Tinker, Lesley F.

Objective: To examine prospective associations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test positivity, coronavirus disease 2019 (COVID-2019) symptom severity, and COVID-2019 hospitalization with incident clinical diabetes among aging women. Methods: A cohort study was conducted using data from 34,405 eligible Women’s Health Initiative participants who completed ≥1 COVID-2019 surveys (Survey 1: June–December 2020; Survey 2: June 2021–February 2022) and were followed up for an average of 1.86 (±0.49) years, yielding 399 incident diabetes cases. Results: SARS-CoV-2 test positivity was associated with diabetes risk in the age-adjusted Cox regression model (hazard ratio [HR] = 1.76, 95% confidence interval [CI]: 1.10, 2.82), but not when fully adjusted (HR = 1.43, 95% CI: 0.88, 2.31). Diabetes risk was higher among those with 1–2 COVID-19 symptoms (HR = 1.39, 95% CI: 1.09, 1.77) and those with 3± COVID-2019 symptoms (HR = 1.53, 95% CI: 1.06, 2.22) compared with those without COVID-2019 symptoms in fully-adjusted models, irrespective of self-reported SARS-CoV-2 testing. COVID-2019 hospitalization was associated with 2–3 times the risk of clinical diabetes in age-adjusted (HR = 2.95, 95% CI: 1.52, 5.72) and fully-adjusted (HR = 1.90, 95% CI: 0.97, 3.72) models. Conclusions: Age-adjusted self-reported SARS-CoV-2 test positivity was associated with a higher incidence of diabetes. Reporting of COVID-2019 symptoms and being hospitalized for COVID-2019 were each associated with higher incidence of diabetes in aging women, after controlling for demographic, socioeconomic, lifestyle, and health characteristics.

Abstract Obesity has been associated with non‐Hodgkin lymphoma (NHL), but the evidence is inconclusive. We examined the association between genetically determined adiposity and four common NHL subtypes: diffuse large B‐cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia, and marginal zone lymphoma, using eight genome‐wide association studies of European ancestry ( N = 10,629 cases, 9505 controls) and constructing polygenic scores for body mass index (BMI), waist‐to‐hip ratio (WHR), and waist‐to‐hip ratio adjusted for BMI (WHRadjBMI). Higher genetically determined BMI was associated with an increased risk of DLBCL [odds ratio (OR) per standard deviation (SD) = 1.18, 95% confidence interval (95% CI): 1.05–1.33, p = .005]. This finding was consistent with Mendelian randomization analyses, which demonstrated a similar increased risk of DLBCL with higher genetically determined BMI (OR per SD = 1.12, 95% CI: 1.02–1.23, p = .03). No significant associations were observed with other NHL subtypes. Our study demonstrates a positive link between a genetically determined BMI and an increased risk of DLBCL, providing additional support for increased adiposity as a risk factor for DLBCL.

Objective Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions These data suggest several plausible genetic links between DLBCL and SLE.

Abstract Background: Chronic inflammation is implicated in pancreatic cancer carcinogenesis. Advanced glycation end-products (AGEs), which are rich in cooked red meat and cigarette smoke, can perpetuate inflammation by binding to the receptor for advanced glycation end products (AGER, also known as RAGE). We hypothesized that genetic variation of the AGEs/AGER pathway affects pancreatic cancer risk by modulating chronic inflammation. Methods: We conducted a two-stage case-control study to examine the association between 96 single nucleotide polymorphisms (SNPs) in 21 genes (GLO1, MSR1, PINK1, KIF17, AGPAT1, AKR1B1, DDOST, CD36, SCARB1, AGER, APP, HMGB1, S100A8, S100B, S100P, S100A12, MMP9, ADAM10, PPARG, NOTCH4, and PDGF) of the AGEs/AGER pathway and risk of pancreatic cancer. The discovery study was conducted in 672 pancreatic cancer cases and 1361 controls ascertained from the Women’s Health Initiative (WHI) Study matched on age, race/ethnicity and study arm. The validation study was conducted in a PANC4 pooled hospital-based case-control study of 1,034 women cases and 989 women controls. A pooled analysis of 1706 cases and 2350 controls was also performed. SNP data were obtained or imputed from the previously performed GWASs. Pancreatic cancer risk was calculated as odds ratios (ORs) and 95% confidence intervals (Cis) using logistic regression models adjusting for age, race/ethnicity, body mass index (BMI), type 2 diabetes, and smoking using an additive genetic model. The potential interaction between individual SNP and red meat intake and cigarette smoking was examined. A false discovery rate (FDR) adjusted q value < 0.20 was considered statistically significant in the pooled analyses. We also conducted logistic-Kernel machine (LKM) test to examine the association between sets of SNP and risk of pancreatic cancer in the pooled dataset. Results: We identified 11 SNPs with raw P values < 0.10 in the discovery stage in the WHI study. However, none of the SNPs was validated in the validation and pooled dataset. The LKM test showed that sets of SNPs in CD36 (P = 9.3E-10), GLO1(P =2.0E-7), and DDOST (P = 2.5E-4) were significantly associated with pancreatic cancer risk. We found an interaction effect between the GLO1 SNP rs6932648 and smoking status (never versus ever) in the WHI study (P for interaction = 0.01) and the pooled dataset (P for interaction = 0.049). In the pooled dataset, the variant T allele of rs6932648 (MAF = 0.12) was associated with increased risk of pancreatic cancer among ever smokers (additive OR = 1.26, 95% CI: 1.02-1.55), but not among never smokers (additive OR = 0.94, 95% CI: 0.78-1.14), compared with the C allele. Summary and Conclusion: We did not observe significant association between any of 96 single SNP and pancreatic cancer risk. However, we found combined set of SNPs in the GLO1, DDOST, and CD36 genes were associated with risk of pancreatic cancer. GLO SNP rs6932648 may modify the association between smoking and risk of pancreatic cancer. GLO1, DDOST, and CD36 are involved in detoxification or clearance of AGEs compounds. Further investigation of AGEs and receptors systems in pancreatic cancer is warranted. Citation Format: Guochong Jia, Kathryn Royse, Hongwei Tang, Donghui Li, Liang Chen, Lesley Tinker, Gloria Petersen, Alison Klein, Peter Richardson, Donna White, Haleh Sangi-Haghapeykar, Hashem B. El-Serag, Li Jiao. Genetic variations in the AGEs/AGER pathway and risk of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-160. doi:10.1158/1538-7445.AM2017-LB-160

OBJECTIVE To examine elevated depressive symptoms and antidepressant use in relation to diabetes incidence in the Women’s Health Initiative. RESEARCH DESIGN AND METHODS A total of 161,808 postmenopausal women were followed for over an average of 7.6 years. Hazard ratios (HRs) estimating the effects of elevated depressive symptoms and antidepressant use on newly diagnosed incident diabetes were obtained using Cox proportional hazards models adjusted for known diabetes risk factors. RESULTS Multivariable-adjusted HRs indicated an increased risk of incident diabetes with elevated baseline depressive symptoms (HR 1.13 [95% CI 1.07–1.20]) and antidepressant use (1.18 [1.10–1.28]). These associations persisted through year 3 data, in which respective adjusted HRs were 1.23 (1.09–1.39) and 1.31 (1.14–1.50). CONCLUSIONS Postmenopausal women with elevated depressive symptoms who also use antidepressants have a greater risk of developing incident diabetes. In addition, longstanding elevated depressive symptoms and recent antidepressant medication use increase the risk of incident diabetes.