Thorball, C. W. | Search bioRxiv

bioRxiv2018

Genetic factors and age are the strongest predictors of humoral immune responses to common pathogens and vaccines

IntroductionHumoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence suggests that human genetic variation influences (i) serum immunoglobulin levels, (ii) seroconversion rates, and (iii) intensity of antigen-specific immune responses. Here, we evaluate the impact of intrinsic (age and sex), environmental and genetic factors on the variability of humoral response to common pathogens and vaccines.\n\nMethodsWe characterized the serological response to 15 antigens from common human pathogens or vaccines, in an age- and sex-stratified cohort of 1,000 healthy individuals (Milieu Interieur cohort). Using clinical-grade serological assays, we measured total IgA, IgE, IgG and IgM levels, as well as qualitative (serostatus) and quantitative IgG responses to cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1 & 2, varicella zoster virus, Helicobacter pylori, Toxoplasma gondii, influenza A virus, measles, mumps, rubella, and hepatitis B virus. Following genome-wide genotyping of single nucleotide polymorphisms and imputation, we examined associations between ~5 million genetic variants and antibody responses using single marker and gene burden tests.\n\nResults and discussionWe identified age and sex as important determinants of humoral response, with older individuals and women having higher rates of seropositivity for most antigens. Genome-wide association studies revealed significant associations between variants in the human leucocyte antigen (HLA) class II region on chromosome 6 and anti-EBV and anti-rubella IgG levels. We used HLA imputation to fine map these associations to amino acid variants in the peptide-binding groove of HLA-DR{beta}1 and HLA-DP{beta}1, respectively. We also observed significant associations for total IgA levels with two loci on chromosome 2 and with specific KIR-HLA combinations.\n\nConclusionsUsing extensive serological testing and genome-wide association analyses in a well-characterized cohort of healthy individuals, we demonstrate that age, sex and specific human genetic variants contribute to inter-individual variability in humoral response. By highlighting genes and pathways implicated in the normal antibody response to frequently encountered antigens, these findings provide a basis to better understand disease pathogenesis.

genomics↗

bioRxiv2017

A genome-wide polygenic approach to HIV uncovers link to inflammatory bowel disease and identifies potential novel genetic variants

Polygenic approaches using genome-wide data have been hugely successful in confirming and quantifying the heritability of complex human traits. Here, we highlight their ability to identify potential novel risk variants by looking for variants with pleiotropic effect in genetically overlapping phenotypes.\n\nWe used LD Score Regression in a sample of 6,315 HIV+ European individuals and 7,247 controls to test for phenotypes genetically overlapping with susceptibility to HIV-1 infection. Using LD Hub, a web tool that performs LD Score Regression, identified two phenotypes with significant genetic overlap: schizophrenia (rG =0.19, p=0.0007 and ulcerative colitis (rG=0.22, p= 0.0061). We further showed that the genetic overlap between HIV acquisition and schizophrenia is likely driven in part by their shared overlap with cannabis use and sexual behavior. BUMHBOX analyses suggested that these genetic overlaps were driven by genome-wide pleiotropy with HIV acquisition rather than heterogeneity within the HIV acquisition sample. The two diseases identified as genetically overlapping with HIV-1 acquisition have >100 associated variants, and we tested if any of them significantly associated with HIV acquisition. We observed three variants that exceeded our threshold for statistical significance. Two of these were eQTLs in whole blood for genes coding for proteins suspected to be involved in HIV biology: rs1819333 in CCR6 (p=0.0002) and rs4932178 in FURIN (p=0.00033). However, no signal was found for these variants in two smaller African samples totaling 1015 cases and 963 controls, though the mode of acquisition and genetic architecture of these populations differed.\n\nThese results highlight the ability to use polygenic methods to gain new insights into complex diseases and identify potential associations with individual variants. Crucially, the leveraging of existing, publically available data makes these methods a cost-effective approach. In this case, our results add to the evidence for the role of risk taking behavior and inflammation of the bowel in HIV acquisition.\n\nAuthor SummaryThe biology of what puts certain individuals at greater risk of HIV acquisition is poorly understood. Using several novel polygenic methods, we identify supporting evidence for two important factors leading to acquisition. First, the role of an individuals genetic predisposition to risk taking behaviours such as number of sexual partners, age at first sexual intercourse drug use, and mental health problems. Second, the role of gut inflammation, in particular a genetic overlap between HIV acquisition with inflammatory bowel disease and the potential role of CCR6 during infection.

genomics↗