Biology subjects

Kachroo, P.

Publications and source records attributed to Kachroo, P..

7 recordsLinked to original sources

bioRxiv2025

DNA-methylation markers associated with lung function at birth and childhood reveal early life programming of inflammatory pathways

RationaleLung function deficits may be caused by early life epigenetic programming. Early childhood studies are necessary to understand life-course trends in lung diseases. ObjectivesWe aimed to examine whether DNA-methylation at birth and childhood is associated with lung function growth. MethodsWe measured DNA-methylation in leukocytes from participants in two childhood asthma cohorts (CAMP [n=703, mean-age 12.9 years] and GACRS [n=788, mean-age 9.3 years]) and cord blood from participants in the VDAART study (n=572) to identify CpGs and pathways associated with lung function. ResultsWe identified 1,049 consistent differentially methylated CpGs (608 relatively hypermethylated) across all three studies (FDR-P<0.05). Relatively hypomethylated CpGs were enriched for gluconeogenesis, cell adhesion and VEGF signaling. Relatively hypermethylated CpGs were enriched for Hippo, B-cell and growth hormone receptor signaling. Functional enrichment suggested potential regulatory roles for active enhancers and histone modifications. Additionally, enrichment in PI3K/AKT and Notch pathways in males and enrichment in hormonal pathways in females was identified. Gaussian graphical models identified sex-differential DNA-methylation nodes and hub scores at birth and childhood. Integrating with previously identified polygenic risk scores for asthma and drug-target enrichment identified seven robust genes including MPO, CHCHD3, CACNA1S, PI4KA, EP400, CREBBP and KCNA10 with known associations as biomarkers for asthma severity and drug targets for airway inflammation. ConclusionsEpigenetic variability from birth through puberty provides mechanistic insights into fetal programming of developmental and immune pathways associated with lung function. These early life observations reveal potential targets for mitigating risk for lung function decline and asthma progression in later life. Key messagesO_LIWe identified consistent DNA methylation signatures between birth and childhood in critical metabolic, lung development and immune pathways that were associated with lung function and may be influenced by sex and genetics. C_LIO_LIOur integrative findings provide a deeper understanding for accelerated lung function decline across the life-course and could pave the way for translational interventions for lung diseases based on epigenetic plasticity. C_LI

genomics↗

bioRxiv2024

Network Analysis Reveals Protein Modules Associated with Childhood Respiratory Diseases

BackgroundThe first year of life is a period of rapid immune development that can impact health trajectories and the risk of developing respiratory-related diseases, such as asthma, recurrent infections, and eczema. However, the biology underlying subsequent disease development remains unknown. MethodsUsing weighted gene correlation network analysis (WGCNA), we derived modules of highly correlated immune-related proteins in plasma samples from children at age 1 year (N=294) from the Vitamin D Antenatal Asthma Reduction Trial (VDAART). We applied regression analyses to assess relationships between protein modules and development of childhood respiratory diseases up to age 6 years. We then characterized genomic, environmental, and metabolomic factors associated with modules. ResultsWGCNA identified four protein modules at age 1 year associated with incidence of childhood asthma and/or recurrent wheeze (Padj range: 0.02-0.03), respiratory infections (Padj range: 6.3x10-9-2.9x10-6), and eczema (Padj=0.01) by age 6 years; three modules were associated with at least one environmental exposure (Padj range: 2.8x10-10-0.03) and disrupted metabolomic pathway(s) (Padj range: 2.8x10-6-0.04). No genome-wide SNPs were identified as significant genetic risk factors for any protein module. Relationships between protein modules with clinical, environmental, and omic factors were temporally sensitive and could not be recapitulated in protein profiles at age 6 years. ConclusionThese findings suggested protein profiles as early as age 1 year predicted development of respiratory-related diseases through age 6 and were associated with changes in pathways related to amino acid and energy metabolism. These may inform new strategies to identify vulnerable individuals based on immune protein profiling.

bioinformatics↗

bioRxiv2023

OMICmAge: An integrative multi-omics approach to quantify biological age with electronic medical records

Biological aging is a multifactorial process involving complex interactions of cellular and biochemical processes that is reflected in omic profiles. Using common clinical laboratory measures in ~30,000 individuals from the MGB-Biobank, we developed a robust, predictive biological aging phenotype, EMRAge, that balances clinical biomarkers with overall mortality risk and can be broadly recapitulated across EMRs. We then applied elastic-net regression to model EMRAge with DNA-methylation (DNAm) and multiple omics, generating DNAmEMRAge and OMICmAge, respectively. Both biomarkers demonstrated strong associations with chronic diseases and mortality that outperform current biomarkers across our discovery (MGB-ABC, n=3,451) and validation (TruDiagnostic, n=12,666) cohorts. Through the use of epigenetic biomarker proxies, OMICmAge has the unique advantage of expanding the predictive search space to include epigenomic, proteomic, metabolomic, and clinical data while distilling this in a measure with DNAm alone, providing opportunities to identify clinically-relevant interconnections central to the aging process.

bioinformatics↗

bioRxiv2020

SVEP1, a novel human coronary artery disease locus, promotes atherosclerosis

A low-frequency variant of SVEP1, an extracellular matrix protein, is associated with risk of coronary disease in humans independent of plasma lipids. Despite a robust statistical association, however, it was unclear if and how SVEP1 might contribute to atherosclerosis. Here, using Mendelian randomization and complementary mouse models, we provide evidence that SVEP1 promotes atherosclerosis in humans and mice. We find that SVEP1 is expressed by vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque. VSMCs also interact with SVEP1, causing proliferation and dysregulation of key differentiation pathways, including integrin and Notch signaling. Fibroblast growth factor receptor transcription increases in VSMCs interacting with SVEP1, and is further increased by the coronary disease-associated SVEP1 variant. These effects ultimately drive inflammation and promote atherosclerosis. Taken together, our results suggest that VSMC-derived SVEP1 is a pro-atherogenic factor, and support the concept that pharmacological inhibition of SVEP1 should protect against atherosclerosis in humans.

genetics↗

bioRxiv2020

Population genomic molecular epidemiological study of macrolide resistant Streptococcus pyogenes in Iceland,1995-2016: Identification of a large clonal population with a pbp2x mutation conferring reduced in vitro beta-lactam susceptibility

Resistance to macrolide antibiotics is a global concern in the treatment of Streptococcus pyogenes (Group A Streptococcus, GAS) infections. In Iceland, since the detection of the first macrolide-resistant isolate in 1998, three epidemic waves of macrolide-resistant GAS infections have occurred with peaks in 1999, 2004, and 2008. We conducted whole genome sequencing of all 1,575 available GAS macrolide-resistant clinical isolates of all infection types collected at the national reference laboratory in Reykjavik from 1998 to 2016. Among 1,515 erythromycin-resistant isolates, 90.3% were of only three emm types: emm4 (n = 713), emm6 (n = 324), and emm12 (n = 332), with each being predominant in a distinct epidemic peak. The antibiotic efflux pump genes, mef(A) and msr(D), were present on chimeric mobile genetic elements in 99.3% of the macrolide-resistant isolates of these emm types. Of note, in addition to macrolide resistance, virtually all emm12 isolates had a single amino acid substitution in penicillin-binding protein PBP2X that conferred a two-fold increased penicillin G and ampicillin MIC among isolates tested. We conclude that each of the three large epidemic peaks of macrolide-resistant GAS infections occurring in Iceland since 1998 was caused by the emergence and clonal expansion of progenitor strains, with macrolide resistance being conferred predominantly by inducible Mef(A)-Msr(D) drug efflux pumps. The occurrence of emm12 strains with macrolide resistance and decreased beta-lactam susceptibility was unexpected and is of public health concern. RepositoriesGenomic sequencing data for all 1,515 macrolide/erythromycin-resistant isolates were deposited into the National Center for Biotechnology Information Sequence Read Archive under bioproject accession PRJNA614628 and assembled sequences for composite elements {Phi}29854, {Phi}29862 and {Phi}29661 were deposited in Genbank under accessions ###, ### and ### respectively.

genomics↗

bioRxiv2019

An exact, unifying framework for region-based association testing in family-based designs, including higher criticism approaches, SKATs, multivariate and burden tests

Analysis of rare variants in family-based studies remains a challenge. To perform a region/set-based association analysis of rare variants in family-based studies, we propose a general methodological framework that integrates higher criticism, maximum, SKATs, and burden approaches into the family-based association testing (FBAT) framework. Using the haplotype algorithm for FBATs to compute the conditional genotype distribution under the null hypothesis of Mendelian transmissions, virtually any association test statistics can be implemented in our approach and simulation-based or exact p-values can be computed without the need for asymptotic settings. Using simulations, we compare the features of the proposed test statistics in our framework with the existing region-based methodology for family-based studies under various scenarios. The tests of our framework outperform the existing approaches. We provide general guidelines for which scenarios, e.g., sparseness of the signals or local LD structure, which test statistic will have distinct power advantages over the others. We also illustrate our approach in an application to a whole-genome sequencing dataset with 897 asthmatic trios.

genetics↗

bioRxiv2019

Genetic heterogeneity of the Spy1336/R28 - Spy1337 Virulence Axis in Streptococcus pyogenes and Effect on Gene Transcript Levels and Pathogenesis

Streptococcus pyogenes is a strict human pathogen responsible for more than 700 million infections annually worldwide. Strains of serotype M28 S. pyogenes are typically among the five more abundant types causing invasive infections and pharyngitis in adults and children. Type M28 strains also have an unusual propensity to cause puerperal sepsis and neonatal disease. We recently discovered that a one-nucleotide indel in an intergenic homopolymeric tract located between genes Spy1336/R28 and Spy1337 altered virulence in a mouse model of infection. In the present study, we analyzed size variation in this homopolymeric tract and determined the extent of heterogeneity in the number of tandemly-repeated 79-amino acid domains in the coding region of Spy1336/R28 in large samples of strains recovered from humans with invasive infections. Both repeat sequence elements are highly polymorphic in natural populations of M28 strains. Variation in the homopolymeric tract results in (i) changes in transcript levels of Spy1336/R28 and Spy1337 in vitro, (ii) differences in virulence in a mouse model of necrotizing myositis, and (iii) global transcriptome changes as shown by RNAseq analysis of isogenic mutant strains. Variation in the number of tandem repeats in the coding sequence of Spy1336/R28 is responsible for size variation of R28 protein in natural populations. Isogenic mutant strains in which genes encoding R28 or transcriptional regulator Spy1337 are inactivated are significantly less virulent in a nonhuman primate model of necrotizing myositis. Our findings provide impetus for additional studies addressing the role of R28 and Spy1337 variation in pathogen-host interactions.

microbiology↗