Autosomal dominant ApoA4 mutations present as tubulointerstitial kidney disease with medullary amyloidosis.

Sporadic cases of apolipoprotein A-IV medullary amyloidosis have been reported. Here we describe five families found to have autosomal dominant medullary amyloidosis due to two different pathogenic APOA4 variants. A large family with autosomal dominant chronic kidney disease (CKD) and bland urinary sediment underwent whole genome sequencing with identification of a chr11:116692578 G>C (hg19) variant encoding the missense mutation p.L66V of the ApoA4 protein. We identified two other distantly related families from our registry with the same variant and two other distantly related families with a chr11:116693454 C>T (hg19) variant encoding the missense mutation p.D33N. Both mutations are unique to affected families, evolutionarily conserved and predicted to expand the amyloidogenic hotspot in the ApoA4 structure. Clinically affected individuals suffered from CKD with a bland urinary sediment and a mean age for kidney failure of 64.5 years. Genotyping identified 48 genetically affected individuals; 44 individuals had an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73 m2, including all 25 individuals with kidney failure. Significantly, 11 of 14 genetically unaffected individuals had an eGFR over 60 ml/min/1.73 m2. Fifteen genetically affected individuals presented with higher plasma ApoA4 concentrations. Kidney pathologic specimens from four individuals revealed amyloid deposits limited to the medulla, with the mutated ApoA4 identified by mass-spectrometry as the predominant amyloid constituent in all three available biopsies. Thus, ApoA4 mutations can cause autosomal dominant medullary amyloidosis, with marked amyloid deposition limited to the kidney medulla and presenting with autosomal dominant CKD with a bland urinary sediment. Diagnosis relies on a careful family history, APOA4 sequencing and pathologic studies.

Survey of stigma across healthcare workers in an urban, academic medical center regarding perinatal patients using opioids.

BACKGROUND AND OBJECTIVES: To examine healthcare workers' attitudes towards pregnant woman using opioids across provider type, specialty, and years of service. METHODS: Cross-sectional, anonymous survey of healthcare workers at an urban, academic medical center regarding attitudes towards pregnant women using opioids. RESULTS: One hundred and nineteen surveys were completed. Nurses were less likely to feel sympathetic towards pregnant women that use opioids (p = .016). DISCUSSION AND CONCLUSIONS: Differences in attitudes towards pregnant women using opioids were found between clinicians and nurses. SCIENTIFIC SIGNIFICANCE: Training and experience may contribute to attitude differences towards pregnant women using opioids.

A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus.

Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.

The Next Step in Integrated Care: Universal Primary Mental Health Providers.

Current models of mental health care often do not address three barriers to mental health: the binary view of mental illness (healthy vs. mentally ill), stigma, and prevention. Care models where some patients are selected for referral or consultation with a mental health professional can reinforce this binary view and the stigma associated with seeing mental health services. By only selecting patients who currently are experiencing mental health problems, current integrated care models do not offer sufficient avenues for prevention. To address these barriers, this article proposes building on current models through the development of primary mental health providers (PMHPs). PMHPs-like primary care providers-would provide regular check-ups, assessments, prevention interventions, first-line treatment, or referral to more specialized professionals. This universal approach will help decrease the binary view of mental health, decrease the stigma of seeing a mental health professional through universal access, and improve prevention efforts.

Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression.

Genetic variants at chromosomal region 11q23.3, near the gene ETS1, have been associated with systemic lupus erythematosus (SLE), or lupus, in independent cohorts of Asian ancestry. Several recent studies have implicated ETS1 as a critical driver of immune cell function and differentiation, and mice deficient in ETS1 develop an SLE-like autoimmunity. We performed a fine-mapping study of 14,551 subjects from multi-ancestral cohorts by starting with genotyped variants and imputing to all common variants spanning ETS1. By constructing genetic models via frequentist and Bayesian association methods, we identified 16 variants that are statistically likely to be causal. We functionally assessed each of these variants on the basis of their likelihood of affecting transcription factor binding, miRNA binding, or chromatin state. Of the four variants that we experimentally examined, only rs6590330 differentially binds lysate from B cells. Using mass spectrometry, we found more binding of the transcription factor signal transducer and activator of transcription 1 (STAT1) to DNA near the risk allele of rs6590330 than near the non-risk allele. Immunoblot analysis and chromatin immunoprecipitation of pSTAT1 in B cells heterozygous for rs6590330 confirmed that the risk allele increased binding to the active form of STAT1. Analysis with expression quantitative trait loci indicated that the risk allele of rs6590330 is associated with decreased ETS1 expression in Han Chinese, but not other ancestral cohorts. We propose a model in which the risk allele of rs6590330 is associated with decreased ETS1 expression and increases SLE risk by enhancing the binding of pSTAT1.

Analysis of Whole Exome Sequencing with Cardiometabolic Traits Using Family-Based Linkage and Association in the IRAS Family Study.

Family-based methods are a potentially powerful tool to identify trait-defining genetic variants in extended families, particularly when used to complement conventional association analysis. We utilized two-point linkage analysis and single variant association analysis to evaluate whole exome sequencing (WES) data from 1205 Hispanic Americans (78 families) from the Insulin Resistance Atherosclerosis Family Study. WES identified 211,612 variants above the minor allele frequency threshold of ≥0.005. These variants were tested for linkage and/or association with 50 cardiometabolic traits after quality control checks. Two-point linkage analysis yielded 10,580,600 logarithm of the odds (LOD) scores with 1148 LOD scores ≥3, 183 LOD scores ≥4, and 29 LOD scores ≥5. The maximal novel LOD score was 5.50 for rs2289043:T>C, in UNC5C with subcutaneous adipose tissue volume. Association analysis identified 13 variants attaining genome-wide significance (P < 5 × 10-08 ), with the strongest association between rs651821:C>T in APOA5 and triglyceride levels (P = 3.67 × 10-10 ). Overall, there was a 5.2-fold increase in the number of informative variants detected by WES compared to exome chip analysis in this population, nearly 30% of which were novel variants relative to the Database of Single Nucleotide Polymorphisms (dbSNP) build 138. Thus, integration of results from two-point linkage and single-variant association analysis from WES data enabled identification of novel signals potentially contributing to cardiometabolic traits.

Cancer Risk Factor Knowledge Among Young Adults.

Cancer is the second leading cause of death in the USA. Incidence and mortality rates for cancer have risen steadily and cost the healthcare system over $264 billion annually. Cancer risk can be reduced by restricting alcohol consumption, avoiding tobacco, eating a balanced diet, limiting sun exposure, exercising, and seeking routine cancer screenings. The purpose of this study is to examine cancer risk factor knowledge among college students. Researchers surveyed undergraduate and graduate students (n = 758) at a mid-sized public university in the Southeast about their knowledge regarding cancer risk factors including smoking, alcohol consumption, diet, obesity, hypertension, and human papillomavirus (HPV). Participants were mostly able to identify the association between cancers and health risk behaviors that have received widespread media coverage, are somewhat intuitive, or are salient to their life stage such as drinking, tanning, and smoking. Nearly all participants correctly reported exposure to ultraviolet (UV) rays, and smoking increased risk of developing skin and lung cancer, respectively. Most students correctly identified an increased risk of liver cancer associated with alcohol use but missed head/neck and breast cancer. However, knowledge of less publicized relationships was insufficient. The findings offer encouragement to public health professionals that campaigns have increased awareness of cancer risk. However, there were many relationships that revealed a lack of knowledge, and future campaigns can target lesser-known cancer risk relationships to reduce the personal tragedy and societal burden of cancer.

Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA.

OBJECTIVES: Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (CR2/CD21) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association. METHODS: Genotyped and imputed genetic variants spanning CR2 were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR. RESULTS: The strongest association signal was detected at rs1876453 in intron 1 of CR2 (pmeta=4.2×10(-4), OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control pmeta=7.6×10(-7), OR 0.71; case-only pmeta=1.9×10(-4), OR 0.75). Although allele-specific effects on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR. CONCLUSIONS: These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications.

Patient Satisfaction with Bedside Teaching Rounds Compared with Nonbedside Rounds.

OBJECTIVES: Many barriers have been cited in reference to why bedside teaching rounds have decreased in frequency during graduate medical education. One perceived barrier to the use of bedside teaching rounds is a fear of it causing patient discomfort or dissatisfaction. The objective of this study was to compare patient perception of bedside versus nonbedside teaching rounds. METHODS: Study participants were adults admitted to a family medicine inpatient team at a large university teaching hospital. Upon admission, participants were randomized to receive bedside or nonbedside teaching rounds conducted by a team consisting of medical students, family medicine residents, and one attending physician. Each participant completed a questionnaire administered on the day of discharge assessing patients' perception of their involvement in medical decision making, trust in the medical team, satisfaction with care, and provider compassion. Statistical analysis was performed to examine any differences between the two groups. RESULTS: The vast majority of the sample indicated that they knew what they were being treated for in the hospital (n = 105, 98%), reported the medical team spent an adequate amount of time with them (n = 100, 94%), and reported the medical team explained the diagnosis and care in easy-to-understand terms (n = 101, 94%). On 1- to 5-point scales, participants reported that the medical team involved them in making decisions (4.62, standard deviation [SD] 0.72), they trusted the medical team (4.91, SD 0.32), they were satisfied with their care (4.85, SD 0.38), and their medical team was compassionate toward them (4.84, SD 0.44). Overall levels of satisfaction were positive on all of the measures, with no statistical significance between the two groups regarding measures of involvement in medical decision making, trust in the medical team, and satisfaction with care. Interestingly, subjects perceived level of compassion of their medical team to be significantly higher with a bedside teaching approach compared with a nonbedside approach. CONCLUSIONS: Despite concerns that bedside teaching rounds may lead to patient discomfort, this study found no evidence supporting this perception. In fact, patients may perceive a medical team that engages in bedside teaching rounds as being more compassionate providers, supporting a patient-centered argument that teaching rounds should return to the bedside.

Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study.

Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified. In this study, we sought to replicate 1,580 variants showing suggestive association with SLE in a previously published GWA scan of European Americans; we tested a multiethnic population consisting of 7,998 SLE cases and 7,492 controls of European, African American, Asian, Hispanic, Gullah, and Amerindian ancestry to find association with the disease. Several genes relevant to immunological pathways showed association with SLE. Three loci exceeded the genome-wide significance threshold: interferon regulatory factor 8 (IRF8; rs11644034; p(meta-Euro) = 2.08 × 10(-10)), transmembrane protein 39A (TMEM39A; rs1132200; p(meta-all) = 8.62 × 10(-9)), and 17q21 (rs1453560; p(meta-all) = 3.48 × 10(-10)) between IKAROS family of zinc finger 3 (AIOLOS; IKZF3) and zona pellucida binding protein 2 (ZPBP2). Fine mapping, resequencing, imputation, and haplotype analysis of IRF8 indicated that three independent effects tagged by rs8046526, rs450443, and rs4843869, respectively, were required for risk in individuals of European ancestry. Eleven additional replicated effects (5 × 10(-8) < p(meta-Euro) < 9.99 × 10(-5)) were observed with CFHR1, CADM2, LOC730109/IL12A, LPP, LOC63920, SLU7, ADAMTSL1, C10orf64, OR8D4, FAM19A2, and STXBP6. The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation.

Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease.

Lung disease is the major cause of morbidity and mortality in cystic fibrosis, an autosomal recessive disease caused by mutations in CFTR. In cystic fibrosis, chronic infection and dysregulated neutrophilic inflammation lead to progressive airway destruction. The severity of cystic fibrosis lung disease has considerable heritability, independent of CFTR genotype. To identify genetic modifiers, here we performed a genome-wide single nucleotide polymorphism scan in one cohort of cystic fibrosis patients, replicating top candidates in an independent cohort. This approach identified IFRD1 as a modifier of cystic fibrosis lung disease severity. IFRD1 is a histone-deacetylase-dependent transcriptional co-regulator expressed during terminal neutrophil differentiation. Neutrophils, but not macrophages, from Ifrd1-deficient mice showed blunted effector function, associated with decreased NF-kappaB p65 transactivation. In vivo, IFRD1 deficiency caused delayed bacterial clearance from the airway, but also less inflammation and disease-a phenotype primarily dependent on haematopoietic cell expression, or lack of expression, of IFRD1. In humans, IFRD1 polymorphisms were significantly associated with variation in neutrophil effector function. These data indicate that IFRD1 modulates the pathogenesis of cystic fibrosis lung disease through the regulation of neutrophil effector function.

Lupus nephritis susceptibility loci in women with systemic lupus erythematosus.

Lupus nephritis is a manifestation of SLE resulting from glomerular immune complex deposition and inflammation. Lupus nephritis demonstrates familial aggregation and accounts for significant morbidity and mortality. We completed a meta-analysis of three genome-wide association studies of SLE to identify lupus nephritis-predisposing loci. Through genotyping and imputation, >1.6 million markers were assessed in 2000 unrelated women of European descent with SLE (588 patients with lupus nephritis and 1412 patients with lupus without nephritis). Tests of association were computed using logistic regression adjusting for population substructure. The strongest evidence for association was observed outside the MHC and included markers localized to 4q11-q13 (PDGFRA, GSX2; P=4.5×10(-7)), 16p12 (SLC5A11; P=5.1×10(-7)), 6p22 (ID4; P=7.4×10(-7)), and 8q24.12 (HAS2, SNTB1; P=1.1×10(-6)). Both HLA-DR2 and HLA-DR3, two well established lupus susceptibility loci, showed evidence of association with lupus nephritis (P=0.06 and P=3.7×10(-5), respectively). Within the class I region, rs9263871 (C6orf15-HCG22) had the strongest evidence of association with lupus nephritis independent of HLA-DR2 and HLA-DR3 (P=8.5×10(-6)). Consistent with a functional role in lupus nephritis, intra-renal mRNA levels of PDGFRA and associated pathway members showed significant enrichment in patients with lupus nephritis (n=32) compared with controls (n=15). Results from this large-scale genome-wide investigation of lupus nephritis provide evidence of multiple biologically relevant lupus nephritis susceptibility loci.

Identification of a systemic lupus erythematosus susceptibility locus at 11p13 between PDHX and CD44 in a multiethnic study.

Systemic lupus erythematosus (SLE) is considered to be the prototypic autoimmune disease, with a complex genetic architecture influenced by environmental factors. We sought to replicate a putative association at 11p13 not yet exceeding genome-wide significance (p < 5 × 10(-8)) identified in a genome-wide association study (GWAS). Our GWA scan identified two intergenic SNPs located between PDHX and CD44 showing suggestive evidence of association with SLE in cases of European descent (rs2732552, p = 0.004, odds ratio [OR] = 0.78; rs387619, p = 0.003, OR = 0.78). The replication cohort consisted of >15,000 subjects, including 3562 SLE cases and 3491 controls of European ancestry, 1527 cases and 1811 controls of African American (AA) descent, and 1265 cases and 1260 controls of Asian origin. We observed robust association at both rs2732552 (p = 9.03 × 10(-8), OR = 0.83) and rs387619 (p = 7.7 × 10(-7), OR = 0.83) in the European samples with p(meta) = 1.82 × 10(-9) for rs2732552. The AA and Asian SLE cases also demonstrated association at rs2732552 (p = 5 × 10(-3), OR = 0.81 and p = 4.3 × 10(-4), OR = 0.80, respectively). A meta-analysis of rs2732552 for all racial and ethnic groups studied produced p(meta) = 2.36 × 10(-13). This locus contains multiple regulatory sites that could potentially affect expression and functions of CD44, a cell-surface glycoprotein influencing immunologic, inflammatory, and oncologic phenotypes, or PDHX, a subunit of the pyruvate dehydrogenase complex.

Residents' knowledge of standard drink equivalents: implications for screening and brief intervention for at-risk alcohol use.

BACKGROUND AND OBJECTIVES: Screening and brief intervention for reducing alcohol consumption has been demonstrated to be effective in various medical settings. The NIAAA has recommended that physicians screen all patients for at-risk and problem drinking. Often, screening is based on the concept of a "standard drink." METHODS: We administered a survey to residents (N=270) in order to assess their knowledge of standard drink equivalents and quantities of alcohol in various sizes of bottles. RESULTS: Although 89% of the responders stated that they had previously learned about screening for at-risk alcohol use, the majority did not know basic facts about standard drink equivalents. DISCUSSION AND CONCLUSIONS: Many trainees are not familiar with typical standard drink equivalents. This can have a significant impact on the screening of patients for problem drinking using screening tools that rely on standard drink equivalents.

A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveals limited genetic overlap.

In spite of the well-known clustering of multiple autoimmune disorders in families, analyses of specific shared genes and polymorphisms between systemic lupus erythematosus (SLE) and other autoimmune diseases (ADs) have been limited. Therefore, we comprehensively tested autoimmune variants for association with SLE, aiming to identify pleiotropic genetic associations between these diseases. We compiled a list of 446 non-Major Histocompatibility Complex (MHC) variants identified in genome-wide association studies (GWAS) of populations of European ancestry across 17 ADs. We then tested these variants in our combined Caucasian SLE cohorts of 1,500 cases and 5,706 controls. We tested a subset of these polymorphisms in an independent Caucasian replication cohort of 2,085 SLE cases and 2,854 controls, allowing the computation of a meta-analysis between all cohorts. We have uncovered novel shared SLE loci that passed multiple comparisons adjustment, including the VTCN1 (rs12046117, P = 2.02×10(-06)) region. We observed that the loci shared among the most ADs include IL23R, OLIG3/TNFAIP3, and IL2RA. Given the lack of a universal autoimmune risk locus outside of the MHC and variable specificities for different diseases, our data suggests partial pleiotropy among ADs. Hierarchical clustering of ADs suggested that the most genetically related ADs appear to be type 1 diabetes with rheumatoid arthritis and Crohn's disease with ulcerative colitis. These findings support a relatively distinct genetic susceptibility for SLE. For many of the shared GWAS autoimmune loci, we found no evidence for association with SLE, including IL23R. Also, several established SLE loci are apparently not associated with other ADs, including the ITGAM-ITGAX and TNFSF4 regions. This study represents the most comprehensive evaluation of shared autoimmune loci to date, supports a relatively distinct non-MHC genetic susceptibility for SLE, provides further evidence for previously and newly identified shared genes in SLE, and highlights the value of studies of potentially pleiotropic genes in autoimmune diseases.

Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility.

Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, P(meta) = 6.6×10(-8), OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, P(meta) = 2.9×10(-7), OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ~146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (P(meta) = 3.2×10(-7), OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (P(meta) = 3.5×10(-4), OR = 1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE.

An Undergraduate Health Care Experience Course Increases Confidence and Improves Student Understanding of Health Care Careers.

Increasing the health care work force is critical to underserved communities. Unfortunately, students in these areas lack accessibility to the clinical experiences needed to get an introductory understanding of careers in health care. Therefore, a health care experience (HCE) course was created for undergraduate students that included didactic training, active learning exercises, and coordinated shadowing experiences. To evaluate the effect of the HCE on student interest in science, health care, and rural health a study was performed on HCE participants. This study assessed student background, interest in health care, and plans for future careers in underserved settings. Students who enrolled in the HCE demonstrated high interest in science, health care, and rural health. Evaluation of student reflections indicated students attained novel learning, gained insights, and recognized the importance of communication. The HCE course students exhibited amplified confidence in HCEs and had a significant increase in understanding of health care compared with a control group of students who had not completed the HCE. Undergraduate institutions can include courses like the HCE into curricula to increase accessibility to career experiences for students interested in health care careers.

Clinical Prediction Models Combining Routine Clinical Measures Have High Accuracy in Identifying Youth-Onset Type 2 Diabetes Defined by Maintained Endogenous Insulin Secretion: The SEARCH for Diabetes in Youth Study.

OBJECTIVE: With high prevalence of obesity and overlapping features between diabetes subtypes, accurately classifying youth-onset diabetes can be challenging. We aimed to develop prediction models that, using characteristics available at diabetes diagnosis, can identify youth who will retain endogenous insulin secretion at levels consistent with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We studied 2,966 youth with diabetes in the prospective SEARCH for Diabetes in Youth study (diagnosis age ≤19 years) to develop prediction models to identify participants with fasting C-peptide ≥250 pmol/L (≥0.75 ng/mL) after >3 years' (median 74 months) diabetes duration. Models included clinical measures at the baseline visit, at a mean diabetes duration of 11 months (age, BMI, sex, waist circumference, HDL cholesterol), with and without islet autoantibodies (GADA, IA-2A) and a Type 1 Diabetes Genetic Risk Score (T1DGRS). RESULTS: Models using routine clinical measures with or without autoantibodies and T1DGRS were highly accurate in identifying participants with C-peptide ≥0.75 ng/mL (17% of participants; 2.3% and 53% of those with and without positive autoantibodies) (area under the receiver operating characteristic curve [AUCROC] 0.95-0.98). In internal validation, optimism was very low, with excellent calibration (slope 0.995-0.999). Models retained high performance for predicting retained C-peptide in older youth with obesity (AUCROC 0.88-0.96) and in subgroups defined by self-reported race/ethnicity (AUCROC 0.88-0.97), autoantibody status (AUCROC 0.87-0.96), and clinically diagnosed diabetes types (AUCROC 0.81-0.92). CONCLUSIONS: Prediction models combining routine clinical measures at diabetes diagnosis, with or without islet autoantibodies or T1DGRS, can accurately identify youth with diabetes who maintain endogenous insulin secretion in the range associated with T2D.

Eight-Fold Increased COVID-19 Mortality in Autosomal Dominant Tubulointerstitial Kidney Disease due to MUC1 Mutations: An Observational Study.

Background: MUC1 and UMOD pathogenic variants cause autosomal dominant tubulointerstitial kidney disease (ADTKD). MUC1 is expressed in kidney, nasal mucosa and respiratory tract, while UMOD is expressed only in kidney. Due to haplo-insufficiency ADTKD- MUC1 patients produce approximately 50% of normal mucin-1. Methods: To determine whether decreased mucin-1 production was associated with an increased COVID-19 risk, we sent a survey to members of an ADTKD registry in September 2021, after the initial, severe wave of COVID-19. We linked results to previously obtained ADTKD genotype and plasma CA15-3 (mucin-1) levels and created a longitudinal registry of COVID-19 related deaths. Results: Surveys were emailed to 637 individuals, with responses from 89 ADTKD- MUC1 and 132 ADTKD- UMOD individuals. 19/83 (23%) ADTKD- MUC1 survey respondents reported a prior COVID-19 infection vs. 14/125 (11%) ADTKD- UMOD respondents (odds ratio (OR) 2.35 (95%CI 1.60-3.11, P = 0.0260). Including additional familial cases reported from survey respondents, 10/41 (24%) ADTKD- MUC1 individuals died of COVID-19 vs. 1/30 (3%) with ADTKD- UMOD , with OR 9.21 (95%CI 1.22-69.32), P = 0.03. The mean plasma mucin-1 level prior to infection in 14 infected and 27 uninfected ADTKD- MUC1 individuals was 7.06±4.12 vs. 10.21±4.02 U/mL ( P = 0.035). Over three years duration, our longitudinal registry identified 19 COVID-19 deaths in 360 ADTKD- MUC1 individuals (5%) vs. 3 deaths in 478 ADTKD- UMOD individuals (0.6%) ( P = 0.0007). Multivariate logistic regression revealed the following odds ratios (95% confidence interval) for COVID-19 deaths: ADTKD- MUC1 8.4 (2.9-29.5), kidney transplant 5.5 (1.6-9.1), body mass index (kg/m 2 ) 1.1 (1.0-1.2), age (y) 1.04 (1.0-1.1). Conclusions: Individuals with ADTKD- MUC1 are at an eight-fold increased risk of COVID-19 mortality vs. ADTKD- UMOD individuals. Haplo-insufficient production of mucin-1 may be responsible.

Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups.

OBJECTIVES: The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE. METHODS: We fine-mapped ≥136 SNPs in a ∼227 kb region on Xq28, containing IRAK1, MECP2 and seven adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15 783 case-control subjects derived from four different ancestral groups. RESULTS: Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at p<5×10(-8) with consistent association in subjects with African ancestry. Of these, six SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all four ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest p value in transancestral meta-analysis (p(meta )= 1.3×10(-27), OR=1.43), and thus was considered to be the most likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-κB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (p=0.0012) and healthy controls (p=0.0064). CONCLUSIONS: These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.