Genome-wide analyses in Lyme borreliosis: identification of a genetic variant associated with disease susceptibility and its immunological implications.

BACKGROUND: Genetic variation underly inter-individual variation in host immune responses to infectious diseases, and may affect susceptibility or the course of signs and symptoms. METHODS: We performed genome-wide association studies in a prospective cohort of 1138 patients with physician-confirmed Lyme borreliosis (LB), the most common tick-borne disease in the Northern hemisphere caused by the bacterium Borrelia burgdorferi sensu lato. Genome-wide variants in LB patients-divided into a discovery and validation cohort-were compared to two healthy cohorts. Additionally, ex vivo monocyte-derived cytokine responses of peripheral blood mononuclear cells to several stimuli including Borrelia burgdorferi were performed in both LB patient and healthy control samples, as were stimulation experiments using mechanistic/mammalian target of rapamycin (mTOR) inhibitors. In addition, for LB patients, anti-Borrelia antibody responses were measured. Finally, in a subset of LB patients, gene expression was analysed using RNA-sequencing data from the ex vivo stimulation experiments. RESULTS: We identified a previously unknown genetic variant, rs1061632, that was associated with enhanced LB susceptibility. This polymorphism was an eQTL for KCTD20 and ETV7 genes, and its major risk allele was associated with upregulation of the mTOR pathway and cytokine responses, and lower anti-Borrelia antibody production. In addition, we replicated the recently reported SCGB1D2 locus that was suggested to have a protective effect on B. burgdorferi infection, and associated this locus with higher Borrelia burgdorferi antibody indexes and lower IL-10 responses. CONCLUSIONS: Susceptibility for LB was associated with higher anti-inflammatory responses and reduced anti-Borrelia antibody production, which in turn may negatively impact bacterial clearance. These findings provide important insights into the immunogenetic susceptibility for LB and may guide future studies on development of preventive or therapeutic measures. TRIAL REGISTRATION: The LymeProspect study was registered with the International Clinical Trials Registry Platform (NTR4998, registration date 2015-02-13).

Potential determinants of antibody responses after vaccination against SARS-CoV-2 in older persons: the Doetinchem Cohort Study.

BACKGROUND: Immune responses to vaccination vary widely between individuals. The aim of this study was to identify health-related variables potentially underlying the antibody responses to SARS-CoV-2 vaccination in older persons. We recruited participants in the long-running Doetinchem Cohort Study (DCS) who underwent vaccination as part of the national COVID-19 program, and measured antibody concentrations to SARS-CoV-2 Spike protein (S1) and Nucleoprotein (N) at baseline (T0), and a month after both the first vaccination (T1), and the second vaccination (T2). Associations between the antibody concentrations and demographic variables, including age, sex, socio-economic status (SES), comorbidities (cardiovascular diseases and immune mediated diseases), various health parameters (cardiometabolic markers, inflammation markers, kidney- and lung function) and a composite measure of frailty ('frailty index', ranging from 0 to 1) were tested using multivariate models. RESULTS: We included 1457 persons aged 50 to 92 years old. Of these persons 1257 were infection naïve after their primary vaccination series. The majority (N = 954) of these individuals were vaccinated with two doses of BNT162b2 (Pfizer) and their data were used for further analysis. A higher frailty index was associated with lower anti-S1 antibody responses at T1 and T2 for both men (RT1 = -0.095, PT1 = 0.05; RT2 = -0.11, PT2 = 0.02) and women (RT1 = -0.24, PT1 < 0.01; RT2 = -0.15, PT2 < 0.01). After correcting for age and sex the frailty index was also associated with the relative increase in anti-S1 IgG concentrations between the two vaccinations (ß = 1.6, P < 0.01). Within the construct of frailty, history of a cardiac catheterization, diabetes, gastrointestinal disease, a cognitive speed in the lowest decile of the population distribution, and impaired lung function were associated with lower antibody responses after both vaccinations. CONCLUSIONS: Components of frailty play a key role in the primary vaccination response to the BNT162b2 vaccine within an ageing population. Older persons with various comorbidities have a lowered immune response after their first vaccination, and while frail and sick older persons see a stronger increase after their second vaccination compared to healthy people, they still have a lower antibody response after their second vaccination.

Reprogramming of myeloid cells and their progenitors in patients with non-medullary thyroid carcinoma.

Myeloid cells, crucial players in antitumoral defense, are affected by tumor-derived factors and treatment. The role of myeloid cells and their progenitors prior to tumor infiltration is poorly understood. Here we show single-cell transcriptomics and functional analyses of the myeloid cell lineage in patients with non-medullary thyroid carcinoma (TC) and multinodular goiter, before and after treatment with radioactive iodine compared to healthy controls. Integrative data analysis indicates that monocytes of TC patients have transcriptional upregulation of antigen presentation, reduced cytokine production capacity, and overproduction of reactive oxygen species. Interestingly, these cancer-related pathological changes are partially removed upon treatment. In bone marrow, TC patients tend to shift from myelopoiesis towards lymphopoiesis, reflected in transcriptional differences. Taken together, distinct transcriptional and functional changes in myeloid cells arise before their infiltration of the tumor and are already initiated in bone marrow, which suggests an active role in forming the tumor immune microenvironment.

The Genetic Risk for COVID-19 Severity Is Associated With Defective Immune Responses.

Recent genome-wide association studies (GWASs) of COVID-19 patients of European ancestry have identified genetic loci significantly associated with disease severity. Here, we employed the detailed clinical, immunological and multi-omics dataset of the Human Functional Genomics Project (HFGP) to explore the physiological significance of the host genetic variants that influence susceptibility to severe COVID-19. A genomics investigation intersected with functional characterization of individuals with high genetic risk for severe COVID-19 susceptibility identified several major patterns: i. a large impact of genetically determined innate immune responses in COVID-19, with ii. increased susceptibility for severe disease in individuals with defective cytokine production; iii. genetic susceptibility related to ABO blood groups is probably mediated through the von Willebrand factor (VWF) and endothelial dysfunction. We further validated these identified associations at transcript and protein levels by using independent disease cohorts. These insights allow a physiological understanding of genetic susceptibility to severe COVID-19, and indicate pathways that could be targeted for prevention and therapy.

A genome-wide functional genomics approach uncovers genetic determinants of immune phenotypes in type 1 diabetes.

Background: The large inter-individual variability in immune-cell composition and function determines immune responses in general and susceptibility o immune-mediated diseases in particular. While much has been learned about the genetic variants relevant for type 1 diabetes (T1D), the pathophysiological mechanisms through which these variations exert their effects remain unknown. Methods: Blood samples were collected from 243 patients with T1D of Dutch descent. We applied genetic association analysis on >200 immune-cell traits and >100 cytokine production profiles in response to stimuli measured to identify genetic determinants of immune function, and compared the results obtained in T1D to healthy controls. Results: Genetic variants that determine susceptibility to T1D significantly affect T cell composition. Specifically, the CCR5+ regulatory T cells associate with T1D through the CCR region, suggesting a shared genetic regulation. Genome-wide quantitative trait loci (QTLs) mapping analysis of immune traits revealed 15 genetic loci that influence immune responses in T1D, including 12 that have never been reported in healthy population studies, implying a disease-specific genetic regulation. Conclusions: This study provides new insights into the genetic factors that affect immunological responses in T1D. Funding: This work was supported by an ERC starting grant (no. 948207) and a Radboud University Medical Centre Hypatia grant (2018) to YL and an ERC advanced grant (no. 833247) and a Spinoza grant of the Netherlands Association for Scientific Research to MGN CT received funding from the Perspectief Biomarker Development Center Research Programme, which is (partly) financed by the Netherlands Organisation for Scientific Research (NWO). AJ was funded by a grant from the European Foundation for the Study of Diabetes (EFSD/AZ Macrovascular Programme 2015). XC was supported by the China Scholarship Council (201706040081).

Every year around the world, over 100,000 people are diagnosed with type 1 diabetes. This disease develops when the immune system mistakenly destroys the cells that produce a hormone called insulin, leaving affected individuals unable to regulate their blood sugar levels. Type 1 diabetes patients must rely on regular injections of manufactured insulin to survive. The composition and activity of the human immune system is under genetic control, and people with certain changes in their genes are more susceptible than others to develop type 1 diabetes. Previous studies have identified around 60 locations in the human DNA (known as loci) associated with the condition, but it remains unclear how these loci influence the immune system and whether diabetes will emerge. Chu, Janssen, Koenen et al. explored how variations in genetic information can influence the composition of the immune system, and the type of molecules it releases to perform its role. To do so, blood samples from 243 individuals of Dutch descent with type 1 diabetes were collected, and genetic associations were investigated. The results revealed that a major type of immune actors known as T cells are under the control of genetic factors associated with type 1 diabetes susceptibility. For instance, a specific type of T cells showed shared genetic control with type 1 diabetes. In addition, 15 loci were identified that influenced immune responses in the patients. Among those, 12 have never been reported to be involved in immune responses in healthy people, implying that these regions might only regulate the immune system of individuals with type 1 diabetes and other similar disorders. Finally, Chu, Janssen, Koenen et al. propose 11 genes within the identified loci as potential targets for new diabetes medication. These results represent an important resource for researchers exploring the genetic and immune basis of type 1 diabetes, and they could open new avenues for drug development.

Evolutionary Trajectories of Complex Traits in European Populations of Modern Humans.

Humans have a great diversity in phenotypes, influenced by genetic, environmental, nutritional, cultural, and social factors. Understanding the historical trends of physiological traits can shed light on human physiology, as well as elucidate the factors that influence human diseases. Here we built genome-wide polygenic scores for heritable traits, including height, body mass index, lipoprotein concentrations, cardiovascular disease, and intelligence, using summary statistics of genome-wide association studies in Europeans. Subsequently, we applied these scores to the genomes of ancient European populations. Our results revealed that after the Neolithic, European populations experienced an increase in height and intelligence scores, decreased their skin pigmentation, while the risk for coronary artery disease increased through a genetic trajectory favoring low HDL concentrations. These results are a reflection of the continuous evolutionary processes in humans and highlight the impact that the Neolithic revolution had on our lifestyle and health.

Evolution of cytokine production capacity in ancient and modern European populations.

As our ancestors migrated throughout different continents, natural selection increased the presence of alleles advantageous in the new environments. Heritable variations that alter the susceptibility to diseases vary with the historical period, the virulence of the infections, and their geographical spread. In this study we built polygenic scores for heritable traits that influence the genetic adaptation in the production of cytokines and immune-mediated disorders, including infectious, inflammatory, and autoimmune diseases, and applied them to the genomes of several ancient European populations. We observed that the advent of the Neolithic was a turning point for immune-mediated traits in Europeans, favoring those alleles linked with the development of tolerance against intracellular pathogens and promoting inflammatory responses against extracellular microbes. These evolutionary patterns are also associated with an increased presence of traits related to inflammatory and auto-immune diseases.