A Coding Variant of ANO10, Affecting Volume Regulation of Macrophages, Is Associated with Borrelia Seropositivity.
In a first genome-wide association study (GWAS) approach to anti-Borrelia seropositivity, we identified two significant single nucleotide polymorphisms (SNPs) (rs17850869, P = 4.17E-09; rs41289586, P = 7.18E-08). Both markers, located on chromosomes 16 and 3, respectively, are within or close to genes previously connected to spinocerebellar ataxia. The risk SNP rs41289586 represents a missense variant (R263H) of anoctamin 10 (ANO10), a member of a protein family encoding Cl(-) channels and phospholipid scramblases. ANO10 augments volume-regulated Cl(-) currents (IHypo) in Xenopus oocytes, HEK293 cells, lymphocytes and macrophages and controls volume regulation by enhancing regulatory volume decrease (RVD). ANO10 supports migration of macrophages and phagocytosis of spirochetes. The R263H variant is inhibitory on IHypo, RVD and intracellular Ca(2+) signals, which may delay spirochete clearance, thereby sensitizing adaptive immunity. Our data demonstrate for the first time that ANO10 has a central role in innate immune defense against Borrelia infection.
Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
Christian
C
Hammer
Institut für Physiologie, Universität Regensburg, Regensburg, Germany.
Podchanart
P
Wanitchakool
Institut für Physiologie, Universität Regensburg, Regensburg, Germany.
Lalida
L
Sirianant
Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
Sergi
S
Papiol
Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
Mathieu
M
Monnheimer
Institut für Physiologie, Universität Regensburg, Regensburg, Germany.
Diana
D
Faria
Institut für Physiologie, Universität Regensburg, Regensburg, Germany.
Jiraporn
J
Ousingsawat
Department of Neurology, University of Ulm, Ulm, Germany.
Natalie
N
Schramek
Institute of Virology, Hannover Medical School, Hannover, Germany.
Corinna
C
Schmitt
National Reference Center for Borrelia, Bavarian Health and Food Safety Authority, Oberschleissheim, Germany.
Gabriele
G
Margos
Division of Genome Modifications and Carcinogenesis, Infections and Cancer Program, German Cancer Research Center, Heidelberg, Germany.
Angelika
A
Michel
Institute of Medical Microbiology and Infection Control, University Hospital of Frankfurt am Main, Frankfurt/Main, Germany.
Peter
P
Kraiczy
Division of Genome Modifications and Carcinogenesis, Infections and Cancer Program, German Cancer Research Center, Heidelberg, Germany.
Michael
M
Pawlita
Institut für Physiologie, Universität Regensburg, Regensburg, Germany.
Rainer
R
Schreiber
Institute of Virology, Hannover Medical School, Hannover, Germany.
Thomas F
TF
Schulz
National Reference Center for Borrelia, Bavarian Health and Food Safety Authority, Oberschleissheim, Germany.
Volker
V
Fingerle
Department of Neurology, University of Ulm, Ulm, Germany.
Hayrettin
H
Tumani
Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.|DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
Hannelore
H
Ehrenreich
Institut für Physiologie, Universität Regensburg, Regensburg, Germany.
Karl
K
Kunzelmann
D000818:Animals; D000075368:Anoctamins; D000907:Antibodies, Bacterial / Q000097:blood / Q000276:immunology; D001898:Borrelia / Q000276:immunology*; D001899:Borrelia Infections / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology; D016022:Case-Control Studies; D002460:Cell Line; D048429:Cell Size; D015870:Gene Expression; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D001523:Mental Disorders / Q000235:genetics / Q000382:microbiology; D009865:Oocytes; D016366:Open Reading Frames; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016036:Seroepidemiologic Studies
C000594870:ANO10 protein, human; D000075368:Anoctamins; D000907:Antibodies, Bacterial; D008565:Membrane Proteins