Infectious disease is the result of interactions between host and pathogen and can depend on genetic variations in both. We conduct a genome-to-genome study of paired human and Mycobacterium tuberculosis genomes from a cohort of 1556 tuberculosis patients in Lima, Peru. We identify an association between a human intronic variant (rs3130660, OR = 10.
View Article and Find Full Text PDFAims/hypothesis: Type 1 diabetes is associated with excess coronary artery disease (CAD) risk even when known cardiovascular risk factors are accounted for. Genetic perturbation of haematopoiesis that alters leukocyte production is a novel independent modifier of CAD risk. We examined whether there are shared genetic determinants and causal relationships between type 1 diabetes, CAD and leukocyte counts.
View Article and Find Full Text PDFA quarter of humanity is estimated to have been exposed to Mycobacterium tuberculosis (Mtb) with a 5-10% risk of developing tuberculosis (TB) disease. Variability in responses to Mtb infection could be due to host or pathogen heterogeneity. Here, we focused on host genetic variation in a Peruvian population and its associations with gene regulation in monocyte-derived macrophages and dendritic cells (DCs).
View Article and Find Full Text PDFThe morphology of cells is dynamic and mediated by genetic and environmental factors. Characterizing how genetic variation impacts cell morphology can provide an important link between disease association and cellular function. Here, we combine genomic sequencing and high-content imaging approaches on iPSCs from 297 unique donors to investigate the relationship between genetic variants and cellular morphology to map what we term cell morphological quantitative trait loci (cmQTLs).
View Article and Find Full Text PDFA quarter of humanity is estimated to be latently infected with () with a 5-10% risk of developing tuberculosis (TB) disease. Variability in responses to infection could be due to host or pathogen heterogeneity. Here, we focused on host genetic variation in a Peruvian population and its associations with gene regulation in monocyte-derived macrophages and dendritic cells (DCs).
View Article and Find Full Text PDFThe genotyping of millions of human samples has made it possible to evaluate variants across the human genome for their possible association with risks for numerous diseases and other traits by using genome-wide association studies (GWASs). The associations between phenotype and genotype found in GWASs make possible the construction of polygenic scores (PGSs), which aim to predict a trait or disease outcome in an individual on the basis of their genotype (in the disease case, the term polygenic risk score [PRS] is often used). PGSs have shown promise for studying the biology of complex traits and as a tool for evaluating individual disease risks in clinical settings.
View Article and Find Full Text PDFWe investigated whether ancestry-specific genetic factors affect tuberculosis (TB) progression risk in a cohort of admixed Peruvians. We genotyped 2,105 patients with TB and 1,320 household contacts (HHCs) who were infected with () but did not develop TB and inferred each individual's proportion of native Peruvian genetic ancestry. Our HHC study design and our data on potential confounders allowed us to demonstrate increased risk independent of socioeconomic factors.
View Article and Find Full Text PDFAs single-cell datasets grow in sample size, there is a critical need to characterize cell states that vary across samples and associate with sample attributes, such as clinical phenotypes. Current statistical approaches typically map cells to clusters and then assess differences in cluster abundance. Here we present co-varying neighborhood analysis (CNA), an unbiased method to identify associated cell populations with greater flexibility than cluster-based approaches.
View Article and Find Full Text PDFPharmacogenomic studies have revealed associations between rs1967309 in the adenylyl cyclase type 9 () gene and clinical responses to the cholesteryl ester transfer protein (CETP) modulator dalcetrapib, however, the mechanism behind this interaction is still unknown. Here, we characterized selective signals at the locus associated with the pharmacogenomic response in human populations and we show that rs1967309 region exhibits signatures of positive selection in several human populations. Furthermore, we identified a variant in , rs158477, which is in long-range linkage disequilibrium with rs1967309 in the Peruvian population.
View Article and Find Full Text PDFDespite thousands of reported patients with pandemic-associated pernio, low rates of seroconversion and PCR positivity have defied causative linkage to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pernio in uninfected children is associated with monogenic disorders of excessive IFN-1 immunity, whereas severe COVID-19 pneumonia can result from insufficient IFN-1. Moreover, SARS-CoV-2 spike protein and robust IFN-1 response are seen in the skin of patients with pandemic-associated pernio, suggesting an excessive innate immune skin response to SARS-CoV-2.
View Article and Find Full Text PDFMultimodal T cell profiling can enable more precise characterization of elusive cell states underlying disease. Here, we integrated single-cell RNA and surface protein data from 500,089 memory T cells to define 31 cell states from 259 individuals in a Peruvian tuberculosis (TB) progression cohort. At immune steady state >4 years after infection and disease resolution, we found that, after accounting for significant effects of age, sex, season and genetic ancestry on T cell composition, a polyfunctional type 17 helper T (T17) cell-like effector state was reduced in abundance and function in individuals who previously progressed from Mycobacterium tuberculosis (M.
View Article and Find Full Text PDFOn average, Peruvian individuals are among the shortest in the world. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvian individuals, and identify a population-specific, missense variant in the FBN1 gene (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency of 4.
View Article and Find Full Text PDFOf the 1.8 billion people worldwide infected with Mycobacterium tuberculosis, 5-15% will develop active tuberculosis (TB). Approximately half will progress to active TB within the first 18 months after infection, presumably because they fail to mount an effective initial immune response.
View Article and Find Full Text PDFAcute liver failure (ALF) or fulminant hepatitis is a rare, yet severe outcome of infection with hepatitis B virus (HBV) that carries a high mortality rate. The occurrence of a life-threatening condition upon infection with a prevalent virus in individuals without known risk factors is suggestive of pathogen-specific immune dysregulation. In the absence of established differences in HBV virulence, we hypothesized that ALF upon primary infection with HBV could be due to rare deleterious variants in the human genome.
View Article and Find Full Text PDFAn inverted (intussuscepted) appendix is a rare finding, often mistaken for a polyp as it presents with vague symptoms. This can result in misdiagnosis and inappropriate management. Diagnosis is usually made through surgery.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
August 2017
Viral respiratory infections are usually mild and self-limiting; still they exceptionally result in life-threatening infections in previously healthy children. To investigate a potential genetic cause, we recruited 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Using exome and transcriptome sequencing, we identified and characterized three rare loss-of-function variants in which encodes an RIG-I-like receptor involved in the sensing of viral RNA.
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