, insulin resistance andadipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10function in zebrafish in vivo accelerates diet-induced body weight gainand adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human andmurine adipocytes decreases adipocyte serine uptake and total glutathionelevels and promotes reactive oxygen species (ROS) generation. Conversely,SLC7A10 overexpression decreases ROS generation and increases mitochondrialrespiratory capacity. RNA-sequencing revealed consistent changes in geneexpression between human adipocytes and zebrafish visceral adipose tissuefollowing loss of SLC7A10, e.g., upregulation of SCD (lipid storage) anddownregulation of CPT1A (lipid oxidation). Interestingly, ROS scavengerreduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10inhibition. These data uncover adipocyte SLC7A10 as a novel important regulatorof adipocyte resilience to nutrient and oxidative stress, in part by enhancingglutathione levels and mitochondrial respiration, conducive to decreased ROS generation,lipid accumulation, adipocyte hypertrophy, insulin resistance and type 2diabetes.