Genetic Variants in <em>PNPLA3</em> and Risk of Non-Alcoholic Fatty Liver Disease in a Han Chinese Population

<div><p>We investigated the possible association between genetic variants in the Patatin like phospholipase-3 (<em>PNPLA3</em>) gene and nonalcoholic fatty liver disease (NAFLD) in a Han Chinese population. We evaluated twelve tagging single-nucleotide polymorphisms (tSNPs) of the <em>PNPLA3</em> gene in a frequency matched case–control study from Fuzhou city of China (553 cases, 553 controls). In the multivariate logistic regression analysis, the rs738409 GG or GC, and rs139051 TT genotypes were found to be associated with increased risk of NAFLD, and a significant trend of increased risk with increasing numbers of risk genotype was observed in the cumulative effect analysis of these single nucleotide polymorphisms. Furthermore, haplotype association analysis showed that, compared with the most common haplotype, the CAAGAA<b>TG</b>CGTG and CGAAGG<b>TG</b>TCCG haplotypes conferred a statistically significant increased risk for NAFLD, while the CGGGAA<b>CC</b>CGCG haplotype decreased the risk of NAFLD. Moreover, rs738409 C>G appeared to have a multiplicative joint effect with tea drinking (P<0.005) and an additive joint effect with obesity (Interaction contrast ratio (ICR) = 2.31, 95% CI: 0.7–8.86), hypertriglyceridemia (ICR = 3.07, 95% CI: 0.98–5.09) or hypertension (ICR = 1.74, 95% CI: 0.52–3.12). Our data suggests that <em>PNPLA3</em> genetic polymorphisms might influence the susceptibility to NAFLD development independently or jointly in Han Chinese.</p> </div

Associations between risk of NAFLD and frequencies of inferred haplotypes on the basis of the observed genotypes in NAFLD cases and controls.

a<p>In the order of rs738407, rs734561, and rs2006943);</p>b<p>In the order of rs1883350, rs2076208, rs3810622 and rs2294918;</p>c<p>In the order of rs2076212, rs139047, rs9625961, rs738407, rs734561, rs2006943, rs139051, rs738409, rs1883350, rs2076208, rs3810622, and rs2294918.</p>d<p>p value was adjusted by multiple comparisons corrections; e:OR (odds ratio) was adjusted for sex, age, body mass index and other clinical characteristics; CI: confidence interval.</p>f<p>All other haplotypes that had frequency <2% in either cases or controls were pooled.</p

Cumulative effect of adverse genotypes in PNPLA3 rs738409 and rs139051 on NAFLD.

a<p>Risk genotypes were GC/GG for rs734089 and TT for rs139051.</p>b<p>Individuals with no risk genotype were set as the reference group. OR (odds ratio) was determined using logistic regression and adjusted for sex, age, body mass index and other clinical characteristics; CI: confidence interval.</p>c<p><i>P</i>-value based on the Wald test;</p

Association between the genotypes of rs738409 and rs139051 and risk of NAFLD.

<p>n: number of individuals; OR (odds ratio) was determined using logistic regression and adjusted for sex, age, body mass index and other clinical characteristics; CI: confidence interval.</p>a<p>P-value based on the Wald test.</p

Combined effects^a of <i>PNPLA3</i> polymorphisms and environmental and ‘internal’ exposures on the risk of NAFLD.

a<p>Included ORs and their corresponding 95% CIs.</p>b<p>Adjusted for age, sex, education, marriage, smoking, income status, and other confounding characteristics.</p

Image_1_Blood-nerve barrier disruption and coagulation system activation induced by mechanical compression injury participate in the peripheral sensitization of trigeminal neuralgia.TIF

IntroductionThe aim of this study was to investigate the effect and possible mechanisms of the blood-nerve barrier (BNB) and the coagulation-anticoagulation system in modulating the mechanical allodynia in a trigeminal neuralgia (TN) rat model induced by chronic compression of the trigeminal root entry zone (TREZ).MethodsVon Frey filaments were applied to determine the orofacial mechanical allodynia threshold. The BNB permeability was evaluated by Evans blue extravasation test. Immunohistochemical staining and laser confocal microscopy were used to measure the length of the depletion zones of the nodes of Ranvier in the TREZ, the diameter of nerve fibers and the length of the nodal gap. The transcriptional levels of prothrombin and endogenous thrombin inhibitor protease nexin-1 (PN-1) in the TREZ of TN rats were assessed by RT-qPCR. A Western blotting assay was performed to detect the expression of paranodal proteins neurofascin-155 (NF155) and neurofascin-125 (NF125) in the TREZ. The spatiotemporal expression pattern of thrombin activated receptor (i.e. protease activated receptor 1, PAR1) in TREZ were defined by immunostaining and immunoblotting assays. PAR1 receptor inhibitors SCH79797 were administrated to TN rats to analyze the effect of thrombin-PAR1 on orofacial hyperalgesia.ResultsA compression injury of a rat’s TREZ successfully induced TN-like behavior and was accompanied by the destruction of the permeability of the BNB and the promotion of prothrombin and thrombin inhibitor protease nexin-1 (PN-1) expression. The expression of the paranodal proteins neurofascin-155 (NF155) and neurofascin-125 (NF125) was increased, while the nodal gap length of the nodes of Ranvier was widened and the length of node-depleted zones was shortened. Moreover, the expression of PAR1 within the TREZ was upregulated at an early stage of TN, and administration of the PAR1 antagonist SCH79797 effectively ameliorated orofacial mechanical allodynia.ConclusionA compression injury of the TREZ increased the permeability of the BNB and induced disturbances in the local coagulation-anticoagulation system, concomitant with the structural changes in the nodes of Ranvier, thrombin-PAR1 may play a critical role in modulating orofacial mechanical hyperalgesia in a TN rat model.</p