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Aims/hypothesis We investigated whether the impacts of childhood adiposity on adult-onset diabetes differ across proposed diabetes subtypes using a Mendelian randomisation (MR) design. Methods We performed MR analysis using data from European genome-wide association studies of childhood adiposity, latent autoimmune diabetes in adults (LADA, proxy for severe autoimmune diabetes), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD) and mild age-related diabetes (MARD). Results Higher levels of childhood adiposity had positive genetically predicted effects on LADA (OR 1.62, 95% CI 1.05, 2.52), SIDD (OR 2.11, 95% CI 1.18, 3.80), SIRD (OR 2.76, 95% CI 1.60, 4.75) and MOD (OR 7.30, 95% CI 4.17, 12.78), but not MARD (OR 1.06, 95% CI 0.70, 1.60). Conclusions/interpretation Childhood adiposity is a risk factor not only for adult-onset diabetes primarily characterised by obesity or insulin resistance, but also for subtypes primarily characterised by insulin deficiency or autoimmunity. These findings emphasise the importance of preventing childhood obesity. Graphical abstract

Type 2 diabetes has been reproducibly clustered into five subtypes with different disease progression and risk of complications; however, etiological differences are unknown. We used genome-wide association and genetic risk score (GRS) analysis to compare the underlying genetic drivers. Individuals from the Swedish ANDIS (All New Diabetics In Scania) study were compared to individuals without diabetes; the Finnish DIREVA (Diabetes register in Vasa) and Botnia studies were used for replication. We show that subtypes differ with regard to family history of diabetes and association with GRS for diabetes-related traits. The severe insulin-resistant subtype was uniquely associated with GRS for fasting insulin but not with variants in the TCF7L2 locus or GRS reflecting insulin secretion. Further, an SNP (rs10824307) near LRMDA was uniquely associated with mild obesity-related diabetes. Therefore, we conclude that the subtypes have partially distinct genetic backgrounds indicating etiological differences. Genome-wide association and genetic risk score analyses highlight differences in genetic architecture across five subtypes of diabetes.

Sudden unexpected death in epilepsy (SUDEP) is a leading epilepsy-related cause of death. Researchers have highlighted the similarities between SUDEP and sudden infant death syndrome (SIDS), but perinatal risk factors such as those identified for SIDS have not been assessed previously for SUDEP. We conducted a population-based case-control study of 58 SUDEP individuals and 384 living epilepsy controls born after 1982, utilizing the Swedish Medical Birth Register together with other national health registers and individual medical records to examine if prenatal and perinatal factors are associated with SUDEP risk. We observed a 3-fold SUDEP risk increase for infants who were small for gestational age (SGA) (odds ratio [OR] 3.13; 95% confidence interval [CI] 1.05-9.30) and for those with an Apgar score of 0-6 compared to 9-10 at 10 min (OR 3.22; 95% CI 1.05-9.87). After adjusting for a number of known SUDEP risk factors, we observed that the Apgar score between 0 and 6 after 10 min had a 10-fold increased risk for SUDEP OR 10.37 (95% CI 1.49-72.01) and over a 2-fold risk for those born after the 40th gestational week (OR 2.42; 95% CI 1.03-5.65). The potential mechanisms linking low Apgar score, gestational age, and SGA to SUDEP risk remain to be explored.

Objective Population‐based data on epilepsy syndromes and etiologies in early onset epilepsy are scarce. The use of next‐generation sequencing (NGS) has hitherto not been reported in this context. The aim of this study is to describe children with epilepsy onset before 2 years of age, and to explore to what degree whole exome and whole genome sequencing (WES/WGS) can help reveal a molecular genetic diagnosis. Methods Children presenting with a first unprovoked epileptic seizure before age 2 years and registered in the Stockholm Incidence Registry of Epilepsy (SIRE) between September 1, 2001 and December 31, 2006, were retrieved and their medical records up to age 7 years reviewed. Children who met the epilepsy criteria were included in the study cohort. WES/WGS was offered in cases of suspected genetic etiology regardless of whether a structural or metabolic diagnosis had been established. Results One hundred sixteen children were included, of which 88 had seizure onset during the first year of life and 28 during the second, corresponding to incidences of 139 and 42/100 000 person‐years, respectively. An epilepsy syndrome could be diagnosed in 54% of cases, corresponding to a birth prevalence of 1/1100. Structural etiology was revealed in 34% of cases, a genetic cause in 20%, and altogether etiology was known in 65% of children. The highest diagnostic yield was seen in magnetic resonance imaging (MRI) with 65% revealing an etiology. WES/WGS was performed in 26/116 cases (22%), with a diagnostic yield of 58%. Significance Epilepsy syndromes can be diagnosed and etiologies revealed in a majority of early onset cases. NGS can identify a molecular diagnosis in a substantial number of children, and should be included in the work‐up, especially in cases of epileptic encephalopathy, cerebral malformation, or metabolic disease without molecular diagnosis. A genetic diagnosis is essential to genetic counselling, prenatal diagnostics, and precision therapy.

Our aim was to synthesize current evidence on the association between parental smoking and incidence of type 1 diabetes and islet autoantibody positivity (IA) in the offspring by conducting a systematic review and meta-analysis.We searched Medline, Embase, and Cochrane Library until January 21, 2021, for human studies with parental tobacco use as exposure, type 1 diabetes or IA as outcome, and hazard, risk, or odds ratios as effect estimates. Summary relative risks (RR) and 95% confidence intervals (CI) were estimated with random-effects models. Heterogeneity was quantified with the IWe identified 535 records of which 23 were eligible including 25 927 cases of type 1 diabetes. Maternal smoking during pregnancy was associated with a reduced risk of type 1 diabetes (n = 22, RR 0.78, CI 0.71-0.86, IMaternal smoking during pregnancy may reduce the risk of type 1 diabetes in the offspring. Further studies are needed to elucidate potential mechanisms underlying this association.Prospero CRD42021236717.

Aims/hypotheses Smoking and use of smokeless tobacco (snus) are associated with an increased risk of type 2 diabetes. We investigated whether smoking and snus use increase the risk of latent autoimmune diabetes in adults (LADA) and elucidated potential interaction with HLA high-risk genotypes. Methods Analyses were based on Swedish case–control data (collected 2010–2019) with incident cases of LADA (n=593) and type 2 diabetes (n=2038), and 3036 controls, and Norwegian prospective data (collected 1984–2019) with incident cases of LADA (n=245) and type 2 diabetes (n=3726) during 1,696,503 person-years of follow-up. Pooled RRs with 95% CIs were estimated for smoking, and ORs for snus use (case–control data only). The interaction was assessed by attributable proportion (AP) due to interaction. A two-sample Mendelian randomisation (MR) study on smoking and LADA/type 2 diabetes was conducted based on summary statistics from genome-wide association studies. Results Smoking (RRpooled 1.30 [95% CI 1.06, 1.59] for current vs never) and snus use (OR 1.97 [95% CI 1.20, 3.24] for ≥15 box-years vs never use) were associated with an increased risk of LADA. Corresponding estimates for type 2 diabetes were 1.38 (95% CI 1.28, 1.49) and 1.92 (95% CI 1.27, 2.90), respectively. There was interaction between smoking and HLA high-risk genotypes (AP 0.27 [95% CI 0.01, 0.53]) in relation to LADA. The positive association between smoking and LADA/type 2 diabetes was confirmed by the MR study. Conclusions/interpretation Our findings suggest that tobacco use increases the risk of LADA and that smoking acts synergistically with genetic susceptibility in the promotion of LADA. Data availability Analysis codes are shared through GitHub (https://github.com/jeseds/Smoking-use-of-smokeless-tobacco-HLA-genotypes-and-incidence-of-LADA). Graphical abstract

Objective: Type 1 diabetes is described to have an acute onset, but autoantibodies can appear several years preceding diagnosis. This suggests a long preclinical phase, which may also include metabolic parameters. Here we assessed whether elevations in glycaemic, lipid, and other metabolic biomarkers were associated with future type 1 diabetes risk in adults. Research Design and Methods: We studied 591,239 individuals from the Swedish AMORIS cohort followed from 1985-1996 to 2012. Through linkage to national patient, diabetes, and prescription registers, we identified incident type 1 diabetes. Using Cox regression models, we estimated hazard ratios for biomarkers at baseline and incident type 1 diabetes. We additionally assessed trajectories of biomarkers during the 25 years before type 1 diabetes diagnosis in a nested case-control design. Results: We identified 1,122 type 1 diabetes cases during follow-up (average age at diagnosis: 53.3 years). The biomarkers glucose, fructosamine, triglycerides, the apolipoprotein B/A-I ratio, uric acid, alkaline phosphatase, and BMI were positively associated with type 1 diabetes risk. A higher apolipoprotein A-I was associated with a lower type 1 diabetes incidence. Already 15 years before diagnosis, type 1 diabetes cases had higher mean glucose, fructosamine, triglycerides, and uric acid levels compared to controls. Conclusion: Alterations in biomarker levels related to glycaemia, lipid metabolism, and inflammation are associated with clinically diagnosed type 1 diabetes risk, and these may be elevated many years preceding diagnosis.

AimsObservational studies have found an increased risk of latent autoimmune diabetes in adults (LADA) associated with low birth weight and adult overweight/obesity. We aimed to investigate whether these associations are causal, using a two-sample Mendelian randomization (MR) design. In addition, we wanted to compare results for LADA and type 2 diabetes. MethodsWe identified 129 SNPs as instrumental variables (IVs) for birth weight from a genome-wide association study (GWAS) of the Early Growth Genetics Consortium (EGG) and the UK Biobank. We identified 820 SNPs as IVs for adult BMI from a GWAS of the UK Biobank and the Genetic Investigation of ANthropometric Traits consortium (GIANT). Summary statistics for the associations between IVs and LADA were extracted from the only GWAS involving 2,634 cases and 5,947 population controls. We used the inverse-variance weighted (IVW) estimator as our primary analysis, supplemented by a series of sensitivity analyses. ResultsGenetically determined birth weight was inversely associated with LADA (OR per SD [[~]500 g] decrease in birth weight: 2.02, 95% CI: 1.37-2.97). In contrast, genetically predicted BMI in adulthood was positively associated with LADA (OR per SD [[~]4.8 kg/m2] increase in BMI: 1.40, 95% CI: 1.14-1.71). Results persisted in a range of sensitivity analyses using other MR estimators or excluding some IVs. With respect to type 2 diabetes, the association with birth weight was not stronger than in LADA while the association with adult BMI was stronger than in LADA. Conclusions/ interpretationThis study provides genetic support for a causal link between low birth weight, adult overweight/obesity, and LADA. Research in contextO_LIWhat is already known about this subject? (maximum of 3 bullet points) Previous Mendelian randomization studies have found that both lower birth weight and higher adult BMI are associated with an increased risk of type 2 diabetes. In contrast, the evidence on latent autoimmune diabetes in adults (LADA) is very limited. Only a few observational studies indicated an inverse association between birth weight and LADA, or a positive association between adult BMI and LADA. C_LIO_LIWhat is the key question Are birth weight and adult adiposity causally associated with LADA? C_LIO_LIWhat are the new findings Genetically determined birth weight was inversely associated with LADA while genetically predicted BMI in adulthood was positively associated with LADA. The association with birth weight was not weaker for LADA than for type 2 diabetes, while adult BMI had a greater impact on type 2 diabetes than on LADA. C_LIO_LIHow might this impact on clinical practice in the foreseeable future Findings from this study indicate that measures should be taken to reduce the prevalence of adult overweight/obesity for the prevention of diabetes with and without an autoimmune component. The mechanism linking low birth weight to diabetes remains to be explored. C_LI

Aims/hypothesis Observational studies have found an increased risk of latent autoimmune diabetes in adults (LADA) associated with low birthweight and adult overweight/obese status. We aimed to investigate whether these associations are causal, using a two-sample Mendelian randomisation (MR) design. In addition, we compared results for LADA and type 2 diabetes. Methods We identified 43 SNPs acting through the fetal genome as instrumental variables (IVs) for own birthweight from a genome-wide association study (GWAS) of the Early Growth Genetics Consortium (EGG) and the UK Biobank. We identified 820 SNPs as IVs for adult BMI from a GWAS of the UK Biobank and the Genetic Investigation of ANthropometric Traits consortium (GIANT). Summary statistics for the associations between IVs and LADA were extracted from the only GWAS involving 2634 cases and 5947 population controls. We used the inverse-variance weighted (IVW) estimator as our primary analysis, supplemented by a series of sensitivity analyses. Results Genetically determined own birthweight was inversely associated with LADA (OR per SD [~500 g] decrease in birthweight 1.68 [95% CI 1.01, 2.82]). In contrast, genetically predicted BMI in adulthood was positively associated with LADA (OR per SD [~4.8 kg/m2] increase in BMI 1.40 [95% CI 1.14, 1.71]). Robust results were obtained in a range of sensitivity analyses using other MR estimators or excluding some IVs. With respect to type 2 diabetes, the association with birthweight was not stronger than in LADA while the association with adult BMI was stronger than in LADA. Conclusions/ interpretation This study provides genetic support for a causal link between low birthweight, adult overweight/obese status and LADA. Graphical abstract

Background: In order to prevent diabetes it is important to identify common, modifiable risk factors in the population. Such knowledge is extensive for type 2 diabetes but limited for autoimmune forms of diabetes. Objective: This review aims at summarizing the limited literature on potential environmental (lifestyle) risk factors for LADA. Methods: A PubMed search identified 15 papers estimating the risk of LADA in relation to lifestyle. These were based on data from two population-based studies; one Swedish case-control study and one Norwegian cohort study. Results: Studies published to date indicate that the risk of LADA is associated with factors promoting insulin resistance and type 2 diabetes such as overweight, physical inactivity, smoking, low birth weight, sweetened beverage intake and moderate alcohol consumption (protective). Findings also indicate potential effects on autoimmunity exerted by intake of coffee (harmful) and fatty fish (protective). This supports the concept of LADA as being a hybrid form of diabetes with an etiology including factors associated with both insulin resistance and autoimmunity. Conclusion: LADA may in part be preventable through the same lifestyle modifications as type 2 diabetes including weight loss, physical activity and smoking cessation. However, current knowledge is hampered by the small number of studies and the fact that they exclusively are based on Scandinavian populations. There is a great need for additional studies exploring the role of lifestyle factors in the development of LADA.

Background Smoking and use of Swedish smokeless tobacco (snus) are associated with increased risk of type 2 diabetes (T2D). Our aim was to estimate the unique and shared genetic components of these traits and to what extent the association is explained by shared genetic factors. Methods We used twins of the Swedish Twin Registry who responded to a questionnaire between 1998 and 2006 (n = 40 247) and were followed until 2015 in the National Prescription and Patient Registries. We estimated hazard ratios (HRs) and odds ratios (ORs) for the association between smoking/snus use and T2D (n = 2130) and used structural equation models to estimate genetic and environmental variance components and genetic correlations. Results Current smokers [HR 1.69, 95% confidence interval (CI), 1.49–1.92] and snus users (HR 1.19, 95% CI 1.01–1.41) had an increased risk of T2D. In within-pair analyses of monozygotic twins, corresponding ORs were 1.36, 95% CI 0.75–2.46 (smoking) and 1.54, 95% CI 0.80–2.99 (snus). Heritability was 43% (95% CI 36–51) for ever smoking, 58% (95% CI 44– 70) for ever snus use and 66% (95% CI 59–72) for T2D. The genetic correlation with T2D was 18% (95% CI 1–35) for smoking and –6% (95% CI –24 to 4) for snus use, indicating that only a small fraction of the genetic influence is shared. Conclusions We could confirm that consumers of snus and cigarettes are at increased risk of T2D. Both snus use and smoking have strong genetic components, which appears to be attributable primarily to genes that are distinct from those promoting T2D.

Purpose Sweetened beverage consumption is associated with type 2 diabetes (T2D) and LADA. We investigated to what extent this association is mediated by BMI and whether it is modified by genotypes of HLA, TCF7L2 rs7903146, or FTO rs9939609. Methods Swedish case–control data including incident cases of LADA (n = 386) and T2D (n = 1253) with matched population-based controls (n = 1545) was used. We estimated adjusted ORs of diabetes (95% CI) in relation to sweetened beverage intake (per daily 200 mL serving) and genotypes. The impact of BMI was estimated using causal mediation methodology. Associations with HOMA-IR and HOMA-B were explored through linear regression. Results Sweetened beverage intake was associated with increased risk of LADA (OR 1.15, 95% CI 1.03–1.29) and T2D (OR 1.21, 1.11–1.32). BMI was estimated to mediate 17% (LADA) and 56% (T2D) of the total risk. LADA was associated with risk variants of HLA (3.44, 2.63–4.50) and TCF7L2 (1.27, 1.00–1.61) but not FTO. Only among non-carriers of high-risk HLA genotypes was sweetened beverage intake associated with risk of LADA (OR 1.32, 1.06–1.56) and HOMA-IR (beta = 0.162, p = 0.0047). T2D was associated with TCF7L2 and FTO but not HLA, and the risk conferred by sweetened beverages appeared modified by FTO (OR 1.45, 95% CI 1.21–1.73 in non-carriers). Conclusions Our findings suggest that sweetened beverages are associated with LADA and T2D partly through mediation by excess weight, but possibly also through other mechanisms including adverse effects on insulin sensitivity. These effects seem more pronounced in individuals without genetic susceptibility.

Purpose Red meat consumption is positively associated with type 1 (T1D) and type 2 (T2D) diabetes. We investigated if red meat consumption increases the risk of latent autoimmune diabetes in adults (LADA) and T2D, and potential interaction with family history of diabetes (FHD), HLA and TCF7L2 genotypes. Methods Analyses were based on Swedish case–control data comprising incident cases of LADA (n = 465) and T2D (n = 1528) with matched, population-based controls (n = 1789; n = 1553 in genetic analyses). Multivariable-adjusted ORs in relation to self-reported processed and unprocessed red meat intake were estimated by conditional logistic regression models. Attributable proportion (AP) due to interaction was used to assess departure from additivity of effects. Results Consumption of processed red meat was associated with increased risk of LADA (per one servings/day OR 1.27, 95% CI 1.07–1.52), whereas no association was observed for unprocessed red meat. For T2D, there was no association with red meat intake once BMI was taken into account. The combination of high (> 0.3 servings/day vs. less) processed red meat intake and high-risk HLA-DQB1 and -DRB1 genotypes yielded OR 8.05 (95% CI 4.86–13.34) for LADA, with indications of significant interaction (AP 0.53, 95% CI 0.32–0.73). Results were similar for the combination of FHD-T1D and processed red meat. No interaction between processed red meat intake and FHD-T2D or risk variants of TCF7L2 was seen in relation to LADA or T2D. Conclusion Consumption of processed but not unprocessed red meat may increase the risk of LADA, especially in individuals with FHD-T1D or high-risk HLA genotypes.

Aims: We investigated the risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes in relation to a healthy lifestyle, the proportion of patients attributable to an unhealthy lifestyle, and the influence of family history of diabetes (FHD) and genetic susceptibility. Methods: The population-based study included incident LADA (n = 571), type 2 diabetes (n = 1962), and matched controls (n = 2217). A healthy lifestyle was defined by BMI < 25 kg/m2, moderate-to-high physical activity, a healthy diet, no smoking, and moderate alcohol consumption. We estimated odds ratios (OR) with 95% confidence intervals (CIs) adjusted for age, sex, education, and FHD. Results: Compared to a poor/moderate lifestyle, a healthy lifestyle was associated with a reduced risk of LADA (OR 0.51, CI 0.34-0.77) and type 2 diabetes (OR 0.09, CI 0.05-0.15). A healthy lifestyle conferred a reduced risk irrespective of FHD and high-risk HLA genotypes. Having a BMI < 25 kg/m2 conferred the largest risk reduction for both LADA (OR 0.54, CI 0.43-0.66) and type 2 diabetes (OR 0.12, CI 0.10-0.15) out of the individual items. Conclusion: People with a healthy lifestyle, especially a healthy body weight, have a reduced risk of LADA including those with genetic susceptibility to diabetes. (C) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

PurposeThe paper explores a management fashion within the Swedish Public Sector called intrapreneurships. Intrapreneurships became popular during a period of public debate on what forms of organizing are most suitable for the production of welfare. However, while the popularity of the model was short-lived, a few municipalities nevertheless constitute examples of where it was supported for a longer period. The aim of this paper is to investigate how the model became continuously legitimate having lost its appeal elsewhere.Design/methodology/approachThe paper comprises a longitudinal analysis of two municipalities. Field-material was collected through qualitative methods including interviews (35 interviews, 42 interviewees) and document analysis.FindingsThe results draw attention to how management fashions become enduring. The metaphor of translation highlights how different professional actors in a local setting apply editing rules, and how they constitute work acquired for continuous translation of the model in order to make it legitimate, disseminated and supported. The study draws particular attention to the large number of actors involved in the editing process.Originality/valueBesides an extended understanding of management concepts, to explain the anomaly of a long-standing management fashion, the paper illustrates the importance of acknowledging editing as processes and not process. A key notion in why intrapreneurships became legitimate is that professional actors edited the model differently in order to satisfy their desires and needs. This contradicts the more common case study design in translation studies, which seeks a unitary translation process, in a single local setting.

Type 2 diabetes has been reproducibly clustered into five subtypes with different disease progression and risk of complications; however, etiological differences are unknown. We used genome-wide association and genetic risk score (GRS) analysis to compare the underlying genetic drivers. Individuals from the Swedish ANDIS (All New Diabetics In Scania) study were compared to individuals without diabetes; the Finnish DIREVA (Diabetes register in Vasa) and Botnia studies were used for replication. We show that subtypes differ with regard to family history of diabetes and association with GRS for diabetes-related traits. The severe insulin-resistant subtype was uniquely associated with GRS for fasting insulin but not with variants in the TCF7L2 locus or GRS reflecting insulin secretion. Further, an SNP (rs10824307) near LRMDA was uniquely associated with mild obesity-related diabetes. Therefore, we conclude that the subtypes have partially distinct genetic backgrounds indicating etiological differences.

BackgroundType 2 diabetes (T2D) is a multi-organ disease defined by hyperglycemia resulting from different disease mechanisms. Using clinical parameters measured at diagnosis (age, BMI, HbA1c, HOMA2-B, HOMA2-IR and GAD autoantibodies) adult patients with diabetes have been reproducibly clustered into five subtypes, that differed clinically with respect to disease progression and outcomes.1 In this study we use genetic information to investigate if these subtypes have distinct underlying genetic drivers.MethodsGenome-wide association (GWAS) and genetic risk score (GRS) analysis was performed in Swedish (N=12230) and Finnish (N=4631) cohorts. Family history was recorded by questionnaires.ResultsSevere insulin-deficient diabetes (SIDD) and mild obesity-related diabetes (MOD) groups had the strongest family history of T2D. A GRS including known T2D loci was strongly associated with SIDD (OR per 1 SD increment [95% CI]=1.959 [1.814-2.118]), MOD (OR 1.726 [1.607-1.855]) and mild age-related diabetes (MARD) (OR 1.771 [1.671-1.879]), whereas it was less strongly associated with severe insulin-resistant diabetes (SIRD, OR 1.244 [1.157-1.337]), which was similar to severe autoimmune diabetes (SAID, OR 1.282 [1.160-1.418]). SAID showed strong association with the GRS for T1D, whereas the non-autoimmune subtype SIDD was most strongly associated with the GRS for insulin secretion rate (P−9). SIRD showed no association with variants in TCF7L2 or any GRS reflecting insulin secretion. Instead, only SIRD was associated with GRS for fasting insulin (P=3.10×10−8). Finally, a T2D locus, rs10824307 near the ZNF503 gene was uniquely associated with MOD (ORmeta=1.266 (1.170-1.369), P=4.3×10−9).ConclusionsNew diabetes subtypes have partially different genetic backgrounds and subtype-specific risk loci can be identified. Especially the SIRD subtype stands out by having lower heritability and less involvement of beta-cell related pathways in its pathogenesis.Research in contextEvidence before this studyIn March 2018 we suggested a novel subclassification of diabetes into five subtypes. This classification was based on clustering using clinical parameters commonly measured at diabetes diagnosis (age at diabetes onset, HbA1c, bodymass index, presence of GAD autoantibodies and HOMA2 indices for insulin resistance and secretion). These subtypes differed with respect to clinical characteristics, disease progression and risk of complications, but it remained unclear to what extent these subtypes have different underlying pathologies. In our original publication we analysed a small set of genetic risk variants for diabetes and found differential associations between subtypes, suggesting potential aetiological differences.Added value of this studyIn this study we have conducted a full genome analysis of the original ANDIS cohort, including genome-wide association studies and polygenic risk score analysis with replication in an independent cohort. We have also compared heritability and prevalence of having a family history of diabetes in the subtypes.Implications of all the available evidenceWe demonstrate that stratification into subtypes facilitates identification of genetic risk loci and that the aetiology of the subtypes is at least partially distinct. These results are especially important for the future study and treatment of individuals belonging to the severe insulin-resistant diabetes (SIRD) subtype, whose pathogenesis appears to differ substantially from that of traditional T2D.

Objective We conducted a long-term follow-up of a cohort of children with newly diagnosed unprovoked seizures to assess treatment with antiepileptic drugs (AEDs), neuroleptics, antidepressants and medication for attention deficit hyperactivity disorder (ADHD) with special attention to the impact of comorbidities on the use of such medication. Methods Our study cohort comprised 769 children (28 days-18 years), living in Stockholm Sweden, with a first unprovoked seizure identified between 2001 and 2006. Information on neurodevelopmental comorbidities and Cerebral Palsy (CP) at seizure onset was collected from medical records. Information on treatment with AEDs, neuroleptics, antidepressants and ADHD medication was retrieved by linkage to the Swedish National Prescription Registry between 2005 and 2014. The association between comorbidities and drug treatments was assessed by odds ratios (OR) with 95 % confidence intervals (CI), adjusted for age and sex. Results Eight years after the index seizure, 31 % of the children were on AEDs, and this was more common among children with any of the comorbidities studied (OR; 4.0 95 % CI 2.9−5.6) compared to those without such comorbidities, and within this group of comorbidities particularly for those with CP (OR; 5.2 95 % CI: 2.9−9.3). Children with neurodevelopmental comorbidity or CP at baseline were more likely to receive neuroleptics (ORs 8 years after the index seizure; 6.9, 95 % CI: 2.4−19.8), antidepressants (OR; 2.3, 95 % CI: 1.0−5.5) and ADHD medication (OR; 3.6, 95 % CI: 1.8−7.2) than children without the studied comorbidities. Conclusion Children with seizures in combination with neurodevelopmental comorbidities or CP, especially CP, have a more frequent use of AEDs, neuroleptics, antidepressants, and ADHD medication up to 13 years following the initial seizure than children without comorbidity. Our data highlight the treatment burden in children with epilepsy and comorbidities.

ObjectiveWe conducted a nationwide case-control study in Sweden to test the hypothesis that specific clinical characteristics are associated with increased risk of sudden unexpected death in epilepsy (SUDEP).MethodsThe study included 255 SUDEP cases (definite and probable) and 1,148 matched controls. Clinical information was obtained from medical records and the National Patient Register. The association between SUDEP and potential risk factors was assessed by odds ratios (ORs) and 95% confidence intervals (CIs) and interaction assessed by attributable proportion due to interaction (AP).ResultsExperiencing generalized tonic-clonic seizures (GTCS) during the preceding year was associated with a 27-fold increased risk (OR 26.81, 95% CI 14.86–48.38), whereas no excess risk was seen in those with exclusively non-GTCS seizures (OR 1.15, 95% CI 0.54–48.38). The presence of nocturnal GTCS during the last year of observation was associated with a 15-fold risk (OR 15.31, 95% CI 9.57–24.47). Living alone was associated with a 5-fold increased risk of SUDEP (OR 5.01, 95% CI 2.93–8.57) and interaction analysis showed that the combination of not sharing a bedroom and having GTCS conferred an OR of 67.10 (95% CI 29.66–151.88), with AP estimated at 0.69 (CI 0.53–0.85). Among comorbid diseases, a previous diagnosis of substance abuse or alcohol dependence was associated with excess risk of SUDEP.ConclusionsIndividuals with GTCS who sleep alone have a dramatically increased SUDEP risk. Our results indicate that 69% of SUDEP cases in patients who have GTCS and live alone could be prevented if the patients were not unattended at night or were free from GTCS.

Export Date: 31 October 2018 Aim. - Coffee consumption is inversely related to risk of type 2 diabetes (T2D). In contrast, an increased risk of latent autoimmune diabetes in adults (LADA) has been reported in heavy coffee consumers, primarily in a subgroup with stronger autoimmune characteristics. Our study aimed to investigate whether coffee consumption interacts with HLA genotypes in relation to risk of LADA. Methods. - This population-based study comprised incident cases of LADA (n = 484) and T2D (n = 1609), and also 885 healthy controls. Information on coffee consumption was collected by food frequency questionnaire. Odds ratios (ORs) with 95% CIs of diabetes were calculated and adjusted for age, gender, BMI, education level, smoking and alcohol intake. Potential interactions between coffee consumption and high-risk HLA genotypes were calculated by attributable proportion (AP) due to interaction. Results. - Coffee intake was positively associated with LADA in carriers of high-risk HLA genotypes (OR: 1.14 per cup/day, 95% CI: 1.02-1.28), whereas no association was observed in non-carriers (OR: 1.04, 95% CI: 0.93-1.17). Subjects with both heavy coffee consumption (>= 4 cups day) and high-risk HLA genotypes had an OR of 5.74 (95% Cl: 3.34-9.88) with an estimated AP of 0.36 (95% CI: 0.01-0.71; P = 0.04370). Conclusion. - Our findings suggest that coffee consumption interacts with HLA to promote LADA. (C) 2018 Elsevier Masson SAS. All rights reserved.

OBJECTIVE Given the increasing attention being paid to potential strategies for sudden unexpected death in epilepsy (SUDEP) prevention, we analyzed the circumstances of SUDEP and its incidence in relation to time of year, week, and day. METHODS Prospective case-series based on persons with an International Classification of Diseases (ICD-10) code for epilepsy in the Swedish Patient Registry 1998-2005, who were alive on June 30, 2006 (n = 60 952). Linkage to the National Cause-of-Death Registry identified all deaths from July 2006 through December 2011, with epilepsy mentioned on death certificate, together with all deaths during 2008 (n = 3166). Death certificates, medical charts, autopsy, and police reports were reviewed to identify SUDEP cases and related circumstances. Autopsied non-SUDEP deaths (n = 60) from the study population served as a reference. RESULTS There were 329 SUDEPs (63% men) of which 167 were definite, 89 probable, and 73 possible. SUDEP cases were younger at death (50.8 years) than non-SUDEP deaths (73.3 years) (P < .001) and more likely to be male (63% vs 55%, P = .0079). Most SUDEP cases died at night (58%), at home (91%), and 65% were found dead in bed. When documented, 70% were found in prone position. In 17%, death was witnessed and in 88% of these, a seizure was observed. Of the 329 SUDEP cases, 71% were living alone and 14% shared a bedroom. Compared to an autopsied non-SUDEP reference group, definite SUDEPs were more likely to die at home, during the night, unwitnessed, in the prone position, to live alone, and more often with a preceding seizure. SIGNIFICANCE SUDEP cases live alone, die unwitnessed at home at night, with indication of a preceding seizure, supporting the critical role of lack of supervision. These facts need to be considered in the development of preventive strategies.

Aims/hypothesis Excessive weight is a risk factor for type 2 diabetes, but its role in the promotion of autoimmune diabetes is not clear. We investigated the risk of latent autoimmune diabetes in adults (LADA) in relation to overweight/obesity in two large population-based studies. Methods Analyses were based on incident cases of LADA (n = 425) and type 2 diabetes (n = 1420), and 1704 randomly selected control participants from a Swedish case–control study and prospective data from the Norwegian HUNT Study including 147 people with LADA and 1,012,957 person-years of follow-up (1984–2008). We present adjusted ORs and HRs with 95% CI. Results In the Swedish data, obesity was associated with an increased risk of LADA (OR 2.93, 95% CI 2.17, 3.97), which was even stronger for type 2 diabetes (OR 18.88, 95% CI 14.29, 24.94). The association was stronger in LADA with low GAD antibody (GADA

ObjectiveTo study the risk for injuries/accidents in people with newly diagnosed epileptic seizures in relation to comorbidities.MethodsBetween September 1, 2001, and August 31, 2008, individuals in northern Stockholm with incident unprovoked seizures (epilepsy; n = 2,130) were included in a registry. For every epilepsy patient, 8 individuals matched for sex and inclusion year (n = 16,992) were randomly selected as references from the population of the catchment area. Occurrence of injuries/accidents was monitored through the national patient and cause of death registers until December 31, 2013. These registers also provided information on comorbidities (e.g., brain tumor, stroke, psychiatric disease, diabetes mellitus).ResultsInjury/accident was demonstrated in 1,033 epilepsy cases and 6,202 references (hazard ratio [HR] 1.71, 95% confidence interval 1.60–1.83). The excess risk was seen mainly during the first 2 years after diagnosis. Sex and educational status had no significant effect on HR. The risk was normal in children but increased in adults. Highest HR was seen for drowning, poisoning, adverse effect of medication, and severe traumatic brain injury. Compared to references without comorbidities, HR was 1.17 (1.07–1.28) in epilepsy without comorbidities, 4.52 (4.18–4.88) in references with comorbidities, and 7.15 (6.49–7.87) in epilepsy with comorbidities.ConclusionPresence of comorbidities should be considered when counseling patients with newly diagnosed epilepsy concerning risk for injuries/accidents. Early information is important, as the risk is highest during the first 2 years following seizure onset.

Background: Numerous dietary components have been linked to the development of islet autoimmunity (IA) and type 1 diabetes (T1D); however, no associations are firmly established. This systematic review and meta-analysis aimed to synthesize current knowledge on diet and incidence of IA and T1D. Methods: Literature search was performed in Medline, Embase, and Cochrane Library, from inception until October 2020. Eligible studies had IA or T1D as outcome; any dietary exposure; case-control, cohort, or randomized controlled trial design; and hazard, risk, or odds ratios as measures of association. Summary relative risks (RR) and 95% confidence intervals (CI) were estimated with random-effects models. Certainty of evidence was assessed with GRADE. PROSPERO registration number: CRD42020212505. Findings: Among 5935 identified records, 96 were eligible, and pooled estimates could be produced for 26 dietary factors. Evidence with moderate/high certainty indicated lower risk of T1D in relation to longer (≥6-12 vs

Aim: It has been suggested that experiencing serious life events may promote Type 1 diabetes in children. Studies in adults are lacking, as are studies on the interaction of life events with genetic factors. We aimed to investigate life events and the risk of latent autoimmune diabetes in adults (LADA) and Type 2 diabetes while taking into account HLA genotype. Methods: Analysis was based on 425 incident cases of LADA, 1417 incident cases of Type 2 diabetes and 1702 population-based controls recruited in Sweden between 2010 and 2016. Self-reported information on life events including conflicts, divorce, illness/accidents, death and financial problems experienced during the 5 years preceding diagnosis/index year was used. Odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated by logistic regression and adjusted for age, sex, BMI, family history of diabetes, smoking, physical activity and education. Results: Overall there was no association between experience of any life event and either LADA (OR 0.86, 95% CI 0.68-1.08) or Type 2 diabetes (OR 1.00, 95% CI 0.83-1.21). The results were similar for individual events as well as in separate analysis of men and women. Similar results were seen in more autoimmune LADA (glutamic acid decarboxylase antibodies > median) [OR (any life event) 0.88, 95% CI 0.64-1.21] and in LADA carriers of the high-risk HLADR4-DQ8 genotype (OR 0.89, 95% CI 0.61-1.29). Conclusions: Our findings indicate that experience of a serious life event, including the death of a family member, divorce or financial problems, is not associated with an increased risk of LADA, overall or in genetically susceptible individuals.

Objective We investigated potential interactions between body mass index (BMI) and genotypes of human leukocyte antigen (HLA), TCF7L2-rs7903146, and FTO-rs9939609 in relation to the risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes. Methods We pooled data from two population-based studies: (i) a Swedish study with incident cases of LADA [positive for glutamic acid decarboxylase autoantibodies (GADA); n = 394) and type 2 diabetes (negative for GADA; n = 1290) and matched controls without diabetes (n = 2656) and (ii) a prospective Norwegian study that included incident cases of LADA (n = 131) and type 2 diabetes (n = 1901) and 886,120 person-years of follow-up. Analyses were adjusted for age, sex, physical activity, and smoking. Interaction between overweight (BMI ≥ 25 kg/m2) and HLA/TCF7L2/FTO high-risk genotypes was assessed by attributable proportion due to interaction (AP). Results The combination of overweight and high-risk genotypes of HLA, TCF7L2, and FTO was associated with pooled relative risk (RRpooled) of 7.59 (95% CI, 5.27 to 10.93), 2.65 (95% CI, 1.97 to 3.56), and 2.21 (95% CI, 1.60 to 3.07), respectively, for LADA, compared with normal-weight individuals with low/intermediate genetic risk. There was a significant interaction between overweight and HLA (AP, 0.29; 95% CI, 0.10 to 0.47), TCF7L2 (AP, 0.31; 95% CI, 0.09 to 0.52), and FTO (AP, 0.38; 95% CI, 0.15 to 0.61). The highest risk of LADA was seen in overweight individuals homozygous for the DR4 genotype [RR, 26.76 (95% CI, 15.42 to 46.43); AP, 0.58 (95% CI, 0.32 to 0.83) (Swedish data)]. Overweight and TCF7L2 also significantly interacted in relation to type 2 diabetes (AP, 0.26; 95% CI, 0.19 to 0.33), but no interaction was observed with high-risk genotypes of HLA or FTO. Conclusions Overweight interacts with HLA high-risk genotypes but also with genes associated with type 2 diabetes in the promotion of LADA.

Aims/hypothesis The workplace is a potentially important arena for prevention of type 2 diabetes and the first step is to identify occupations where the disease is common and/or risk is high. Therefore, our aim was to analyse incidence and prevalence of type 2 diabetes across all occupational groups in Sweden. Methods This nationwide study included all Swedish citizens born between 1937 and 1979 and gainfully employed between 2001 and 2013 (N = 4,550,892), and followed for a diagnosis of diabetes from 2006 to 2015 (n = 201,717) through national registers. Prevalence in 2013 (mean age 51 years; range 35–67) and age-standardised incidence (per 1000 person-years) were analysed across the 30 most common occupations among men and women. Information on BMI, physical fitness and smoking was obtained through the National Conscription (mean age 18) and Medical Birth Registers (mean age 29). Results Prevalence of type 2 diabetes was 5.2% in men and 3.2% in women; in men it was highest among motor vehicle drivers (8.8%) and in women it was highest among manufacturing workers (6.4%). Incidence varied dramatically across occupational groups. In men, it was highest among manufacturing workers (9.41) and professional drivers (9.32) and lowest among university teachers (3.44). In women, incidence was highest in manufacturing workers (7.20) and cleaners (6.18) and lowest in physiotherapists (2.20). We found major differences in the prevalence of being overweight and smoking and in the level of physical fitness across these occupational groups even at young ages. Conclusions/interpretation Professional drivers, manufacturing workers and cleaners have a threefold increased risk of type 2 diabetes compared with university teachers and physiotherapists. These differences most likely reflect dramatic differences in the prevalence of lifestyle risk factors. If workplace interventions could reduce weight and increase physical activity among employees in these occupations, major health gains may be made.

OBJECTIVE Smoking is an established risk factor for type 2 diabetes. In contrast, it has been proposed that smoking may reduce the risk of latent autoimmune diabetes in adults (LADA), but studies are scarce. We aimed to study the impact of smoking on LADA and type 2 diabetes risks. RESEARCH DESIGN AND METHODS We used data from a Swedish case-control study including incident case patients with LADA (GAD antibody [GADA] positive, n = 377) and type 2 diabetes (GADA negative, n = 1,188) and control subjects randomly selected from the population (n = 1,472). We calculated odds ratios (ORs) with 95% CIs by logistic regression, adjusted for age, sex, BMI, family history of diabetes, and alcohol consumption. RESULTS There was no indication of reduced risk of LADA in smokers; instead, heavy smoking was associated with an increased risk of LADA (OR 1.37, 95% CI 1.02–1.84). Heavy smokers had higher levels of HOMA of insulin resistance (9.89 vs. 4.38, P = 0.0479) and HOMA of β-cell function (55.7 vs. 42.5, P = 0.0204), but lower levels of GADA (75 vs. 250, P = 0.0445), compared with never smokers. Smokers also displayed an increased risk of type 2 diabetes (OR in ever smokers 1.53, 95% CI 1.25–1.88). CONCLUSIONS In this large population of LADA patients, we did not observe a protective effect of smoking on autoimmunity and the risk of LADA. A protective effect could possibly be masked by a smoking-induced aggravation of insulin resistance, akin to the diabetogenic effect seen in individuals with type 2 diabetes.

Prompted by a recent report on declining incidence of sudden unexpected death in epilepsy (SUDEP) following implantation of a vagus nerve stimulator (VNS), we analyzed SUDEP risk over 6 years in a population-based cohort of 60 952 epilepsy patients in Sweden. All deaths from July 1, 2006 through December 31, 2011, were identified. Those with epilepsy mentioned on the death certificate were adjudicated for SUDEP using medical records and autopsy reports. In all, 292 SUDEP cases were identified. Comparing the first years (2006-2007) with the subsequent 4 years (2008-2011), the crude and standardized (to the US 2000 population) incidence of SUDEP (whether or not possible SUDEP was included) was significantly lower during the second time period; Incidence rate ratios based on standardized rates was estimated at 0.76 (95% confidence interval [CI] 0.60-0.97, P = .027) for SUDEP. The incidence of SUDEP decreased by 7% per year during the 6-year follow-up. Our data thus suggest that, for unknown reasons, incidence of SUDEP decreases with duration of follow-up. This has implications for patient counseling as well as for the design of studies attempting to assess the effectiveness of an intervention against SUDEP, which clearly needs to include a control group.

To follow children with newly diagnosed unprovoked seizures to determine (1) whether the prevalence of neurodevelopmental comorbidities and cerebral palsy (CP) changed after the initial seizure, and (2) the association between studied comorbidities and seizures 13-24 months after seizure onset or initiation of treatment.Analyses were based on 750 children (28 days-18 years) with a first unprovoked seizure (index) included in a population-based Incidence Registry in Stockholm between 2001 and 2006. The children were followed for two years and their medical records were examined for a priori defined neurodevelopmental/psychiatric comorbidities and CP and seizure frequency. Baseline information was collected from medical records from before, and up to six months after, the index seizure. Odds ratios (OR) of repeated seizures 13-24 months after the first seizure or after initiation of anti-epileptic drug treatment was calculated by logistic regression and adjusted for age and sex.At baseline, 32% of the children had neurodevelopmental/psychiatric comorbidities or CP compared to 35%, 24 months later. Children with such comorbidities more often experienced seizures 13-24 months after the index seizure (OR 2.87, CI 2.07-3.99) with the highest OR in those with CP or attention deficit hyperactivity disorder (ADHD). Children diagnosed at age1 year exhibited the highest prevalence of comorbidities as well as OR for repeated seizures. A combination of young age and comorbidity was associated with an OR for repeated seizures of 5.12 (CI 3.03-8.65). Among the children without comorbidities 76% were seizure free 13-24 months after the index seizure or after initiation of AED treatment compared to 53% of children with comorbidities.This study indicates that neurodevelopmental comorbidities and CP in children with epilepsy tend to be present already at seizure onset and that such comorbidities are strong indicators of poor outcome regarding seizure control with or without treatment.

Aims To describe trajectories for metabolic risk factors for type 2 diabetes (T2D) up to 25 years prior to diagnosis and to estimate the absolute 20-year risk for T2D based on a simple set of commonly measured key risk factors. Methods From the Swedish AMORIS cohort we included 296 428 individuals with data on fasting glucose obtained in health examinations during 1985-1996 (baseline period). All participants were followed until 2012 for development of incident T2D. The 20-year T2D risk based on age, sex, body mass index (BMI), fasting glucose and triglycerides was estimated. Trajectories for biomedical risk factors of T2D starting from >20 years before diagnosis and including fasting glucose, triglycerides and BMI were evaluated according to yearly means for cases and controls. Results We identified 28 244 new T2D cases during the study period, with an average 20-year risk of 8.1%. This risk was substantially increased in overweight and obese participants and those with elevated fasting glucose and triglyceride levels, in both men and women. T2D cases had higher mean BMI and fasting glucose and triglyceride levels compared with controls >20 years before diagnosis and the difference in fasting glucose levels increased over time. Conclusions Development of T2D is associated with subtle elevations in glucose and lipid levels >20 years before diagnosis. This suggests that diabetogenic processes tied to chronic insulin resistance operate for decades prior to the development of T2D. A simple risk classification can help in early identification of individuals who are at increased risk.

Summary Objective To quantify the risk of unprovoked seizures after traumatic brain injury (TBI) Methods We used the Stockholm Incidence Registry on Epilepsy to carry out a population-based case–control study, including 1,885 cases with incident unprovoked seizures from September 1, 2000 through August 31, 2008, together with 15,080 matched controls. Information of prior hospitalizations for TBI was obtained through record linkage with the Swedish National Inpatient Registry for the period 1980–2008. Relative risks (RRs) for unprovoked seizures were estimated after various TBI diagnoses, and influences of TBI severity and time since trauma were studied in detail. Results After hospitalization for mild TBI, the RR was 2.0 (95% confidence interval [CI] 1.5–2.7). The RR was higher after brain contusion (5.9, 95% CI 2.4–15.0) or intracranial hemorrhage (ICH) (4.5, 95% CI 2.2–9.0), whereas a combination of both diagnoses led to a further sevenfold increase in RR (42.6, 95% CI 12.2–148.5). The risk was greatest during the first 6 months after severe TBI (RR 48.9, 95% CI 10.9–218.9) or mild TBI (RR 8.1, 95% CI 3.1–21.7), but was still elevated >10 years after any TBI. Significance Herein we present a large population-based case–control study on TBI as a risk factor for unprovoked epileptic seizures, including cases of all ages with individually validated seizure diagnoses. The risk for epileptic seizures was substantially increased after TBI, especially during the first 6 months after the injury and in patients with a combination of ICH and brain contusion.

Smoking and nicotine exposure increase insulin resistance and the risk of type 2 diabetes. Swedish smokeless tobacco (snus) is high in nicotine, and its use is prevalent in Scandinavian countries, but few studies have investigated snus use in relation to diabetes risk.To explore the association between snus use and risk of type 2 diabetes using pooled data from five cohorts.Analyses were based on prospective studies conducted between 1990 and 2013 including 54 531 never-smoking men and 2441 incident cases of type 2 diabetes identified through screening, self-reporting and hospital and prescription registries. Hazard ratios (HRs) and 95% confidence intervals (CIs) were assessed and adjusted for age, body mass index, educational level, alcohol consumption and physical activity.Compared to never users, the HR of type 2 diabetes was 1.15 (95% CI: 1.00-1.32) in current users of snus. In individuals consuming 5-6 boxes per week, the HR was 1.42 (95% CI: 1.07-1.87); in those consuming ≥7 boxes per week, the HR was 1.68 (95% CI: 1.17-2.41). Each additional box of snus consumed per week yielded an HR of 1.08 (95% CI: 1.01-1.16).Our findings indicate that high consumption of snus is a risk factor for type 2 diabetes. The risk was similar to that in smokers, implying that smokers will not reduce their risk of type 2 diabetes by changing to snus use. The results also support the notion that nicotine increases the risk of type 2 diabetes.

Objective:To identify all cases of sudden unexpected death in epilepsy (SUDEP) among people in Sweden during 1 year and to determine the SUDEP incidence in relation to age, sex, and psychiatric comorbidity.Methods:We included all individuals with a hospital-based ambulatory care or hospital discharge diagnosis of epilepsy in the Swedish National Patient Registry during 1998–2005 who were alive on January 1, 2008. Deaths during 2008 were identified by linkage to the National Cause of Death Registry. Death certificates, medical charts, and police and autopsy reports were extensively reviewed to identify SUDEP cases.Results:Of 57,775 epilepsy patients alive on January 1, 2008, 1,890 died (3.3%) during 2008. Of these, 99 met the Annegers SUDEP criteria (49 definite, 19 probable, and 31 possible). SUDEP accounted for 5.2% of all deaths and 36% of deaths in the 0–15 years age group. The incidence of definite/probable SUDEP was 1.20/1,000 person-years, and higher in men (1.41) than in women (0.96). All SUDEP cases 50 years was 1.11, 1.13, and 1.29, respectively, per 1,000 person-years. The incidence was 5-fold increased among female patients with psychiatric comorbidities compared to those without. Epilepsy was mentioned on the death certificate in only 62 of the 99 (63%) SUDEP cases.Conclusions:Methods relying on death certificates underestimate SUDEP incidence. SUDEP risk has been underestimated especially in boys and in older people regardless of sex. Patients with psychiatric comorbidities, women in particular, are at increased SUDEP risk.