Life is pain: Fibromyalgia as a nexus of multiple liability distributions.

Fibromyalgia is a complex disease of unclear etiology that is complicated by difficulties in diagnosis, treatment, and clinical heterogeneity. To clarify this etiology, healthcare-based data are leveraged to assess the influences on fibromyalgia in several domains. Prevalence is less than 1% of females in our population register data, and about 1/10th that in males. Fibromyalgia often presents with co-occurring conditions including back pain, rheumatoid arthritis, and anxiety. More comorbidities are identified with hospital-associated biobank data, falling into three broad categories of pain-related, autoimmune, and psychiatric disorders. Selecting representative phenotypes with published genome-wide association results for polygenic scoring, we confirm genetic predispositions to psychiatric, pain sensitivity, and autoimmune conditions show associations with fibromyalgia, although these may differ by ancestry group. We conduct a genome-wide association analysis of fibromyalgia in biobank samples, which did not result in any genome-wide significant loci; further studies with increased sample size are necessary to identify specific genetic effects on fibromyalgia. Overall, fibromyalgia appears to have strong clinical and likely genetic links to several disease categories, and could usefully be understood as a composite manifestation of these etiological sources.

Identifying High-Risk Comorbidities Associated with Opioid Use Patterns Using Electronic Health Record Prescription Data.

Introduction: Opioid use disorders (OUDs) constitute a major public health issue, and we urgently need alternative methods for characterizing risk for OUD. Electronic health records (EHRs) are useful tools for understanding complex medical phenotypes but have been underutilized for OUD because of challenges related to underdiagnosis, binary diagnostic frameworks, and minimally characterized reference groups. As a first step in addressing these challenges, a new paradigm is warranted that characterizes risk for opioid prescription misuse on a continuous scale of severity, i.e., as a continuum. Methods: Across sites within the PsycheMERGE network, we extracted prescription opioid data and diagnoses that co-occur with OUD (including psychiatric and substance use disorders, pain-related diagnoses, HIV, and hepatitis C) for over 2.6 million patients across three health registries (Vanderbilt University Medical Center, Mass General Brigham, Geisinger) between 2005 and 2018. We defined three groups based on levels of opioid exposure: no prescriptions, minimal exposure, and chronic exposure and then compared the comorbidity profiles of these groups to the full registries and to those with OUD diagnostic codes. Results: Our results confirm that EHR data reflects known higher prevalence of substance use disorders, psychiatric disorders, medical, and pain diagnoses in patients with OUD diagnoses and chronic opioid use. Comorbidity profiles that distinguish opioid exposure are strikingly consistent across large health systems, indicating the phenotypes described in this new quantitative framework are robust to health systems differences. Conclusion: This work indicates that EHR prescription opioid data can serve as a platform to characterize complex risk markers for OUD using existing data.

Vascular alterations impede fragile tolerance to pregnancy in type 1 diabetes.

OBJECTIVE: To determine the impact of autoimmunity in the absence of glycemic alterations on pregnancy in type 1 diabetes (T1D). DESIGN: Because nonobese diabetic (NOD) mice experience autoimmunity before the onset of hyperglycemia, we studied pregnancy outcomes in prediabetic NOD mice using flow cytometry and enzyme-linked immunosorbent assays. Once we determined that adverse events in pregnancy occurred in euglycemic mice, we performed an exploratory study using electronic health records to better understand pregnancy complications in humans with T1D and normal hemoglobin A1c levels. SETTING: University Medical Center. PATIENT(S)/ANIMAL(S): Nonobese diabetic mice and electronic health records from Vanderbilt University Medical Center. INTERVENTION(S): Nonobese diabetic mice were administered 200 µg of an anti-interleukin 6 (IL-6) antibody every other day starting on day 5 of gestation. MAIN OUTCOME MEASURE(S): Changes in the number of abnormal and reabsorbed pups in NOD mice and odds of vascular complications in pregnancy in T1D in relation to A1c. RESULT(S): Prediabetic NOD mice had increased adverse pregnancy outcomes compared with nonautoimmune mice; blockade of IL-6, which was secreted by endothelial cells, decreased the number of reabsorbed and abnormal fetuses. Similarly, vascular complications were increased in pregnant patients with T1D across all A1c values. CONCLUSION(S): The vascular secretion of IL-6 drives adverse pregnancy outcomes in prediabetic NOD mice. Pregnant patients with T1D have increased vascular complications even with normal hemoglobin A1cs, indicating a potential effect of autoimmunity on the placental vasculature.

Calcium-Sensing Receptor Polymorphisms at rs1801725 Are Associated with Increased Risk of Secondary Malignancies.

Dysregulation of systemic calcium homeostasis during malignancy is common in most patients with high-grade tumors. However, it remains unclear whether single nucleotide polymorphisms (SNPs) that alter the sensitivity of the calcium-sensing receptor (CaSR) to circulating calcium are associated with primary and/or secondary neoplasms at specific pathological sites in patients of European and African ancestry. Multivariable logistic regression models were used to analyze the association of CASR SNPs with circulating calcium, parathyroid hormone, vitamin D, and primary and secondary neoplasms. Circulating calcium is associated with an increased risk for breast, prostate, and skin cancers. In patients of European descent, the rs1801725 CASR SNP is associated with bone-related cancer phenotypes, deficiency of humoral immunity, and a higher risk of secondary neoplasms in the lungs and bone. Interestingly, circulating calcium levels are higher in homozygous patients for the inactivating CASR variant at rs1801725 (TT genotype), and this is associated with a higher risk of secondary malignancies. Our data suggest that expression of CaSR variants at rs1801725 is associated with a higher risk of developing secondary neoplastic lesions in the lungs and bone, due in part to cancer-induced hypercalcemia and/or tumor immune suppression. Screening of patients for CASR variants at this locus may lead to improved management of high calcium associated tumor progression.