Pathogenic monoallelic variants in GLIS3 increase type 2 diabetes risk and identify a subgroup of patients sensitive to sulfonylureas.

AIMS/HYPOTHESIS: GLIS3 encodes a transcription factor involved in pancreatic beta cell development and function. Rare pathogenic, bi-allelic mutations in GLIS3 cause syndromic neonatal diabetes whereas frequent SNPs at this locus associate with common type 2 diabetes risk. Because rare, functional variants located in other susceptibility genes for type 2 diabetes have already been shown to strongly increase individual risk for common type 2 diabetes, we aimed to investigate the contribution of rare pathogenic GLIS3 variants to type 2 diabetes. METHODS: GLIS3 was sequenced in 5471 individuals from the Rare Variants Involved in Diabetes and Obesity (RaDiO) study. Variant pathogenicity was assessed following the criteria established by the American College of Medical Genetics and Genomics (ACMG). To address the pathogenic strong criterion number 3 (PS3), we conducted functional investigations of these variants using luciferase assays, focusing on capacity of GLIS family zinc finger 3 (GLIS3) to bind to and activate the INS promoter. The association between rare pathogenic or likely pathogenic (P/LP) variants and type 2 diabetes risk (and other metabolic traits) was then evaluated. A meta-analysis combining association results from RaDiO, the 52K study (43,125 individuals) and the TOPMed study (44,083 individuals) was finally performed. RESULTS: Through targeted resequencing of GLIS3, we identified 105 rare variants that were carried by 395 participants from RaDiO. Among them, 49 variants decreased the activation of the INS promoter. Following ACMG criteria, 18 rare variants were classified as P/LP, showing an enrichment in the last two exons compared with the remaining exons (p<5×10-6; OR>3.5). The burden of these P/LP variants was strongly higher in individuals with type 2 diabetes (p=3.0×10-3; OR 3.9 [95% CI 1.4, 12]), whereas adiposity, age at type 2 diabetes diagnosis and cholesterol levels were similar between variant carriers and non-carriers with type 2 diabetes. Interestingly, all carriers with type 2 diabetes were sensitive to oral sulfonylureas. A total of 7 P/LP variants were identified in both 52K and TOPMed studies. The meta-analysis of association studies obtained from RaDiO, 52K and TOPMed showed an enrichment of P/LP GLIS3 variants in individuals with type 2 diabetes (p=5.6×10-5; OR 2.1 [95% CI 1.4, 2.9]). CONCLUSIONS/INTERPRETATION: Rare P/LP GLIS3 variants do contribute to type 2 diabetes risk. The variants located in the distal part of the protein could have a direct effect on its functional activity by impacting its transactivation domain, by homology with the mouse GLIS3 protein. Furthermore, rare P/LP GLIS3 variants seem to have a direct clinical effect on beta cell function, which could be improved by increasing insulin secretion via the use of sulfonylureas.

The number of nephroprotection targets attained is associated with cardiorenal outcomes and mortality in patients with diabetic kidney disease. The CKD-REIN cohort study.

AIM: The risk of cardiorenal events remains high among patients with diabetes and chronic kidney disease (CKD), despite the prescription of recommended treatments. We aimed to determine whether the attainment of a combination of nephroprotection targets at baseline (glycated haemoglobin <7.0%, urinary albumin-creatinine ratio <300 mg/g, blood pressure <130/80 mmHg, renin-angiotensin system inhibition) was associated with better cardiorenal outcomes and lower mortality. MATERIALS AND METHODS: From the prospective French CKD-REIN cohort, we studied 1260 patients with diabetes and CKD stages 3-4 (estimated glomerular filtration rate: 15-60 ml/min/1.73 m2); 69% were men, and at inclusion, mean ± SD age: 70 ± 10 years; estimated glomerular filtration rate: 33 ± 11 ml/min/1.73 m2. The median follow-up was 4.9 years. RESULTS: In adjusted Cox regression models, the attainment of two nephroprotection targets was consistently associated with a lower risk of cardiorenal events [hazard ratio 0.70 (95% confidence interval 0.57-0.85)], incident kidney failure with replacement therapy [0.58 (0.43-0.77)], four major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure) [0.75 (0.57-0.99)] and all-cause mortality [0.59 (0.42-0.82)] when compared with the attainment of zero or one target. For patients with a urinary albumin-creatinine ratio ≥300 mg/g, those who attained at least two targets had lower hazard ratios for cardiorenal events [0.61 (0.39-0.96)], four major adverse cardiovascular events [0.53 (0.28-0.98)] and all-cause mortality [0.35 (0.17-0.70)] compared with those who failed to attain any targets. CONCLUSIONS: These findings suggest that the attainment of a combination of nephroprotection targets is associated with better cardiorenal outcomes and a lower mortality rate in people with diabetic kidney disease.

Genetic variants of interferon-response factor 5 are associated with the incidence of chronic kidney disease: the D.E.S.I.R. study.

Inflammation has been associated with renal diseases. The Interferon Regulatory Factor (IRF)-5 is a key transcription factor in the pro-inflammatory polarization of M1-like macrophages. GWAS have reported that the IRF5 locus is associated with autoimmune diseases and with the estimated glomerular filtration rate (eGFR). We study whether allelic variations in IRF5 are associated with the incidence of chronic kidney disease (CKD) in a general population. We genotyped eleven IRF5 SNPs in the French D.E.S.I.R. cohort from the general population (n = 4820). Associations of SNPs with baseline renal parameters were assessed. Data were analyzed for three endpoints during a 9-year follow-up, incidence of:at least stage 3 CKD, the KDIGO criterion "certain drop in eGFR", and incidence of micro/macro albuminuria. In the cross-sectional analysis, rs10954213 and rs10954214 were associated with eGFR and rs1874328 with urinary albumin/creatinine ratio (ACR). Rs3807306, rs11761199, rs78658945, rs1874328, rs10954213 and rs11770589 were associated with the incidence of stage 3 CKD in multi-adjusted models. Rs4731532, rs3807306, and rs11761199 were associated with the incidence of CKD defined by the KDIGO. Rs4731532, rs3807306, rs11761199 and rs79288514 were associated with the incidence of micro/macro albuminuria. Our results support the hypothesis of the importance of IRF5 mediated macrophage polarization in the etiology of CKD.

Plasma proteomic signatures of a direct measure of insulin sensitivity in two population cohorts.

AIMS/HYPOTHESIS: The euglycaemic-hyperinsulinaemic clamp (EIC) is the reference standard for the measurement of whole-body insulin sensitivity but is laborious and expensive to perform. We aimed to assess the incremental value of high-throughput plasma proteomic profiling in developing signatures correlating with the M value derived from the EIC. METHODS: We measured 828 proteins in the fasting plasma of 966 participants from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study and 745 participants from the Uppsala Longitudinal Study of Adult Men (ULSAM) using a high-throughput proximity extension assay. We used the least absolute shrinkage and selection operator (LASSO) approach using clinical variables and protein measures as features. Models were tested within and across cohorts. Our primary model performance metric was the proportion of the M value variance explained (R2). RESULTS: A standard LASSO model incorporating 53 proteins in addition to routinely available clinical variables increased the M value R2 from 0.237 (95% CI 0.178, 0.303) to 0.456 (0.372, 0.536) in RISC. A similar pattern was observed in ULSAM, in which the M value R2 increased from 0.443 (0.360, 0.530) to 0.632 (0.569, 0.698) with the addition of 61 proteins. Models trained in one cohort and tested in the other also demonstrated significant improvements in R2 despite differences in baseline cohort characteristics and clamp methodology (RISC to ULSAM: 0.491 [0.433, 0.539] for 51 proteins; ULSAM to RISC: 0.369 [0.331, 0.416] for 67 proteins). A randomised LASSO and stability selection algorithm selected only two proteins per cohort (three unique proteins), which improved R2 but to a lesser degree than in standard LASSO models: 0.352 (0.266, 0.439) in RISC and 0.495 (0.404, 0.585) in ULSAM. Reductions in improvements of R2 with randomised LASSO and stability selection were less marked in cross-cohort analyses (RISC to ULSAM R2 0.444 [0.391, 0.497]; ULSAM to RISC R2 0.348 [0.300, 0.396]). Models of proteins alone were as effective as models that included both clinical variables and proteins using either standard or randomised LASSO. The single most consistently selected protein across all analyses and models was IGF-binding protein 2. CONCLUSIONS/INTERPRETATION: A plasma proteomic signature identified using a standard LASSO approach improves the cross-sectional estimation of the M value over routine clinical variables. However, a small subset of these proteins identified using a stability selection algorithm affords much of this improvement, especially when considering cross-cohort analyses. Our approach provides opportunities to improve the identification of insulin-resistant individuals at risk of insulin resistance-related adverse health consequences.

Comparison of surgical procedures for benign prostatic hyperplasia of medium-volume prostates: evaluation of the causes of rehospitalization from the French National Hospital Database (PMSI-MCO).

PURPOSE: In France, transurethral resection of the prostate (TURP) is still the most commonly used surgical treatment for medium sized benign prostatic hyperplasia (BPH), but the Holmium Laser Enucleation of the Prostate (HoLEP) and laser vaporization procedures are becoming more common. For these three surgical procedures, we evaluate the initial complications, the short term (3 months) and the 4-12-month postoperative complications necessitating re-hospitalization. METHODS: From the French national hospital data base (PMSI-MCO), all hospitalizations for BPH treatment in 2018 were extracted. We document the complications during the initial hospitalization and any subsequent rehospitalizations during the one-year postoperative period. RESULTS: In 2018, 67,220 patients were treated for BPH: 46,242 TURP, 13,509 HoLEP and 7469 laser vaporization. Age and anticoagulation medications were similar for men treated by the three procedures, but TURP patients were more often hypertensive. Infections and hemorrhagic complications were the most common complications at the initial hospitalization: 17%, 10%, 13% for infections and 15%, 8.1%, 11% for hemorrhagic complications respectively, and TURP performed worse than the other two procedures at the initial hospitalization. During the first three months and then the subsequent nine months, there were fewer complications than initially, with little difference between the three procedures, all differences being less than 1%. CONCLUSION: Laser vaporization techniques led to fewer complications. However, the PMSI-MCO only registers complications during hospitalizations. This study should be extended to non-hospitalized, more minor complications.

Rare and low-frequency coding variants alter human adult height.

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

Complications after partial nephrectomy: robotics overcomes open surgery and laparoscopy: the PMSI French national database.

PURPOSE: To evaluate three partial nephrectomies (PN) procedures: open (OPN), standard laparoscopy (LPN), and robot-assisted laparoscopy (RAPN), for the risk of initial complications and rehospitalization for two years after the surgery. MATERIALS AND METHODS: From the French national hospital database (PMSI-MCO), every hospitalization in French hospitals for renal tumor PN in 2016-2017 were extracted. Complications were documented from the initial hospitalization and any rehospitalization over two years. Chi-square and ANOVA tests compared the frequency of complications and length of initial hospitalization between the three surgical procedures. Relative risks (RR) and 95% confidence intervals were computed. RESULTS: The 9119 initial hospitalizations included 4035 OPN, 1709 LPN, and 1900 RAPN; 1475 were excluded as the laparoscopic procedure performed was not determined. The average length of hospitalization was 8.1, 6.2, and 4.5 days for OPN, LPN, and RAPN, respectively. Compared to OPN, there were fewer complications at the time of initial hospitalization for the mini-invasive procedures: 29% for OPN vs. 20% for LPN (0.70 [0.63;0.78]) and 12% for RAPN (RR=0.43, 95%CI [0.38;0.49]). For RAPN compared to LPN, there were fewer haemorrhages (RR=0.55 [0.43;0.72]), anemia (0.69 {0.48;0.98]), and sepsis (0.51 [0.36;0.71]); during follow up, there were fewer urinary tract infections (0.64 [0.45;0.91]) but more infectious lung diseases (1.69 [1.03;2.76]). Over the two-year postoperative period, RAPN was associated with fewer acute renal failures (RR=0.73 [0.55;0.98]), renal abscesses (0.41 [0.23;0.74]), parietal complications (0.69 [0.52;0.92]) and urinary tract infections (0.54 [0.40;0.73]) than for OPN. CONCLUSIONS: Conservative renal surgery is associated with postoperative morbidity related to the surgical procedure fashion. Mini-invasive procedures, especially robot-assisted surgery, had fewer complications and shorter hospital lengths of stay.

Incident cardiovascular disease by clustering of favourable risk factors in type 1 diabetes: the EURODIAB Prospective Complications Study.

AIMS: The aim of this prospective study was to examine CVD risk reduction in type 1 diabetes (1) for people with favourable cardiovascular health metrics and (2) by clustering of these metrics. METHODS: Data from 2313 participants from the EURODIAB Prospective Complications Study were analysed. All had type 1 diabetes (51% men, mean ± SD age 32 ± 9 years). Seven cardiovascular health metrics were studied-smoking, BMI, physical activity, a diet score, total cholesterol/HDL-cholesterol ratio, combined systolic and diastolic BP and HbA1c-divided into favourable/less favourable categories. Cox proportional hazards models were used to calculate HRs (95% CIs) of incident CVD for each metric. Clusters were made by scoring each individual by the number of favourable metrics. RESULTS: A total of 163 people developed incident CVD during a mean ± SD follow-up of 7.2 ± 1.3 years. Participants with more favourable HbA1c levels of <57 mmol/mol (<7.4%) had a 37% significantly lower CVD risk than those with a less favourable HbA1c (HR [95% CI] 0.63 [0.44, 0.91]), and participants with a more favourable BP (systolic BP <112 mmHg and diastolic BP <70 mmHg) had a 44% significantly lower CVD risk than participants in the less favourable BP group (HR [95% CI] 0.56 [0.34, 0.92]). There was a dose-response relation with a lower HR observed with greater clustering of more favourable metrics: people with four or more favourable metrics had an HR of 0.37 (95% CI 0.18, 0.76), adjusted for sex and age at diabetes diagnosis, compared with those with no favourable metrics. CONCLUSIONS/INTERPRETATION: Low HbA1c and low BP were protective cardiovascular health metrics in our study of people with type 1 diabetes. Targeting all cardiovascular health metrics could be more effective in preventing CVD than targeting single metrics.

Impact of diabetes on COVID-19 prognosis beyond comorbidity burden: the CORONADO initiative.

AIMS/HYPOTHESIS: Diabetes has been recognised as a pejorative prognostic factor in coronavirus disease 2019 (COVID-19). Since diabetes is typically a disease of advanced age, it remains unclear whether diabetes remains a COVID-19 risk factor beyond advanced age and associated comorbidities. We designed a cohort study that considered age and comorbidities to address this question. METHODS: The Coronavirus SARS-CoV-2 and Diabetes Outcomes (CORONADO) initiative is a French, multicentric, cohort study of individuals with (exposed) and without diabetes (non-exposed) admitted to hospital with COVID-19, with a 1:1 matching on sex, age (±5 years), centre and admission date (10 March 2020 to 10 April 2020). Comorbidity burden was assessed by calculating the updated Charlson comorbidity index (uCCi). A predefined composite primary endpoint combining death and/or invasive mechanical ventilation (IMV), as well as these two components separately, was assessed within 7 and 28 days following hospital admission. We performed multivariable analyses to compare clinical outcomes between patients with and without diabetes. RESULTS: A total of 2210 pairs of participants (diabetes/no-diabetes) were matched on age (mean±SD 69.4±13.2/69.5±13.2 years) and sex (36.3% women). The uCCi was higher in individuals with diabetes. In unadjusted analysis, the primary composite endpoint occurred more frequently in the diabetes group by day 7 (29.0% vs 21.6% in the no-diabetes group; HR 1.43 [95% CI 1.19, 1.72], p<0.001). After multiple adjustments for age, BMI, uCCi, clinical (time between onset of COVID-19 symptoms and dyspnoea) and biological variables (eGFR, aspartate aminotransferase, white cell count, platelet count, C-reactive protein) on admission to hospital, diabetes remained associated with a higher risk of primary composite endpoint within 7 days (adjusted HR 1.42 [95% CI 1.17, 1.72], p<0.001) and 28 days (adjusted HR 1.30 [95% CI 1.09, 1.55], p=0.003), compared with individuals without diabetes. Using the same adjustment model, diabetes was associated with the risk of IMV, but not with risk of death, within 28 days of admission to hospital. CONCLUSIONS/INTERPRETATION: Our results demonstrate that diabetes status was associated with a deleterious COVID-19 prognosis irrespective of age and comorbidity status. TRIAL REGISTRATION: ClinicalTrials.gov NCT04324736.

The JUBILE cohort: Quality of life after more than 40 years with type 1 diabetes.

AIM: The incidence of type 1 diabetes is increasing, and more people are going to live many years with the disease. Quality of life might become the most challenging long-term complication. The JUBILE study describes the quality of life of people living with type 1 diabetes for more than 40 years. METHODS: Patients were recruited from 35 French regional or university hospitals: patients and physicians completed questionnaires, validated by the Delphi method. From 1200 questionnaires circulated, 808 patients and their physicians returned questionnaires. RESULTS: The duration of type 1 diabetes was 49 ± 6 years (mean±SD), age at diagnosis 15 ± 10 years, HbA1c 7.4 ± 0.9% [58 ± 10 mmol/mol] and 52% were men. Macrovascular disease was present in 32%, 46% had no or only mild non proliferative retinopathy. Insulin pumps were used by 25% and insulin pen/syringe users injected 3.9 ± 2.1 times per day. Blood glucose was self monitored at least five times per day by 67% of patients. Men had 1.8 ± 1.2 children, women 1.4 ± 1.0. More than half (55%) of this population was working, 38% had a university degree. Patients still had a busy life, going out (59%), eating out (82%), playing sports (38%) and travelling (66%). No differences appeared based on age, duration of diabetes, demography or social features. CONCLUSIONS: Living a long and pleasant life is possible with type 1 diabetes. Diabetes does not prevent people from having children, working at highly qualified jobs, travelling abroad: a message of hope that is comforting for patients, their family, relatives and the medical teams.

Plasma total adiponectin and changes in renal function in a cohort from the community: the prospective Data from an Epidemiological Study on the Insulin Resistance Syndrome study.

BACKGROUND: High adiponectin levels are associated with diabetic nephropathy. Nevertheless, it is not known whether plasma adiponectin is associated with renal function decline in the general population. We evaluated whether adiponectin concentrations were associated with changes in renal function in a community cohort, the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. METHODS: Plasma adiponectin concentrations were measured in a random sample of 3284 people from the DESIR study, a 9-year prospective cohort from the general population. Data were analysed for three endpoints during follow-up: incidence of Stage 3 chronic kidney disease (CKD); the Kidney Disease: Improving Global Outcomes (KDIGO) criterion 'certain drop in eGFR' and rapid kidney function decline [estimated glomerular filtration rate (eGFR) slope steeper than -3 mL/min/1.73 m2/year]. RESULTS: After exclusion of participants with an eGFR <60 mL/min/1.73 m2 at baseline and those with type 2 diabetes or impaired fasting glycaemia at any time during follow-up (remaining n = 2174), there was a 113% higher risk for a rapid decline in kidney function in participants with adiponectin above the third tertile (T3) versus below the first tertile (T1) (Ptrend = 0.004) and a 53% higher risk for kidney function decline as defined by the KDIGO criterion (Ptrend = 0.04). In a cross-sectional analysis, adiponectin was positively associated with urinary albumin:creatinine ratio at baseline (P = 0.009). CONCLUSIONS: In a healthy cohort from the general population, higher levels of plasma adiponectin were associated with decreased renal function at baseline and at follow-up. This result is similar to what is observed in people with diabetic nephropathy, in contrast with animal models of nephropathy.

Higher mortality risk among kidney transplant recipients than among estimated glomerular filtration rate-matched patients with CKD-preliminary results.

BACKGROUND: Although kidney transplantation prolongs survival relative to dialysis, it is associated with a higher death rate than in the general population. The objective of the present study was to assess and compare the risk of mortality and frequency of non-lethal cardiovascular (CV) events in kidney transplant recipients (KTRs) beyond 1 year after successful transplantation versus patients with chronic kidney disease (CKD) using propensity score-matched analysis of estimated glomerular filtration rate (eGFR) and other parameters. METHODS: After propensity score matching, we studied 340 KTRs from the French Données Informatisées et Validées en Transplantation cohort and 605 non-transplant patients with CKD (CKDps) from the French Chronic Kidney Disease-Renal Epidemiology and Information Network cohort. The mean ± standard deviation eGFR was 42 ± 13 and 41 ± 12 mL/min/ 1.73 m2, respectively (P = 0.649). Descriptive data were completed by a survival analysis with Cox regression models. RESULTS: After a median follow-up period of 2.8 years (KTRs 2.0 years, CKDp 2.9 years), 71 deaths were recorded (31 and 40 in the KTR and CKD groups, respectively). Univariate analysis showed that KTRs had a significantly greater risk of mortality than CKDps. In multivariable analysis, KTRs were found to have a 2.7-fold greater risk of mortality [hazard ratio 2.7 (95% confidence interval 1.6-4.7); P = 0.005]. There was no between-group difference concerning the risk of CV events (P = 0.448). CV death rates in KTRs (29.0%) approximated those of CKDps (22.5%), whereas death rates due to infections were higher in KTRs (19.4% versus 10.0%). CONCLUSION: Beyond 1 year after transplantation, KTRs, who possibly had a longer CKD history, had a significantly greater mortality risk than eGFR-matched CKDps. The excess risk was not associated with CV events.

Type 2 diabetes and its characteristics are associated with poor oral health: findings from 60,590 senior women from the E3N study.

BACKGROUND: Type 2 diabetes (T2D) has been identified as a risk factor for poor oral health, however, a limited number of oral health and T2D characteristics have been studied so far. We sought to assess T2D status, age at diagnosis, duration since diagnosis and treatment in relation to a variety of oral diseases. METHODS: Cross-sectional data were analyzed from the E3N (Etude Epidémiologique auprès de femmes de l'Education Nationale) cohort study which enrolled 60,590 women. Participants self-reported oral health status, and T2D cases were identified using diabetes-specific questionnaires and drug reimbursement insurance databases. Multivariable-adjusted ORs and 95% CIs were estimated using logistic regression models. RESULTS: The mean age (SD) of the women was 70 years (7.2), and 4.7% (n = 2857) had T2D. Compared to women without T2D, women with T2D were more likely to report a poor perceived oral health (OR 1.37 [95% CI 1.18, 1.60]), wearing dental prostheses (1.26 [1.14, 1.39]) and having problems of biting and chewing food (1.19 [1.07, 1.33]). In addition, for women with T2D the age at diagnosis (inversely) and the duration (positively) were associated with the likelihood to report poor oral health. CONCLUSIONS: For women with T2D, duration and age at diagnosis are associated with wearing prostheses, problems of biting and chewing, periodontitis and gingivitis.

Complex interaction of fasting glucose, body mass index, age and sex on all-cause mortality: a cohort study in 15 million Korean adults.

AIMS/HYPOTHESIS: The aim of this work was to examine whether synergistic associations with mortality exist for BMI and fasting blood glucose (FBG) and to identify FBG-BMI combined subgroups with higher mortality according to sex and age. METHODS: A total of 15,149,275 Korean adults participated in health examinations during 2003-2006 and were followed up until December 2018. Mortality HRs of 40 FBG-BMI combined groups were assessed by Cox proportional hazards models. RESULTS: During a mean 13.7 years of follow-up, 1,213,401 individuals died. A J-shaped association was seen between FBG and all-cause mortality for all BMI categories. Those with BMI <20 kg/m2 had the highest mortality for any given FBG level, followed by those with BMI 20-22.4 kg/m2. The detrimental effect of elevated FBG was greater among leaner individuals than more corpulent individuals. Moreover, the synergistic adverse effects of hyperglycaemia and leanness was stronger in younger adults than in older adults. Compared with the reference group (overweight with normoglycaemia), age- and sex-adjusted HRs of the leanest with normoglycaemia (BMI <20 kg/m2 and FBG 4.4-5.2 mmol/l), overweight with diabetes (BMI 25-27.4 kg/m2 and FBG ≥10.0 mmol/l) and leanest with diabetes (BMI <20 kg/m2 and FBG ≥10.0 mmol/l) were 1.29, 2.59 and 11.18, respectively, in those aged 18-44 years and 1.56, 1.72 and 2.87, respectively, in those aged 75-99 years. The identification of BMI-FBG subgroups associated with higher mortality was not straightforward, illustrated by the group with FBG 6.1-6.9 mmol/l and BMI 20-22.4 kg/m2 having a similar or higher mortality compared with the group with FBG 7.0-9.9 mmol/l and BMI ≥22.5 kg/m2. In women aged <45 years with FBG <6.9 mmol/l, those with BMI ≥27.5 kg/m2 had the highest mortality, whereas individuals with BMI <20 kg/m2 had the highest mortality for each given FBG level in other age and sex groups. CONCLUSIONS/INTERPRETATION: Leanness and hyperglycaemia interact together to increase mortality in a supra-multiplicative manner, especially in younger adults; the interactions of BMI, FBG, sex and age with mortality are complex. Graphical abstract.

General regression model: A "model-free" association test for quantitative traits allowing to test for the underlying genetic model.

Most genome-wide association studies used genetic-model-based tests assuming an additive mode of inheritance, leading to underpowered association tests in case of departure from additivity. The general regression model (GRM) association test proposed by Fisher and Wilson in 1980 makes no assumption on the genetic model. Interestingly, it also allows formal testing of the underlying genetic model. We conducted a simulation study of quantitative traits to compare the power of the GRM test to the classical linear regression tests, the maximum of the three statistics (MAX), and the allele-based (allelic) tests. Simulations were performed on two samples sizes, using a large panel of genetic models, varying genetic models, minor allele frequencies, and the percentage of explained variance. In case of departure from additivity, the GRM was more powerful than the additive regression tests (power gain reaching 80%) and had similar power when the true model is additive. GRM was also as or more powerful than the MAX or allelic tests. The true simulated model was mostly retained by the GRM test. Application of GRM to HbA1c illustrates its gain in power. To conclude, GRM increases power to detect association for quantitative traits, allows determining the genetic model and is easily applicable.

The expression of genes in top obesity-associated loci is enriched in insula and substantia nigra brain regions involved in addiction and reward.

BACKGROUND: Genome-wide association studies (GWAS) have identified more than 250 loci associated with body mass index (BMI) and obesity. However, post-GWAS functional genomic investigations have been inadequate for understanding how these genetic loci physiologically impact disease development. METHODS: We performed a PCR-free expression assay targeting genes located nearby the GWAS-identified SNPs associated with BMI/obesity in a large panel of human tissues. Furthermore, we analyzed several genetic risk scores (GRS) summing GWAS-identified alleles associated with increased BMI in 4236 individuals. RESULTS: We found that the expression of BMI/obesity susceptibility genes was strongly enriched in the brain, especially in the insula (p = 4.7 × 10-9) and substantia nigra (p = 6.8 × 10-7), which are two brain regions involved in addiction and reward. Inversely, we found that top obesity/BMI-associated loci, including FTO, showed the strongest gene expression enrichment in the two brain regions. CONCLUSIONS: Our data suggest for the first time that the susceptibility genes for common obesity may have an effect on eating addiction and reward behaviors through their high expression in substantia nigra and insula, i.e., a different pattern from monogenic obesity genes that act in the hypothalamus and cause hyperphagia. Further epidemiological studies with relevant food behavior phenotypes are necessary to confirm these findings.

Correction to: One hour post-load plasma glucose and 3 year risk of worsening fasting and 2 hour glucose tolerance in the RISC cohort.

The affiliation details for Geltrude Mingrone are corrected below.

Dietary inflammatory index and type 2 diabetes risk in a prospective cohort of 70,991 women followed for 20 years: the mediating role of BMI.

AIMS/HYPOTHESIS: Diet is one of the main lifestyle-related factors that can modulate the inflammatory process. Surprisingly the dietary inflammatory index (DII) has been little investigated in relation to type 2 diabetes, and the role of BMI in this relationship is not well established. We studied this association and the role of BMI in the inflammatory process in a large population-based observational study. METHODS: A total of 70,991 women from the E3N (Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale) cohort study were followed for 20 years. Incident type 2 diabetes cases were identified using diabetes-specific questionnaires and drug reimbursement insurance databases, and 3292 incident cases were validated. The DII was derived from a validated food frequency questionnaire. Multivariable Cox regression models estimated HRs and 95% CIs between DII and incident type 2 diabetes. Interactions were tested between DII and BMI on incident type 2 diabetes and a mediation analysis of BMI was performed. RESULTS: Higher DII scores, corresponding to a higher anti-inflammatory potential of the diet, were associated with a lower risk of type 2 diabetes. Compared with the 1st quintile group, women from the 2nd quintile group (HR 0.85 [95% CI 0.77, 0.94]) up to the 5th quintile group (HR 0.77 [95% CI 0.69, 0.85]) had a lower risk of type 2 diabetes before adjustment for BMI. There was an interaction between DII and BMI on type 2 diabetes risk (pInteraction < 0.0001). The overall association was partly mediated by BMI (58%). CONCLUSIONS/INTERPRETATION: Our findings suggest that a higher anti-inflammatory potential of the diet is associated with a lower risk of type 2 diabetes, and the association may be mediated by BMI. These results may improve our understanding of the mechanisms underlying the role of diet-related anti-inflammation in the pathogenesis of type 2 diabetes in women. Further studies are warranted to validate our results and evaluate whether the results are similar in men.

Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies.

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies. FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Strong adherence to dietary and lifestyle recommendations is associated with decreased type 2 diabetes risk in the AusDiab cohort study.

We aimed to determine whether adherence to the Australian dietary guidelines and an index of healthy behavior was associated with a lower risk of type 2 diabetes (T2D) and to provide estimates of the proportion of preventable cases. Participants of the AusDiab cohort study were followed for 12 years (n = 6242), starting from May 1999, during which T2D cases were identified. The associations between T2D risk and a score of adherence to the dietary guidelines, its components, and a score of adherence to an index of healthy behaviors, (which included smoking, recreational physical activity, waist circumference and adherence to the dietary guidelines), were estimated using Cox proportional hazards ratios (HR) and 95% confidence intervals. The proportion of preventable cases was estimated using the population attributable fraction (PAF). Strong adherence to the dietary guidelines was not associated with T2D risk (HR = 0.64 [95% CI 0.39-1.06]), unless moderate alcohol consumption was considered as beneficial instead of no alcohol consumption (HR = 0.59 [0.36-0.96]). However, strong adherence to the guidelines regarding fruit and dairy intake were both associated with decreased risk of T2D (HR = 0.68 [0.51-0.91]; 0.56 [0.38-0.84], respectively) and could have prevented 23-37% of cases (PAF = 23.3% [7.3-38.2]; 37.1% [14.6-56.0], respectively). Strong adherence to the index of healthy behaviors was associated with decreased risk of T2D (HR = 0.30 [0.17-0.51]) and estimated to prevent almost 60% of T2D (PAF = 59.4% [34.3-76.6]). More than half of T2D cases could be preventable in Australia through modifying health behavior. These results could serve as a basis for prevention programs based on lifestyle modification.