Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Risk Factors for Preoperative Hyperglycemia in Surgical Patients with Diabetes: A Case–Control Study

Background: Patients with diabetes are more likely to undergo a surgical procedure than the rest of the population, and it is well established that preoperative hyperglycemia is associated with adverse surgical outcomes. However, it is currently unknown what factors increase the odds of preoperative hyperglycemia in people with diabetes.  Objective: To identify patient characteristics that increase the risk of preoperative hyperglycemia.  Methods: This retrospective case–control study compared 100 patients with preoperative hyperglycemia on admission for elective surgery at South Health Campus in Calgary, Alberta (blood glucose &gt; 10.9 mmol/L) with 200 controls who did not have preoperative hyperglycemia on admission for elective surgery (blood glucose ≤ 10.9 mmol/L). Multivariate logistic regression was used to identify risk factors for preoperative hyperglycemia.  Results: In the univariate analysis, age, number of comorbidities, increasing glycated hemoglobin (HbA1c), type of diabetes, type of procedure, and diabetes medications (non-insulin, insulin, both, or none) were associated with increased odds of preoperative hyperglycemia (p &lt; 0.05). However, in the adjusted analysis, only increasing HbA1c (odds ratio [OR] 1.69, 95% confidence interval [CI] 1.36–2.12) and type 1 diabetes (OR 4.24, 95% CI 1.11–16.21, relative to type 2 diabetes) were associated with preoperative hyperglycemia.  Conclusions: These results can help clinicians to identify patients who may be at increased risk of hyperglycemia before an elective procedure. They also allow for treatment of those who would benefit most from additional guidance with regard to preoperative glucose management.  RÉSUMÉ  Contexte : Les patients diabétiques sont plus susceptibles que le reste de la population de subir une intervention chirurgicale, et il est bien connu que l’hyperglycémie préopératoire est associée à des résultats chirurgicaux indésirables. Cependant, on ignore actuellement quels facteurs augmentent ce risque chez les personnes atteintes de diabète.  Objectif : Déterminer les caractéristiques des patients qui augmentent le risque d’hyperglycémie préopératoire.  Méthodes : Cette étude cas-témoins rétrospective a comparé 100 patients présentant une hyperglycémie préopératoire à l’admission pour une intervention chirurgicale non urgente au South Health Campus de Calgary, en Alberta (glycémie &gt; 10,9 mmol/L) avec 200 témoins qui n’en présentaient pas (glycémie ≤ 10,9 mmol/L). La détermination des facteurs de risque d’hyperglycémie préopératoire s’est faite par régression logistique multivariée.  Résultats : Dans l’analyse univariée, l’âge, le nombre de comorbidités, l’augmentation du taux d’hémoglobine glyquée (HbA1c), le type de diabète, le type d’intervention et les médicaments contre le diabète (non-insuline, insuline, les deux ou aucun) étaient associés à un risque accru d’hyperglycémie préopératoire (p &lt; 0,05). Cependant, dans l’analyse ajustée, seuls l’augmentation de l’HbA1c (rapport de cotes [RC] 1,69; intervalle de confiance [IC] à 95 % 1,36-2,12) et le diabète de type 1 (RC 4,24; IC à 95 % 1,11-16,21, par rapport au diabète de type 2) étaient associés à une hyperglycémie préopératoire.  Conclusions : Ces résultats peuvent aider les cliniciens à repérer les patients qui pourraient présenter un plus grand risque d’hyperglycémie avant une intervention non urgente. Ils permettent également de traiter ceux qui bénéficieraient le plus de conseils supplémentaires en matière de gestion préopératoire de la glycémie.

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: III. The 2020 Treatment of Chronic GVHD Report

: Positive results from recent clinical trials have significantly expanded current therapeutic options for patients with chronic graft-versus-host disease (GVHD). However, new insights into the associations between clinical characteristics of chronic GVHD, pathophysiologic mechanisms of disease, and the clinical and biological effects of novel therapeutic agents are required to allow for a more individualized approach to treatment. The current report is focused on setting research priorities and direction in the treatment of chronic GVHD. Detailed correlative scientific studies should be conducted in the context of clinical trials to evaluate associations between clinical outcomes and the biological effect of systemic therapeutics. For patients who require systemic therapy but not urgent initiation of glucocorticoids, clinical trials for initial systemic treatment of chronic GVHD should investigate novel agents as monotherapy without concurrently starting glucocorticoids, to avoid confounding biological, pathological, and clinical assessments. Clinical trials for treatment-refractory disease should specifically target patients with incomplete or suboptimal responses to most recent therapy who are early in their disease course. Close collaboration between academic medical centers, medical societies, and industry is needed to support an individualized, biology-based strategic approach to chronic GVHD therapy

Abdominal Aortic Aneurysm Is Associated with a Variant in Low-Density Lipoprotein Receptor-Related Protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10−5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10−5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10−10, odds ratio 1.15 [1.10–1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04–1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression