Faculty Bibliography

Importance:Changes in the prevalence of youth-onset diabetes have previously been observed. Objective:To estimate changes in prevalence of type 1 and type 2 diabetes in youths in the US from 2001 to 2017. Design, Setting, and Participants:In this cross-sectional observational study, individuals younger than 20 years with physician-diagnosed diabetes were enumerated from 6 areas in the US (4 geographic areas, 1 health plan, and select American Indian reservations) for 2001, 2009, and 2017. Exposures:Calendar year. Main Outcomes and Measures:Estimated prevalence of physician-diagnosed type 1 and type 2 diabetes overall and by race and ethnicity, age, and sex. Results:Among youths 19 years or younger, 4958 of 3.35 million had type 1 diabetes in 2001, 6672 of 3.46 million had type 1 diabetes in 2009, and 7759 of 3.61 million had type 1 diabetes in 2017; among those aged 10 to 19 years, 588 of 1.73 million had type 2 diabetes in 2001, 814 of 1.85 million had type 2 diabetes in 2009, and 1230 of 1.85 million had type 2 diabetes in 2017. The estimated type 1 diabetes prevalence per 1000 youths for those 19 years or younger increased significantly from 1.48 (95% CI, 1.44-1.52) in 2001 to 1.93 (95% CI, 1.88-1.98) in 2009 to 2.15 (95% CI, 2.10-2.20) in 2017, an absolute increase of 0.67 per 1000 youths (95%, CI, 0.64-0.70) and a 45.1% (95% CI, 40.0%-50.4%) relative increase over 16 years. The greatest absolute increases were observed among non-Hispanic White (0.93 per 1000 youths [95% CI, 0.88-0.98]) and non-Hispanic Black (0.89 per 1000 youths [95% CI, 0.88-0.98]) youths. The estimated type 2 diabetes prevalence per 1000 youths aged 10 to 19 years increased significantly from 0.34 (95% CI, 0.31-0.37) in 2001 to 0.46 (95% CI, 0.43-0.49) in 2009 to 0.67 (95% CI, 0.63-0.70) in 2017, an absolute increase of 0.32 per 1000 youths (95% CI, 0.30-0.35) and a 95.3% (95% CI, 77.0%-115.4%) relative increase over 16 years. The greatest absolute increases were observed among non-Hispanic Black (0.85 per 1000 youths [95% CI, 0.74-0.97]) and Hispanic (0.57 per 1000 youths [95% CI, 0.51-0.64]) youths. Conclusions and Relevance:In 6 areas of the US from 2001 to 2017, the estimated prevalence of diabetes among children and adolescents increased for both type 1 and type 2 diabetes.

OBJECTIVE:Maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 or type 2 diabetes. Correct diagnosis may result in a change in clinical treatment and impacts prediction of complications and familial risk. In this study, we aimed to assess the prevalence of MODY in multiethnic youth under age 20 years with a clinical diagnosis of type 2 diabetes. RESEARCH DESIGN AND METHODS/METHODS:We evaluated whole-exome sequence data of youth with a clinical diagnosis of type 2 diabetes. We considered participants to have MODY if they carried a MODY gene variant classified as likely pathogenic (LP) or pathogenic (P) according to current guidelines. RESULTS:= 0.006). CONCLUSIONS:= 83) the specific diagnosis would have changed clinical management. No clinical criterion reliably separated the two groups. New tools are needed to find ideal criteria for selection of individuals for genetic testing.

BACKGROUND:Severe hypoxic respiratory failure from COVID-19 pneumonia carries a high mortality risk. There is uncertainty surrounding which patients benefit from corticosteroids in combination with tocilizumab and the dosage and timing of these agents. The balance of controlling inflammation without increasing the risk of secondary infection is difficult. At present, dexamethasone 6 mg is the standard of care in COVID-19 hypoxia; whether this is the ideal choice of steroid or dosage remains to be proven. OBJECTIVES/OBJECTIVE:The primary objective was to assess the impact on mortality of tocilizumab only, corticosteroids only, and combination therapy in patients with COVID-19 respiratory failure. METHODS:A multihospital, retrospective study of adult patients with severe respiratory failure from COVID-19 who received supportive therapy, corticosteroids, tocilizumab, or combination therapy were assessed for 28-day mortality, biomarker improvement, and relative risk of infection. Propensity-matched analysis was performed between corticosteroid alone and combination therapies to further assess mortality benefit. RESULTS:= 0.005] without increasing the risk of infection. CONCLUSION AND RELEVANCE/UNASSIGNED:Combination of tocilizumab and corticosteroids was associated with improved 28-day survival when compared with corticosteroids alone. Modification of steroid dosing strategy as well as steroid type may further optimize therapeutic effect of the COVID-19 treatment.

We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P < 5 × 10^-8) regions, including 36 that are new. We define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4⁺ effector T cells. Using chromatin-accessibility profiling of CD4⁺ T cells from 115 individuals, we map chromatin-accessibility quantitative trait loci and identify five regions where T1D risk variants co-localize with chromatin-accessibility quantitative trait loci. We highlight rs72928038 in BACH2 as a candidate causal T1D variant leading to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps and immune protein-protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D.

Relative to European Americans, African Americans have lower 25-hydroxyvitamin D (25OHD) and vitamin D binding protein (VDBP) concentrations, higher 1,25-dihydroxyvitamin D (1,25(OH)2D3) concentrations and bone mineral density (BMD), and paradoxically reduced burdens of calcified atherosclerotic plaque (subclinical atherosclerosis). To identify genetic factors contributing to vitamin D and BMD measures, association analysis of >14M variants was conducted in a maximum of 697 African American-Diabetes Heart Study participants with type 2 diabetes (T2D). The most significant association signals were detected for VDBP on chromosome 4; variants rs7041 (β = 0.44, SE = 0.019, P = 9.4x10-86) and rs4588 (β = 0.17, SE = 0.021, P = 3.5x10-08) in the group-specific component (vitamin D binding protein) gene (GC). These variants were found to be independently associated. In addition, rs7041 was also associated with bioavailable vitamin D (BAVD; β = 0.16, SE = 0.02, P = 3.3x10-19). Six rare variants were significantly associated with 25OHD, including a non-synonymous variant in HSPG2 (rs116788687; β = -1.07, SE = 0.17, P = 2.2x10-10) and an intronic variant in TNIK (rs143555701; β = -1.01, SE = 0.18, P = 9.0x10-10), both biologically related to bone development. Variants associated with 25OHD failed to replicate in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of vitamin D metabolism and bone mineral density phenotypes in an African American population enriched for T2D could provide insight into ethnic specific differences in vitamin D metabolism and bone mineral density.

OBJECTIVES/OBJECTIVE:Gullah African Americans are descendants of formerly enslaved Africans living in the Sea Islands along the coast of the southeastern U.S., from North Carolina to Florida. Their relatively high numbers and geographic isolation were conducive to the development and preservation of a unique culture that retains deep African features. Although historical evidence supports a West-Central African ancestry for the Gullah, linguistic and cultural evidence of a connection to Sierra Leone has led to the suggestion of this country/region as their ancestral home. This study sought to elucidate the genetic structure and ancestry of the Gullah. MATERIALS AND METHODS/METHODS:We leveraged whole-genome genotype data from Gullah, African Americans from Jackson, Mississippi, African populations from Sierra Leone, and population reference panels from Africa and Europe to infer population structure, ancestry proportions, and global estimates of admixture. RESULTS:Relative to non-Gullah African Americans from the Southeast US, the Gullah exhibited higher mean African ancestry, lower European admixture, a similarly small Native American contribution, and increased male-biased European admixture. A slightly tighter bottleneck in the Gullah 13 generations ago suggests a largely shared demographic history with non-Gullah African Americans. Despite a slightly higher relatedness to populations from Sierra Leone, our data demonstrate that the Gullah are genetically related to many West African populations. DISCUSSION/CONCLUSIONS:This study confirms that subtle differences in African American population structure exist at finer regional levels. Such observations can help to inform medical genetics research in African Americans, and guide the interpretation of genetic data used by African Americans seeking to explore ancestral identities.

The purpose of this study was to examine factors that influence a person's choice of cognitive-behavioral therapy (CBT) or yoga, the stability of these preferences, and the impact of preference on engagement and process measures. We conducted a randomized preference trial of CBT and yoga in 500 adults ≥60 years with symptoms of worry. Participants reported their intervention preference, strength of preference, and factors impacting preference. Engagement in the intervention (session completion and dropout rates) was assessed. Process measures included satisfaction with the intervention, therapeutic alliance, and intervention expectancy. Neither intervention preference (48% and 52% chose CBT and yoga, respectively) nor strength of preference differed significantly between the two preference trial groups. Intervention expectancies at baseline among those in the preference trial were approximately 4.5 units (40-point scale) higher for their preferred intervention (p < .0001 within each group). A principal component analysis of factors influencing preference identified three constructs. Using logistic regression, components focused on attitudes about CBT or yoga were predictive of ultimate preference (odds ratio = 11.5, 95% C.I.6.3-21.0 per 1SD difference in component 1 for choosing CBT; odds ratio = 7.8, 95% CI4.3-13.9 per 1SD difference in component 2 for choosing yoga). There were no significant differences between the randomized and preference trials on intervention adherence, completion of assessments, intervention satisfaction, or working alliance. Receiving a preferred treatment had no significant effects on intervention outcomes through participant engagement or process measures. When options are limited, providers may have confidence in offering the most readily available non-pharmacological treatments.

BACKGROUND:-associated nephropathy currently exists. METHODS:-associated nephropathy in a future when treatment is available. A systematic literature search of the MEDLINE and Embase databases was conducted to identify relevant evidence published from January 1, 2009 to July 14, 2020. RESULTS:-associated nephropathy and on features of a successful education program to raise awareness among the patient community. The group also highlighted the unmet need for a specific treatment and agreed on best practice for management of these patients should a treatment become available. CONCLUSIONS:-associated nephropathy.

OBJECTIVE:high-risk genotypes and kidney outcomes, organ damage accrual and death in 100 Ghanaian patients with SLE. METHODS:This was a prospective cohort study of 100 SLE outpatients who sought care at Korle bu Teaching Hospital in Accra, Ghana. Adult patients who met 4 American College of Rheumatology criteria for SLE were genotyped for APOL1 and followed longitudinally for SLE activity as measured by the Safety of Estrogens in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) hybrid and organ injury as measured by the Systemic Lupus International Collaborating Clinics Damage Index (SDI) at baseline and every 6 months for 1 year. Outcomes of interest were kidney function, SDI and case fatality. RESULTS:high-risk genotype (2RV) associated with end-stage renal disease (ESRD) at an OR of 14 (p=0.008). These patients accrued more SDI points particularly in renal and neurological domains. The SDI was 81.3% higher in 2RV patients compared with 0RV or 1RV patients despite no difference in SLE activity (p=0.01). After a 12-month period of observation, 3/12 (25%) of the 2RV patients died compared with 2/88 (2.3%) of the 0RV or 1RV carriers (OR=13.6, p=0.01). Deaths were due to end-stage kidney disease and heart failure. CONCLUSION/CONCLUSIONS:high-risk patients exhibited progressive renal disease, organ damage accrual and a 13-fold higher case fatality.

The prevalence of type 2 diabetes in youth has increased substantially, yet the genetic underpinnings remain largely unexplored. To identify genetic variants predisposing to youth-onset type 2 diabetes, we formed ProDiGY, a multi-ethnic collaboration of three studies (TODAY, SEARCH, and T2D-GENES) with 3,006 youth type 2 diabetes cases (mean age 15.1±2.9 y) and 6,061 diabetes-free adult controls (mean age 54.2±12.4 y). After stratifying by principal component-clustered ethnicity, we performed association analyses on ∼10 million imputed variants using a generalized linear mixed model incorporating a genetic relationship matrix to account for population structure and adjusting for sex. We identified 7 genome-wide significant loci, including the novel locus rs10992863 in PHF2 (P=3.2×10^-8, odds ratio [OR]=1.23). Known loci identified in our analysis include rs7903146 in TCF7L2 (P=8.0×10^-20, OR 1.58), rs72982988 near MC4R (P=4.4×10^-14, OR=1.53), rs200893788 in CDC123 (P=1.1×10^-12, OR= 1.32), rs2237892 in KCNQ1 (P=4.8×10^-11, OR=1.59), rs937589119 in IGF2BP2 (P=3.1×10^-9, OR=1.34) and rs113748381 in SLC16A11 (P=4.1×10^-8, OR=1.04). Secondary analysis with 856 diabetes-free youth controls uncovered an additional locus in CPEB2 (P=3.2×10^-8, OR=2.1) and consistent direction of effect for diabetes risk. In conclusion, we identified both known and novel loci in the first genome wide association study (GWAS) of youth-onset type 2 diabetes.