School of Medicine

An increasing number of individuals with intellectual developmental disorder (IDD) and heterozygous variants in BCL11A are identified, yet our knowledge of manifestations and mutational spectrum is lacking. To address this, we performed detailed analysis of 42 individuals with BCL11A-related IDD (BCL11A-IDD, a.k.a. Dias-Logan syndrome) ascertained through an international collaborative network, and reviewed 35 additional previously reported patients. Analysis of 77 affected individuals identified 60 unique disease-causing variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique BCL11A microdeletions. We define the most prevalent features of BCL11A-IDD: IDD, postnatal-onset microcephaly, hypotonia, behavioral abnormalities, autism spectrum disorder, and persistence of fetal hemoglobin (HbF), and identify autonomic dysregulation as new feature. BCL11A-IDD is distinguished from 2p16 microdeletion syndrome, which has a higher incidence of congenital anomalies. Our results underscore BCL11A as an important transcription factor in human hindbrain development, identifying a previously underrecognized phenotype of a small brainstem with a reduced pons/medulla ratio. Genotype-phenotype correlation revealed an isoform-dependent trend in severity of truncating variants: those affecting all isoforms are associated with higher frequency of hypotonia, and those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S), are associated with higher frequency of postnatal microcephaly. With the largest international cohort to date, this study highlights persistence of fetal hemoglobin as a consistent biomarker and hindbrain abnormalities as a common feature. It contributes significantly to our understanding of BCL11A-IDD through an extensive unbiased multi-center assessment, providing valuable insights for diagnosis, management and counselling, and into BCL11As role in brain development.

Traditional obesity-related public health messaging often includes physical activity (PA) recommendations. However, at the population level, the data are conflicting, especially when comparing different self-reported vs. measured techniques across different settings and populations. We measured the association between moderate-to-vigorous intensity PA (MVPA) and prospective weight change across five African-origin populations and the extent to which MVPA attenuated weight change over time. At baseline, 2,500 adults (median age: 37y) were recruited into the Modelling the Epidemiologic Transition Study (METS), from Ghana, South Africa, Jamaica, Seychelles, and US. 2000 participants were followed up 8 years later, with 851 participants having complete 7-day accelerometry to measure MVPA at both time points. Generalised estimating equations were used to explore the longitudinal association between weight and MVPA adjusted for several confounders. The obesity prevalence at baseline was 27.5% which increased to 38.0% at follow-up. Baseline MVPA varied from 7 (IQR: 4, 16) min/day in US women to 52 (IQR: 36, 78) min/day in South African men, and similarly at follow-up ranged from 8 min/day to 41 min/day among the same participant groups. While overall, engaging in higher MVPA levels was associated with a lower body weight, such that every additional 30 min of MVPA equalled a 600 g lower body weight (p = 0.04), the interaction between time and MVPA was not statistically significant (p = 0.18). Therefore, regardless of the amount of MVPA at any time point, body weight increased over time. Despite the association between MVPA and weight, our results suggest that objectively measured longitudinal MVPA was not associated with the change in 8-year weight in African-origin adults. Our research confirms that while PA is a critical determinant of cardiovascular health, it alone may not be enough to stem the rising obesity burden.

This study showcases an integrative mass spectrometry-based strategy combining systems antigenomics and systems serology to characterize human antibodies in clinical samples. This strategy involves using antibodies circulating in plasma to affinity-enrich antigenic proteins in biochemically fractionated pools of bacterial proteins, followed by their identification and quantification using mass spectrometry. A selected subset of the identified antigens is then expressed recombinantly to isolate antigen-specific IgG, followed by characterization of the structural and functional properties of these antibodies. We focused on Group A streptococcus (GAS), a major human pathogen lacking an approved vaccine. The data shows that both healthy and GAS-infected individuals have circulating IgG against conserved streptococcal proteins, including toxins and virulence factors. The antigenic breadth of these antibodies remains relatively constant across healthy individuals but changes considerably in GAS bacteremia. Moreover, antigen-specific IgG analysis reveals individual variation in titers, subclass distributions, and Fc-signaling capacity, despite similar epitope and Fc-glycosylation patterns. Finally, we show that GAS antibodies may cross-react with Streptococcus dysgalactiae (SD), a bacterial pathogen that occupies similar niches and causes comparable infections. Collectively, our results highlight the complexity of GAS-specific antibody responses and the versatility of our methodology to characterize immune responses to bacterial pathogens.

BACKGROUND: Host DNA depletion is a critical tool for accessing the microbiomes of samples that have a small amount of microbial DNA contained in a high host background. Of critical practical importance is the ability to identify microbial DNA sequences in frozen tissue specimens. Here, we compare four existing commercial methods and two newly introduced methods involving chromatin immunoprecipitation (ChIP) on frozen human and pig intestinal biopsies. RESULTS: We find that all methods that rely on differential lysis of host and microbial cells introduce substantial biases as assessed by 16 S rRNA gene amplicon profiling. However, ChIP enables 10-fold enrichment of microbial DNA while introducing less bias, sufficient to make assessment possible against background, in both pigs and humans. CONCLUSIONS: We recommend ChIP in situations where host depletion is important but where minimizing taxonomic bias is essential, and the MolYsis or Zymo kit for situations where host depletion level is more important than taxonomic bias. CONCLUSIONS: We recommend ChIP in situations where host depletion is important but where minimizing taxonomic bias is essential, and the MolYsis or Zymo kit for situations where host depletion level is more important than taxonomic bias.

The rising prevalence of chronic kidney disease (CKD), affecting an estimated 37 million adults in the United States, presents a significant global health challenge. CKD is typically assessed using estimated Glomerular Filtration Rate (eGFR), which incorporates serum levels of biomarkers such as creatinine and cystatin C. However, these biomarkers do not directly measure kidney function; their elevation in CKD results from diminished glomerular filtration. Genome-wide association studies (GWAS) based on eGFR formulas using creatinine (eGFRcre) or cystatin C (eGFRcys) have identified distinct non-overlapping loci, raising questions about whether these loci govern kidney function or biomarker metabolism. In this study, we show that GWAS on creatinine and cystatin C levels in healthy individuals reveal both nonoverlapping genetic loci impacting their metabolism as well as overlapping genetic loci associated with kidney function; whereas GWAS on elevated levels of these biomarkers uncover novel loci primarily associated with kidney function in CKD patients.

A hallmark of pulmonary fibrosis is the aberrant activation of lung fibroblasts into pathological fibroblasts that produce excessive extracellular matrix^1-3. Thus, the identification of key regulators that promote the generation of pathological fibroblasts can inform the development of effective countermeasures against disease progression. Here we use two mouse models of pulmonary fibrosis to show that LEPR⁺ fibroblasts that arise during alveologenesis include SCUBE2⁺ alveolar fibroblasts as a major constituent. These alveolar fibroblasts in turn contribute substantially to CTHRC1⁺POSTN⁺ pathological fibroblasts. Genetic ablation of POSTN⁺ pathological fibroblasts attenuates fibrosis. Comprehensive analyses of scRNA-seq and scATAC-seq data reveal that RUNX2 is a key regulator of the expression of fibrotic genes. Consistently, conditional deletion of Runx2 with Lepr^creERT2 or Scube2^creERT2 reduces the generation of pathological fibroblasts, extracellular matrix deposition and pulmonary fibrosis. Therefore, LEPR⁺ cells that include SCUBE2⁺ alveolar fibroblasts are a key source of pathological fibroblasts, and targeting Runx2 provides a potential treatment option for pulmonary fibrosis.

BACKGROUND: Children from racial and ethnic minority groups are at greater risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but it is unclear whether they have increased risk for post-acute sequelae of SARS-CoV-2 (PASC). Our objectives were to assess whether the risk of respiratory and neurologic PASC differs by race/ethnicity and social drivers of health. METHODS: We conducted a retrospective cohort study of individuals <21 years seeking care at 24 health systems across the U.S, using electronic health record (EHR) data. Our cohort included those with a positive SARS-CoV-2 molecular, serology or antigen test, or with a COVID-19, multisystem inflammatory disease in children, or PASC diagnosis from February 29, 2020 to August 1, 2022. We identified children/youth with at least 2 codes associated with respiratory and neurologic PASC. We measured associations between sociodemographic and clinical characteristics and respiratory and neurologic PASC using odds ratios and 95% confidence intervals estimated from multivariable logistic regression models adjusted for other sociodemographic characteristics, social vulnerability index or area deprivation index, time period of cohort entry, presence and complexity of chronic respiratory (respectively, neurologic) condition and healthcare utilization. FINDINGS: Among 771,725 children in the cohort, 203,365 (26.3%) had SARS-CoV-2 infection. Among children with documented infection, 3217 children had respiratory PASC and 2009 children/youth had neurologic PASC. In logistic regression models, children <5 years (Odds Ratio [OR] 1.78, 95% CI 1.62-1.97), and of Hispanic White descent (OR 1.19, 95% CI 1.05-1.35) had higher odds of having respiratory PASC. Children/youth living in regions with higher area deprivation indices (OR 1.25, 95% CI 1.10-1.420 for 60-79th percentile) and with chronic complex respiratory conditions (OR 3.28, 95% CI 2.91-3.70) also had higher odds of respiratory PASC. In contrast, older (OR 1.57, 95% CI 1.40-1.77 for those aged 12-17 years), non-Hispanic White individuals and those with chronic pre-existing neurologic conditions (OR 2.04, 95% CI 1.78-2.35) were more likely to have a neurologic PASC diagnosis. INTERPRETATION: Racial and ethnic differences in healthcare utilization for neurologic and respiratory PASC may reflect social drivers of health and inequities in access to care. FUNDING: National Institutes of Health.

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OBJECTIVE: More than 10% of patients with type 1 diabetes (T1D) do not have high-risk HLA-DR3 or -DR4 haplotypes with distinct clinical features, such as later onset and reduced insulin dependence. We aimed to identify genetic drivers of T1D in the absence of DR3/DR4 and improve prediction of T1D risk in these individuals. RESEARCH DESIGN AND METHODS: We performed T1D association and fine-mapping analyses in 12,316 non-DR3/DR4 samples. Next, we performed heterogeneity tests to examine differences in T1D risk variants in individuals without versus those with DR3/DR4 haplotypes. We further assessed genome-wide differences in gene regulatory element and biological pathway enrichments between the non-DR3/DR4 and DR3/DR4 cohorts. Finally, we developed a genetic risk score (GRS) to predict T1D in individuals without DR3/DR4 and compared with an existing T1D GRS. RESULTS: A total of 18 T1D risk variants in non-DR3/DR4 samples were identified. Risk variants at the MHC and multiple other loci genome wide had heterogeneity in effects on T1D dependent on DR3/DR4 status, and non-DR3/DR4 T1D had evidence for a greater polygenic burden. T1D-associated variants in non-DR3/DR4 were more enriched for regulatory elements and pathways involved in antigen presentation, innate immunity, and β-cells and depleted in T cells compared with DR3/DR4. A non-DR3/DR4 GRS outperformed an existing risk score GRS2 in discriminating non-DR3/DR4 T1D from no diabetes (area under the curve 0.867; P = 7.48 × 10-32) and type 2 diabetes (0.907; P = 4.94 × 10-44). CONCLUSIONS: In total, we identified heterogeneity in T1D genetic risk dependent on high-risk HLA-DR3/DR4 haplotype, which uncovers disease mechanisms and enables more accurate prediction of T1D across the HLA background.

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