Introduction Patients with encephalitis with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E) are typically elderly males with a distinct phenotype, and ~90% carry the class II major histocompatibility (MHC) allele, DRB1*07:01. This allele is found in ~25% of healthy controls, suggesting other genetic and environmental disease factors operate in patients with LGI1-Ab-E. Yet, a previous genome-wide associa- tion study did not find variants attaining genome-wide significance outside the MHC region. Methods LGI1-Ab-E patients were genome-wide genotyped with standard arrays. Missing variants were imputed using Minimac4 and the Haplotype Reference Consortium panel. Population-matched controls were selected from UK Biobank. Genetic association with LGI1-Ab-E was determined with PLINK, SNPTEST and GWAMA and processed using bespoke bioinformatics pipelines. The discovery cohort of 131 French patients (92 men; 70%) was population-matched with 2613 controls (957 men; 36.6%): >6 million SNPs remained after quality control (lambda 1.04). The validation cohort comprises 97 US/UK cases (66 men; 68%) and 1940 matched controls (882 men; 45%), >5 million variants and lambda of 1. Results We replicated the MHC association ( rs2858869 , p=3.371e-52 in the discovery cohort; rs2858870 , p=1.085e-54 in the validation cohort) and will report the extent of non-MHC associations currently under- going bioinformatic assessment and validation.
How human genetic variation contributes to vaccine immunogenicity and effectiveness is unclear, particularly in infants from Africa. We undertook genome-wide association analyses of eight vaccine antibody responses in 2,499 infants from three African countries and identified significant associations across the human leukocyte antigen (HLA) locus for five antigens spanning pertussis, diphtheria and hepatitis B vaccines. Using high-resolution HLA typing in 1,706 individuals from 11 African populations we constructed a continental imputation resource to fine-map signals of association across the class II HLA observing genetic variation explaining up to 10% of the observed variance in antibody responses. Using follicular helper T-cell assays, in silico binding, and immune cell eQTL datasets we find evidence of HLA-DRB1 expression correlating with serological response and inferred protection from pertussis following vaccination. This work improves our understanding of molecular mechanisms underlying HLA associations that should support vaccine design and development across Africa with wider global relevance.
The interplay between genetic and environmental factors plays a significant role in interindividual variation in immune and inflammatory responses. The availability of high-throughput low-cost genotyping and next-generation sequencing has revolutionized our ability to identify human genetic variation and understand how this varies within and between populations, and the relationship with disease. In this review, we explore the potential of genomics for patient benefit, specifically in the diagnosis, prognosis and treatment of inflammatory and immune-related diseases. We summarize the knowledge arising from genetic and functional genomic approaches, and the opportunity for personalized medicine. The review covers applications in infectious diseases, rare immunodeficiencies and autoimmune diseases, illustrating advances in diagnosis and understanding risk including use of polygenic risk scores. We further explore the application for patient stratification and drug target prioritization. The review highlights a key challenge to the field arising from the lack of sufficient representation of genetically diverse populations in genomic studies. This currently limits the clinical utility of genetic-based diagnostic and risk-based applications in non-Caucasian populations. We highlight current genome projects, initiatives and biobanks from diverse populations and how this is being used to improve healthcare globally by improving our understanding of genetic susceptibility to diseases and regional pathogens such as malaria and tuberculosis. Future directions and opportunities for personalized medicine and wider application of genomics in health care are described, for the benefit of individual patients and populations worldwide.
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