Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery datasets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5×10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signaling and cytokine-cytokine pathways, for which relevant therapies exist.

The permeability of a membrane to a penetrating substance is given quantitatively by the amount of the substance which crosses a unit area of the membrane in unit time under the action of a unit force. In simple cases of ionized substances both the amount of substance and the force acting may be expressed in electrical terms. Then the permeability may be ultimately converted into coulombs per second for a square centimeter and a potential difference of 1 volt, which is the conductance, in reciprocal ohms, for a square centimeter. Marine eggs have been measured before and after fertilization and a number of tissues have been measured during activity, but the attempts to interpret the observed conductance changes have not been particularly satisfactory. Since it is quite generally believed that the depolarization of a nerve fiber membrane, during excitation and propagation, involves an increased permeability to ions there have been many attempts to detect and to measure this change as an increase in the electrical conductivity. A decrease in the longitudinal low frequency impedance of frog sdatic nerve during activity was found by Lullies (1930) (also Cole and Curtis, 1936), and a similar change was found in the transverse impedance of the squid giant fiber . In these cases the measuring current was also the stimulating current and it was not possible to analyze the changes satisfactorily. In NiteUa, Blinks (1936) showed with direct current transients that on excitation the membrane impedance decreased under the cathode, but it was not possible to separate the change into resistance and capacity components.

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