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The landscape of human genes involved in the immune response to parasitic worms.

ABSTRACT: BACKGROUND: More than 2 billion individuals worldwide suffer from helminth infections. The highest parasite burdens occur in children and helminth infection during pregnancy is a risk factor for preterm delivery and reduced birth weight. Therefore, helminth infections can be regarded as a strong selective pressure. RESULTS: Here we propose that candidate susceptibility genes for parasitic worm infections can be identified by searching for SNPs that display a strong correlation with the diversity of helminth species/genera transmitted in different geographic areas. By a genome-wide search we identified 3478 variants that correlate with helminth diversity. These SNPs map to 810 distinct human genes including loci involved in regulatory T cell function and in macrophage activation, as well as leukocyte integrins and co-inhibitory molecules. Analysis of functional relationships among these genes identified complex interaction networks centred around Th2 cytokines. Finally, several genes carrying candidate targets for helminth-driven selective pressure also harbour susceptibility alleles for asthma/allergy or are involved in airway hyper-responsiveness, therefore expanding the known parallelism between these conditions and parasitic infections. CONCLUSIONS: Our data provide a landscape of human genes that modulate susceptibility to helminths and indicate parasitic worms as one of the major selective forces in humans.

SUBMITTER: Fumagalli M

PROVIDER: S-EPMC2940816 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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The landscape of human genes involved in the immune response to parasitic worms.

Fumagalli Matteo M Pozzoli Uberto U Cagliani Rachele R Comi Giacomo P GP Bresolin Nereo N Clerici Mario M Sironi Manuela M

BMC evolutionary biology 20100831

<h4>Background</h4>More than 2 billion individuals worldwide suffer from helminth infections. The highest parasite burdens occur in children and helminth infection during pregnancy is a risk factor for preterm delivery and reduced birth weight. Therefore, helminth infections can be regarded as a strong selective pressure.<h4>Results</h4>Here we propose that candidate susceptibility genes for parasitic worm infections can be identified by searching for SNPs that display a strong correlation with ...[more]

PMID: 20807397

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Project description:BackgroundHumans and viruses have co-evolved for millennia resulting in a complex host genetic architecture. Understanding the genetic mechanisms of immune response to viral infection provides insight into disease etiology and therapeutic opportunities.MethodsWe conducted a comprehensive study including genome-wide and transcriptome-wide association analyses to identify genetic loci associated with immunoglobulin G antibody response to 28 antigens for 16 viruses using serological data from 7924 European ancestry participants in the UK Biobank cohort.ResultsSignals in human leukocyte antigen (HLA) class II region dominated the landscape of viral antibody response, with 40 independent loci and 14 independent classical alleles, 7 of which exhibited pleiotropic effects across viral families. We identified specific amino acid (AA) residues that are associated with seroreactivity, the strongest associations presented in a range of AA positions within DRβ1 at positions 11, 13, 71, and 74 for Epstein-Barr virus (EBV), Varicella zoster virus (VZV), human herpesvirus 7, (HHV7), and Merkel cell polyomavirus (MCV). Genome-wide association analyses discovered 7 novel genetic loci outside the HLA associated with viral antibody response (P < 5.0 × 10-8), including FUT2 (19q13.33) for human polyomavirus BK (BKV), STING1 (5q31.2) for MCV, and CXCR5 (11q23.3) and TBKBP1 (17q21.32) for HHV7. Transcriptome-wide association analyses identified 114 genes associated with response to viral infection, 12 outside of the HLA region, including ECSCR: P = 5.0 × 10-15 (MCV), NTN5: P = 1.1 × 10-9 (BKV), and P2RY13: P = 1.1 × 10-8 EBV nuclear antigen. We also demonstrated pleiotropy between viral response genes and complex diseases, from autoimmune disorders to cancer to neurodegenerative and psychiatric conditions.ConclusionsOur study confirms the importance of the HLA region in host response to viral infection and elucidates novel genetic determinants beyond the HLA that contribute to host-virus interaction.

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The landscape of human genes involved in the immune response to parasitic worms.

Publications

The landscape of human genes involved in the immune response to parasitic worms.

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