• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Pleiotropy within gene variants associated with nonalcoholic fatty liver disease and traits of the hematopoietic system

    2021-02-05 03:14:06CarlosJosePirolaAdrianSalatinoSilviaSookoian
    World Journal of Gastroenterology 2021年4期

    Carlos Jose Pirola, Adrian Salatino, Silvia Sookoian

    Abstract Genome-wide association studies of complex diseases, including nonalcoholic fatty liver disease (NAFLD), have demonstrated that a large number of variants are implicated in the susceptibility of multiple traits — a phenomenon known as pleiotropy that is increasingly being explored through phenome-wide association studies. We focused on the analysis of pleiotropy within variants associated with hematologic traits and NAFLD. We used information retrieved from large public National Health and Nutrition Examination Surveys, Genome-wide association studies, and phenome-wide association studies based on the general population and explored whether variants associated with NAFLD also present associations with blood cell-related traits. Next, we applied systems biology approaches to assess the potential biological connection/s between genes that predispose affected individuals to NAFLD and nonalcoholic steatohepatitis, and genes that modulate hematological-related traits—specifically platelet count. We reasoned that this analysis would allow the identification of potential molecular mediators that link NAFLD with platelets. Genes associated with platelet count are most highly expressed in the liver, followed by the pancreas, heart, and muscle. Conversely, genes associated with NAFLD presented high expression levels in the brain, lung, spleen, and colon. Functional mapping, gene prioritization, and functional analysis of the most significant loci (P < 1 × 10-8) revealed that loci involved in the genetic modulation of platelet count presented significant enrichment in metabolic and energy balance pathways. In conclusion, variants in genes influencing NAFLD exhibit pleiotropic associations with hematologic traits, particularly platelet count. Likewise, significant enrichment of related genes with variants influencing platelet traits was noted in metabolic-related pathways. Hence, this approach yields novel mechanistic insights into NAFLD pathogenesis.

    Key Words: Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Platelets; Leukocytes; Hematologic traits; Genetics

    INTRODUCTION

    Nonalcoholic fatty liver disease and pleiotropic associations

    Nonalcoholic fatty liver disease (NAFLD) is regarded as the most prevalent chronic liver disease[1]. A worldwide increase in NAFLD prevalence is acknowledged not only in the adult but also the pediatric population[1]. Consequently, NAFLD has become a serious health issue on a global scale.Like many other complex diseases, NAFLD develops due to the combined effect of environmental and genetic factors[2-4]. NAFLD presents phenotypic complexity and inter-individual variability, implying that its natural course is characterized by different histological stages-from simple fat accumulation to steatohepatitis (NASH), cirrhosis, and eventually to hepatocellular carcinoma[1]—and considerable variability in disease progression exists among affected patients. One of the proposed factors contributing to the observed inter-patient differences in the disease prognosis and severity is genetic susceptibility[2-4], which might explain up to approximately 20% of the disease variance[5].

    Furthermore, NAFLD has not only a high degree of comorbidity with disorders of the metabolic syndrome, including type 2 diabetes, obesity, and cardiovascular disease, but also shared disease mechanisms and disease pathways[6]. These comorbidities have a strong negative impact on the course of NAFLD and vice versa, whereby the presence of NAFLD substantially modifies the course and prognosis of metabolic syndrome-associated diseases[6]. More importantly, the impact of long-term consequences of these comorbidities on cardiovascular health is, at least in part, independent of the presence of general obesity. In fact, it was shown that lean patients with NAFLD have an altered metabolic profile mostly related to increased visceral adiposity that predispose them to cardiovascular risks[7].

    Notably, knowledge gained from genome-wide and exon-wide association studies [Genome-wide association studies (GWAS) and EWAS, respectively] of complex diseases, including NAFLD, shows that a large number of single nucleotide polymorphisms are implicated in the susceptibility of multiple traits, which is known as pleiotropy. Phenome-wide association studies (PheWAS) that exploit a significant amount of clinical characteristics gathered mostly from electronic clinical records have thus become a powerful strategy for uncovering pleiotropy.

    Among the many traits explored to date in large GWAS/EWAS and PheWAS, including disease traits and biochemical parameters, pleiotropy within gene variants associated with NAFLD and biochemical traits of the hematopoietic system is remarkably consistent across different datasets, specifically those concerning platelet count and platelet volume[8-10]. However, the mechanisms behind the biological connection between NAFLD and platelet-related traits remain poorly understood.

    Therefore, in this review, we focused on the analysis of pleiotropy within variants associated with biochemical hematologic traits and NAFLD. We took advantage of information retrieved from large public GWAS and PheWAS based on the general population and examined whether variants known to be associated with NAFLD also exhibit associations with blood cell-related traits, specifically platelet-related phenotypes. After collecting that information, we adopted systems biology approaches to assess the potential biological connection/s between genes that predispose to NAFLD and NASH, and genes that modulate related hematological traits, including platelet count and platelet crit. We reasoned that focusing on clinically meaningful traits for which associations with liver disorders would be plausible from the biological perspective may help elucidate NAFLD biology. Likewise, these analyses would conceptually allow the identification of potential molecular mediators that link NAFLD with platelets.

    NAFLD AND HEMATOLOGICAL TRAITS

    Recent observations shed light on the concept that NAFLD not only co-exists with cardiovascular disease, including functional and structural myocardial abnormalities[11], but is also associated with other diseases, including cancer, kidney disease, and hematological disorders, among many others[5]. To illustrate the relevance of the association between NAFLD and hematological traits, we analyzed data from the National Health and Nutrition Examination Surveys (NHANES) 2017-2018 database. The dataset and further information are freely available online https://www.cdc.gov/nchs/nhanes/index.htm). The NHANES are population-based surveys conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention of the United States. They are frequently used to study liver disease. The National Center for Health Statistics Research Ethics Review Board approved the NHANES protocol, and informed consent was obtained from all participants. Liver steatosis was defined by the controlled attenuation parameter (CAP) obtainedviatransient elastography (FibroScan?). Liver steatosis was diagnosed when CAP >268 dB/m was obtained, which is the threshold for significant steatosis based on a large study[12]. We modeled the relationship between NAFLD and relevant factors by linear logistic regression with an interaction term for the specific hematologic trait and gender while adjusting for subjects' demographic and clinical characteristics. Figure 1 shows the effect of white blood cells (WBC), including lymphocytes (Figure 1A), eosinophils (Figure 1B), neutrophils (Figure 1C), and platelet (Figure 1D) count number by gender. Myeloid and lymphoid lineages, as well as platelets show interaction effects with gender even after adjusting for log-transformed confounding factors such as age, waist circumference, diabetes, glycohemoglobin, total cholesterol, and systolic blood pressure. More importantly, NAFLD risk increased steadily with the number of different blood cell types, particularly in men.

    These results are reproducibly observed in the Asian population. Wanget al[13]reported that WBC count is a significant factor associated with incident NAFLD in Han Chinese[13]. The authors observed that the association between WBC count and NAFLD remained valid after adjusting for confounding factors including age, gender, smoking, regular exercise, BMI, hypertension, hyperglycemia, and lipid traits[13]. Similarly, WBC count was found to be independently associated with NAFLD regardless of components of the metabolic syndrome in the Korean population[14,15].

    PLATELETS AND LIVER DISORDERS—A CONCISE APPRAISAL OF THE RELATIONSHIP

    For many biological reasons, the liver and platelets are biologically connected. For example: (1) The fetal liver is a privileged organ of megakaryocyte progenitor differentiation[16]; (2) Thrombocytopenia is a major and debilitating complication of liver cirrhosis[17]; (3) Platelets are involved in the process of fibrogenesis by remodeling the extracellular matrix[18]and secretion of cytokines, including platelet-derived growth factors[19]; and (4) Platelets functioning in the liver exhibit a collaborative effect with endothelial and Kupffer cells in liver regeneration[20]. A more comprehensive update on the role of platelets in liver disorders has been recently published[21].

    Figure 1 Steatosis and hematological traits. Panels show the interaction effects between hepatic steatosis and hematological traits (A: Lymphocyte number; B: Eosinophil number; C: Neutrophil number; D: Platelet number) on the probability of having hepatic steatosis according to gender. Interaction analyses were performed by linear logistic regression for the presence of steatosis (no = 0, yes = 1) as the dependent variable adding an interaction term among gender (women = 0, men = 1) and the specific continuous variable. Diabetes and log-transformed age, waist, HgbA1c, total cholesterol, systolic blood pressure, and triglycerides were also included as cofactors. The probability of liver fibrosis was estimated by margins as implemented in the STATA software. Data analysis was based on National Health and Nutrition Examination Surveys 2017-2018; the National Center for Health Statistics Research Ethics Review Board approved the National Health and Nutrition Examination Surveys protocol, and participants gave informed consent. Datasets and further information are available online (https://www.cdc. gov/nchs/nhanes/index.htm). Liver steatosis was defined by the controlled attenuation parameter[12]. Only participants that consumed less than 30 g and 20 g of alcohol for men and women, respectively, were included in the present analysis. Those participants with positive tests for viral hepatitis were excluded.

    Earlier evidence also demonstrates that platelets are involved in NASH-related complications. For example, we have observed that patients with NASH have high expression ofTGFB1(transforming grown factor β1)-mRNA in circulating platelets[22]. Platelets are also involved in the process of atherogenesis by upregulating many molecules[23], includingTGFB1[24], which is also related to NAFLD and the risk of cardiovascular disease. Results yielded by a recent study suggest that plateletmediated inflammation in NAFLD drives hepatocellular carcinogenesis[25].

    PLEIOTROPIC EFFECTS OF THE NONSYNONYMOUS PNPLA3-RS738409 (P.ILE148MET) VARIANT

    The nonsynonymous rs738409 C/G variant inPNPLA3(patatin-like phospholipase domain containing protein 3, also known as adiponutrin or calcium-independent phospholipase A2-epsilon), which encodes the amino acid substitution I148M, is regarded as the major genetic variant associated with the susceptibility to NAFLD and NASH[26,27].

    The rs738409 has also been associated with alcoholic liver disease[28-30], hepatitis C[31], hepatitis B[32], and hepatocellular carcinoma[33],[34].

    Results of a large PheWAS performed in subjects of European ancestry (816903 participants) with genome-wide genotyped data linked to phenotypic information, including the United Kingdom Biobank cohort, 23andMe cohort, FINRISK (workingage population of Finland), and Children’s Hospital of Philadelphia, confirmed that rs738409 presents pleiotropic effects beyond the liver. For instance, rs738409-G was associated with increased risk of type 2 diabetes and decreased risk of high total cholesterol, acne, gout, and gallstones; all these associations remained significant after adjusting for elevated transaminases[35].

    In addition, it was suggested that rs738409 might be used to predict race-related hepatotoxicity in pediatric patients with acute lymphoblastic leukemia[9].

    Another study revealed the association of rs738409 with mean corpuscular hemoglobin (P= 6 × 10-9) based on the analysis of individuals of 116666 British ancestry[36]. Consistently, Kichaevet al[37]established the association of rs738409 with mean corpuscular hemoglobin (P= 4 × 10-25) by using genome-wide genotyping array in a sample of 443000 individuals of European ancestry[37]. Variants in or nearPNPLA3have also been associated with the aspartate transaminase-to-platelet ratio index[38].

    A summary picture illustrating the genetic associations withPNPLA3locus, including its pleiotropic effects on diverse laboratory measurements, is shown in Figure 2. It reveals that the strength of the association scores of rs738409 and levels of liver enzymes, particularly ALT levels (association score = 1), is shared with the effect of this variant on many blood-related traits, for instance platelet count (association score = 0.8) (Figure 2).

    PHEWAS: THE EFFECT OF VARIANTS ASSOCIATED WITH NAFLD ON BLOOD-RELATED TRAITS

    We next used information sourced from electronic health records and GWAS data computed from United Kingdom Biobank entries pertaining to 452264 individuals, which was retrieved from the Gene ATLAS (http://geneatlas.roslin.ed.ac.uk) and Neale's database (http://www.nealelab.is/uk-biobank/).

    We specifically searched for PheWAS associations of variants influencing NAFLD, includingPNPLA3-rs738409,TM6SF2-rs58542916,MBOAT7-TMC4rs641738,GCKRrs780094, andHSD17B13-rs72613567. As expected, rs738409, rs58542916, and rs72613567 were associated with liver-related traits in the United Kingdom-Biobank GWAS (Table 1).

    Of note, all aforementioned variants showed GWAS-significant associations (P< 5 × 10?8) with blood-related traits. The strongest associations pertained to platelet traits, including platelet crit (which represents the proportion of blood volume that is occupied by platelets, expressed as a percentage), platelet volume, and platelet count (Table 1). Specifically,PNPLA3-rs738409 was associated with platelet count (P= 2.9 × 10-45) and platelet crit (P= 3.6 × 10-29) with thePvalues for association exceeding those for association with liver diseases (Table 1). A similar pattern was obtained forTM6SF2-rs58542926 andHSD17B13-rs72613567 (Table 1) variants and their associations with platelet traits.

    GENES ASSOCIATED WITH NAFLD AND PLATELET COUNT SHARE PATHWAYS INVOLVED IN EXTRACELLULAR MATRIX REMODELING AND CYTOSKELETAL SIGNALING PROTEINS

    To explore shared pathways between NAFLD and platelet-related traits, we retrieved from the Open Target Genetics platform (https://genetics.opentargets.org) the list of genes (human protein-coding genes) associated with phenotypes of interest. Specifically, we focused on platelet count, which expresses the number of platelets per unit volume in a sample of venous blood.

    The genetic associations in the Open Target platform are derived from GWAS Catalog (https://www.ebi.ac.uk/gwas) and PheWAS (https://phewascatalog.org/), whereby the former contains publications indexed in PubMed and the latter is a repository of electronic medical records with links to the Vanderbilt DNA biobank. The list of genes associated with platelet count (n= 305) and NAFLD (n= 161) is shown in Supplementary Table 1 and Supplementary Table 2, respectively.

    To analyze and interpret the pathways shared between genes associated with NAFLD and those associated with platelet count, we used the FUMA platform available at https://fuma.ctglab.nl/. FUMA utilizes positional expression quantitative trait loci and chromatin interaction mappings to build gene-based pathways and tissueenrichment heatmaps[39]. Hence, we first tested the tissue specificity of the list of genes/proteins associated with each phenotype, namely NAFLD and platelet count. Specifically, we explored tissues in which those genes/proteins present higher expression levels (differentially expressed genes are defined for each label of each expression dataset). Genes showing aP≤ 0.05 after Bonferroni correction and absolute log fold change ≥ 0.58 were defined as differentially expressed. Interestingly, genes associated with platelet count were most highly expressed in the liver, followed by the pancreas, heart, and muscle (Figure 3A). Conversely, genes associated with NAFLD presented high expression levels in the brain, lung, spleen, and colon (Figure 3B).

    Table 1 Phenome-wide association studies associations of variants influencing nonalcoholic fatty liver disease and their effect on blood-related traits

    GCKR-rs780094. Chromosomal position: 27741237. Allele C MAF: 0.38 Blood-related trait Mean reticulocyte volume 0.16064 5.9197e-33 Neutrophil percentage -0.14035 2.7743e-19 Neutrophil count -0.037139 6.3804e-47 Monocyte percentage 0.073076 7.914e-79 Mean platelet (thrombocyte) volume 0.014342 1.3297e-18 Platelet crit -0.0013887 1.3581e-71 Platelet count -1.9052 6.2404e-92 Hematocrit percentage 0.049511 4.3172e-21 Liver diseases K76 Other diseases of liver -0.00058708 0.0026207 K70-K77 Diseases of liver -0.0004415 0.060918 K74 Fibrosis and cirrhosis of liver -0.00011872 0.2169 K75 Other inflammatory liver diseases -0.00012854 0.13954 K70 Alcoholic liver disease 9.7922e-05 0.31331 1Letters and numbers such as K70, K76, K74 and K75 represent the codes for diseases (ICD10) in the United Kingdom Biobank. Approximately 30 million variants in the United Kingdom Biobank from the Gene ATLAS (http://geneatlas.roslin.ed.ac.uk) and Neale's database (http://www.nealelab.is/ukbiobank/) resources were comprehensively tested for their association with liver (ICD10 codes: K70, K76, K74 and K75) and blood cell-associated traits, including platelet, leukocyte and neutrophil counts. PNPLA3: Patatin-like Phospholipase Domain Containing protein 3; TM6SF2: Transmembrane 6 Superfamily Member 2; HSD17B13: Hydroxysteroid 17-Beta Dehydrogenase 13; MBOAT7: Membrane Bound O-Acyltransferase Domain Containing 7; TMC4: Transmembrane channel like 4; GCKR: Glucokinase regulator.

    The Venn diagram provided in Figure 3C shows the genes shared between NAFLD and platelet count according to the information retrieved from GWAS and PheWAS catalogs, as explained earlier, among which we found eleven shared loci that includedPNPLA3. Next, we performed pathway analysis on the list of shared genes, which revealed an enrichment of genes (ACTN1andTNFRSF13B) belonging to the predicted pathway “Syndecan 4 pathway” (PID_SYNDECAN_4_PATHWAY) (Figure 3D). The Syndecan 4 pathway is involved in cell growth, differentiation, and adhesion, and in the modulation of extracellular matrix proteins[40]. Syndecans are type I transmembrane proteins with an N-terminal ectodomain that contains several consensus sequences for attachment to glycosaminoglycan, heparan sulfate, and to a lesser extent chondroitin sulfate chains, and a short C-terminal cytoplasmic domain. Syndecans may act as integrin co-receptors. Interactions between fibronectin and syndecans are modulated by tenascin-C. Syndecans bind a wide variety of soluble and insoluble ligands, including extracellular matrix components, cell adhesion molecules, and growth factors, including VEGFs, cytokines, and proteinases[41]. It is worth noting that parvin beta (PARVB), which has been significantly associated with NAFLD[42,43]and hematological traits[44], encodes a member of the parvin family of actin-binding proteins that play a role in cytoskeleton organization and cell adhesion. This family member binds to alphaPIX and alpha-actinin, and can inhibit the activity of integrinlinked kinase. This protein also functions as a tumor suppressor. As thePARVBlocus is located nearPNPLA3, further studies are needed to establish whether the association of the locus with NAFLD and hematological traits merely reflects a linkage between the two genetic loci.

    Figure 2 PNPLA3 and genetic associations with laboratory measurements in genome-wide association studies and phenome-wide association studies. The score for the associations ranges from 0 to 1, with higher scores indicating stronger evidence for an association. Bubbles in the figure represent the different scores with varying shades of blue: the darker the blue, the stronger the association. Red arrows highlight the association of the rs738409 variant in PNPLA3 and laboratory measurements related with hematological traits. HDL: High density lipoprotein cholesterol; FEV: The ratio of forced expiratory volume to forced vital capacity, used as a measure of pulmonary function; uric: Uric acid; AST: Aspartate aminotransferase level; ALT: Alanine aminotransferase level; total chol: Total cholesterol. Source: Open Target Database (https://genetics.opentargets.org/gene/ENSG00000100344). Score summaries: Data sources and factors that affect the relative strength of the evidence scores can be found at: https://docs.targetvalidation.org/getting-started/scoring.

    We further explored the Gene Ontology (GO) biological processes in which the list of genes associated with platelet count was specifically enriched. We found that, in addition to expected pathways that included hemostasis, response to wound healing, and platelet degranulation, there were pathways that support the plausibility of sharing genes with NAFLD, for example the triglyceride catalytic process. The GO biological processes associated with the top 50 genes on the list of loci associated with platelet count is shown in Figure 4. Remarkably,PNPLA3andFABP6(Fatty Acid Binding Protein 6) are the two overlapping loci that would be responsible for the enrichment of triglyceride metabolism (Figure 4).

    BIOLOGICAL PATHWAYS OF GENES ASSOCIATED WITH PLATELET COUNT VS GENES ASSOCIATED WITH NAFLD

    It is also noteworthy that, despite the shared genes, there are differences in the biological processes in which the sets of genes associated with platelet count and with NAFLD are involved. To explore these pathways, we performed overrepresentation analysis based on a more comprehensive list of genes associated with each phenotype.

    The input list of platelet count-associated variants (P< 1 × 10-6) was generated by searching the United Kingdom Biobank GWAS database as provided by Neale’s lab resource (http://www.nealelab.is/uk-biobank/), which shows variants in about 2424 loci with genome-wide significance (P< 5 × 10-8) for an association with platelet count as a continuous trait (109cells/L; mean = 252.023 ± Std.dev = 60.0604). We used the United Kingdom Biobank GWAS database because it provides one of the largest publically available sources of genetic associations with laboratory traits in the general population involving 479367 individuals of both sexes (http://biobank. ctsu.ox.ac.uk/crystal/field.cgi?id=30080).

    Figure 3 Genes that are shared between nonalcoholic fatty liver disease and platelet count. A and B: Significantly enriched Differentially Expressed Gene (DEG) Sets (Pbon < 0.05) are highlighted in red (FUMA). DEG sets were pre-calculated by performing two-sided t-test for any one of the labels against all others. For this purpose, expression values were normalized (zero-mean) to obtain a log2 transformation of expression value (EPKM or TPM). Genes with P ≤ 0.05 after Bonferroni correction and absolute log fold change ≥ 0.58 were defined as differentially expressed genes in a given label compared to others. In addition to DEG, upregulated DEG and down-regulated DEG were also pre-calculated by taking the sign of t-statistics into account. Input genes were tested against each of the DEG sets using the hypergeometric test. The background genes are genes that have average expression value > 1 in at least one of the labels and exist in the userselected background genes. Significant enrichment at Bonferroni-corrected P ≤ 0.05 is colored in red. C: Venn diagram showing the number of genes that are common (overlapping areas) and dissimilar (non-overlapping areas) in nonalcoholic fatty liver disease (NAFLD) and platelet count gene lists. D: Pathway analysis using all Canonical Pathways (MsigDB c2) in the web-based FUMA platform available at http://fuma.ctglab.nl. Overlapping genes (underlined): ACTN1: Actinin Alpha 1; TNFRSF13B: TNF Receptor Superfamily Member 13B. The input lists of platelet count- and NAFLD-associated variants were generated by searching the Open Target platform, which contains data retrieved from GWAS Catalog (https://www.ebi.ac.uk/gwas) and phenome-wide association studies (https://phewascatalog.org/). The list of genes associated with platelet count contains 305 loci and that associated with NAFLD contains 149 loci, as shown in Supplementary Figures 1 and 2, respectively.

    In the case of NAFLD, and to avoid issues arising from the paucity of GWAS/ EWAS discovered genes, we included a more comprehensive list of 928 loci obtained by data mining[5]that represents genetic and molecular associations with the disease.

    We chose to conduct the overrepresentation analysis on the list of loci obtained from data mining because NAFLD as the disease trait (K76.0 Fatty change of liver: http://biobank.ctsu.ox.ac.uk/crystal/field.cgi?id=41202) is underrepresented in the United Kingdom Biobank GWAS database, affecting only 460 of 410332 individuals whose data are stored in this repository.

    Differences in biological pathway enrichment between the two datasets (NAFLD and platelet count) are summarized in Figure 5, which shows specificity in the function of genes in each of the gene lists. For instance, the NAFLD list of associated genes/proteins is enriched in expected pathways, such as metabolism of lipids and amino acids, purine metabolism, and circadian rhythm, among others (Figure 5). The platelet count list is enriched with genes involved in DNA repair, telomere maintenance, and the Hedgehog pathway, among many others, as shown in Figure 5[45]. Interestingly, some pathways related to platelet-derived growth factors, such as the platelet-derived growth factors receptor-alpha signaling pathway, are over-represented in the list of genes associated with NAFLD. The many types of integrin cell surface interaction pathways seem to play a more important role in NAFLD pathophysiology than in regulating platelet count. Notably, the gene set associated with platelet count presents enrichment in the leukotriene synthesis pathways, which have been linked to the progression of NAFLD[46-49].

    Figure 4 Gene Ontology biological processes of the top 50 genes associated with platelet count. The chart shows fold enrichment in biological processes of genes associated with platelet count with respect to those present in the whole genome. The input list of platelet count-associated variants was generated by conducting a search via the Open Target platform, which contains data retrieved from genome-wide association studies Catalog (https://www.ebi.ac.uk/gwas) and phenome-wide association studies (https://phewascatalog.org/). The whole list of genes associated with platelet count contains 305 loci, as shown in Supplementary Figure 2. Gene mapping and analysis was conducted using the FUMA genome-wide association studies tool (https://fuma.ctglab.nl/). Genes belonging to the pathways as overlapping genes are shown as a heatplot to the right.

    FUNCTIONAL ASSESSMENT OF VARIANTS ASSOCIATED WITH LABORATORY HEMATOLOGICAL-RELATED TRAITS

    To understand the potential involvement of genes associated with laboratory hematological-related traits in NAFLD biology, we performed functional analysis. Based on the reverse biology premise, we reasoned that genes involved in hematological-related traits might be associated with some metabolic function/s that would presumably affect NAFLD pathogenesis. Thus, the top blood-related associated traits in terms of their statistical significance were further searched for genetic associations in the entire United Kingdom Biobank dataset. Specifically, approximately 30 million variants in the United Kingdom Biobank from the Gene ATLAS (http://geneatlas.roslin.ed.ac.uk) and Neale's database (http://www.nealelab.is/ukbiobank/) resources were comprehensively tested for associations with blood cellassociated traits, including platelet, leukocyte and neutrophil counts. We further explored the pathways in which the lists of genes associated with these traits are involved. For this purpose, we used the FUMA resource that allows using functional and biological information to prioritize genes based on GWAS outcomes.

    Interestingly, functional mapping, gene prioritization, and functional analysis using FUMA of the most significant genetic variants (P< 1 × 10-6) revealed 85 mapped genes in the full list of loci associated with hematological traits that are also associated with liver traits, including chronic liver diseases, fibrosis and liver cirrhosis, NAFLD, and other inflammatory liver diseases (Figure 6A).PNPLA3, SAMM50, PARVBandHSD17B13are among the ten genes shared by liver traits and platelet count.TM6SF2is shared by liver traits, platelet count, and neutrophil count, andGCKRis shared by liver and all hematological traits (Figure 6A).

    Figure 5 Overrepresentation analysis of biological pathways of genes associated with platelet count vs. genes associated with nonalcoholic fatty liver disease. Overrepresentation analysis of biological pathways of platelet count-associated genes in comparison with that pertaining to nonalcoholic fatty liver disease-associated genes. The input list of platelet count-associated variants (P < 1 × 10-6) was generated by searching the United Kingdom Biobank genome-wide association studies database as provided by Neale’s lab resource (http://www.nealelab.is/uk-biobank/). The input list associated with nonalcoholic fatty liver disease includes 928 genes/proteins obtained by data mining[5]. The analysis was performed by applying the functional enrichment and interaction network analysis (FunRich) tool[46].

    In addition, Figure 6B shows the consistent association ofPNPLA3, TM6SF2, SAMM50, andPARVBwith liver and hematological traits identifiedviaFUMA analysis in reported GWAS. Finally, we performed functional enrichment analysis on genes significantly associated with platelet count, leukocyte count, and neutrophil count by applying the FunRich tool. Notably, loci involved in the genetic modulation of platelet, leukocyte, and neutrophil counts presented significant enrichment in metabolic, energy balance, xenobiotics, and CYP-450-related pathways (Figure 7A?C). However, platelet-related loci are particularly involved in regulating key aspects of metabolism, while leukocyte and neutrophil counts are related to more general homeostasis regulation processes (Figure 7D?F).

    CONCLUSION

    PheWas revealed that variants in genes influencing NAFLD present pleiotropic associations with laboratory-related hematologic traits and are relevant to the hematopoietic liver function. Similarly, related genes with variants influencing hematological traits, platelet count in particular, presented significant enrichment in metabolic and energy balance-related pathways.

    By using different resources and datasets of variants associated with the genetics of platelet count and NAFLD, we found consistency in the results, suggesting that there are shared mechanisms and pathways between the two phenotypes. In particular, we found metabolic and lipid pathways shared by NAFLD and platelet traits. It is anticipated that potential therapeutic targets, including novel ligands of peroxisome proliferator-activated receptors may also play a role in modulating platelet-related phenotypes such as platelet activation and the cascade of events associated with inflammation and cardiovascular risk.

    In summary, our approach provides novel mechanistic insights into NAFLD pathogenesis. Further research is nonetheless necessary to ascertain whether genes associated with liver diseases present ample pleiotropy and, therefore, modify functions of diverse organs simultaneously. If, conversely, some phenotypes are found to act as intermediaries between genes and disease, a Mendelian Randomization approach can be used to study the relationship between, in this case, hematological and liver traits or vice versa.

    Figure 6 Nonalcoholic fatty liver disease and hematological traits associated genes. A: Venn diagram showing the set of genes associated with liver traits (ICD10 codes: K70, K76, K74 and K75), platelet count, leukocyte count, and neutrophil count, as well as their overlapping genes in the United Kingdom Biobank. Approximately 30 million variants in the United Kingdom Biobank dataset sourced from the Neale's database (http://www.nealelab.is/uk-biobank/) were comprehensively tested for association with liver and blood cell traits, including platelet, leukocyte and neutrophil counts. B: Overlap between nonalcoholic fatty liver disease-associated genes and those associated with hematological traits. The chart shows information on previously known single nucleotide polymorphisms-trait associations reported in the genome-wide association studies (GWAS) catalog for all single nucleotide polymorphisms associated with nonalcoholic fatty liver disease in the United Kingdom Biobank GWAS database; the analysis was conducted using the FUMA GWAS tool (https://fuma.ctglab.nl/).

    Figure 7 Functional assessment of variants associated with laboratory hematological-related traits. A-C: Functional analysis of genes significantly associated with platelet, leukocyte, and neutrophil count in the whole genome-wide association studies dataset (452264 individuals whose data are included in the United Kingdom Biobank). Functional enrichment analysis was performed using the FunRich tool, while Bonferroni and Benjamini-Hochberg methods were used to correct for multiple testing. D-E: Charts show fold changes in biological processes of genes associated with leukocyte or neutrophil counts vs biological processes of genes associated with platelet count. The input list of genes associated with platelet count, leukocyte count, and neutrophil count (P < 1 × 10-8) was generated by searching the United Kingdom Biobank genome-wide association studies database.

    天堂影院成人在线观看| 黄色成人免费大全| 精品国产一区二区三区四区第35| 一二三四社区在线视频社区8| 搡老妇女老女人老熟妇| 亚洲成a人片在线一区二区| 国产av一区在线观看免费| 91在线观看av| 不卡一级毛片| 国产欧美日韩一区二区三| 俄罗斯特黄特色一大片| 在线观看日韩欧美| 国产精品电影一区二区三区| ponron亚洲| 亚洲视频免费观看视频| 一边摸一边抽搐一进一小说| 午夜久久久在线观看| 精品久久久精品久久久| 亚洲伊人色综图| 久久精品影院6| 中国美女看黄片| 欧美一级毛片孕妇| 亚洲av片天天在线观看| 欧美+亚洲+日韩+国产| 岛国视频午夜一区免费看| 国产精品久久久久久人妻精品电影| 国产国语露脸激情在线看| 欧美大码av| 国产精品乱码一区二三区的特点 | 老司机午夜十八禁免费视频| 九色国产91popny在线| 国产精品一区二区精品视频观看| 少妇被粗大的猛进出69影院| 国产精品 国内视频| 女人被狂操c到高潮| 中文字幕av电影在线播放| 精品国产国语对白av| 免费在线观看视频国产中文字幕亚洲| 亚洲国产高清在线一区二区三 | 国产私拍福利视频在线观看| www.www免费av| www.精华液| 欧美精品啪啪一区二区三区| 国产精品香港三级国产av潘金莲| 18禁美女被吸乳视频| 精品国产一区二区久久| 亚洲精品av麻豆狂野| 一区二区三区激情视频| 深夜精品福利| 91国产中文字幕| 午夜福利成人在线免费观看| 国产免费男女视频| 婷婷精品国产亚洲av在线| 啦啦啦 在线观看视频| 一区二区三区精品91| 欧美中文综合在线视频| 国产精品国产高清国产av| 久久国产乱子伦精品免费另类| 日韩视频一区二区在线观看| e午夜精品久久久久久久| www国产在线视频色| 亚洲专区字幕在线| 国产在线观看jvid| 男女下面插进去视频免费观看| 狂野欧美激情性xxxx| 亚洲一区二区三区不卡视频| 精品电影一区二区在线| 在线天堂中文资源库| 制服诱惑二区| 伦理电影免费视频| 亚洲国产高清在线一区二区三 | 国产一区二区三区综合在线观看| 18禁黄网站禁片午夜丰满| 91老司机精品| 免费在线观看影片大全网站| videosex国产| aaaaa片日本免费| 看黄色毛片网站| 亚洲一区二区三区色噜噜| 美女高潮喷水抽搐中文字幕| 国产国语露脸激情在线看| 人人澡人人妻人| 国产一区二区三区视频了| 欧美激情 高清一区二区三区| 男女下面插进去视频免费观看| 美女扒开内裤让男人捅视频| 成人特级黄色片久久久久久久| 久久人人精品亚洲av| 叶爱在线成人免费视频播放| 欧美中文综合在线视频| 身体一侧抽搐| 亚洲狠狠婷婷综合久久图片| 婷婷丁香在线五月| 国产精品免费视频内射| 国产精品免费一区二区三区在线| 亚洲一卡2卡3卡4卡5卡精品中文| 女人爽到高潮嗷嗷叫在线视频| 日本黄色视频三级网站网址| 天堂√8在线中文| 国产av又大| 最近最新中文字幕大全电影3 | 亚洲av成人不卡在线观看播放网| 欧美日韩中文字幕国产精品一区二区三区 | 国产av精品麻豆| 亚洲五月婷婷丁香| 亚洲av片天天在线观看| 日韩成人在线观看一区二区三区| 日韩av在线大香蕉| 欧美日韩亚洲国产一区二区在线观看| 又黄又爽又免费观看的视频| 丁香欧美五月| 母亲3免费完整高清在线观看| 国产成人啪精品午夜网站| 黄色成人免费大全| 欧美激情极品国产一区二区三区| 在线av久久热| 欧美性长视频在线观看| 久久久国产欧美日韩av| av网站免费在线观看视频| 午夜福利成人在线免费观看| 亚洲欧美精品综合一区二区三区| 91成人精品电影| 一个人免费在线观看的高清视频| 校园春色视频在线观看| 女同久久另类99精品国产91| 国产精品九九99| 午夜老司机福利片| 怎么达到女性高潮| 悠悠久久av| 女性生殖器流出的白浆| 女人被狂操c到高潮| 亚洲最大成人中文| 在线永久观看黄色视频| 别揉我奶头~嗯~啊~动态视频| 波多野结衣巨乳人妻| 黑人巨大精品欧美一区二区蜜桃| 黑丝袜美女国产一区| 日本撒尿小便嘘嘘汇集6| 午夜福利影视在线免费观看| 男人舔女人的私密视频| 日韩 欧美 亚洲 中文字幕| 天堂动漫精品| 欧美成人一区二区免费高清观看 | 久久精品国产清高在天天线| 18禁黄网站禁片午夜丰满| 黑人操中国人逼视频| 日韩精品青青久久久久久| 嫩草影院精品99| 最新在线观看一区二区三区| 久热爱精品视频在线9| 黄色女人牲交| 欧美日韩福利视频一区二区| 亚洲中文日韩欧美视频| 亚洲自拍偷在线| 国产成人精品无人区| 欧洲精品卡2卡3卡4卡5卡区| 久久精品91蜜桃| 国产三级黄色录像| 免费不卡黄色视频| 女同久久另类99精品国产91| 女生性感内裤真人,穿戴方法视频| 99久久精品国产亚洲精品| 天天一区二区日本电影三级 | 日日夜夜操网爽| 久久欧美精品欧美久久欧美| 久久久久久久精品吃奶| 久久久久久久久免费视频了| 午夜精品国产一区二区电影| 午夜亚洲福利在线播放| 夜夜躁狠狠躁天天躁| 18禁观看日本| 狠狠狠狠99中文字幕| 欧美国产日韩亚洲一区| 亚洲 国产 在线| 国产精品av久久久久免费| 中文字幕色久视频| 一二三四在线观看免费中文在| 国产一卡二卡三卡精品| 免费在线观看亚洲国产| 亚洲一区中文字幕在线| 国产黄a三级三级三级人| av片东京热男人的天堂| 亚洲五月色婷婷综合| 国产精品二区激情视频| 国内精品久久久久久久电影| 国产精品国产高清国产av| 国产私拍福利视频在线观看| 夜夜夜夜夜久久久久| 无限看片的www在线观看| 精品一品国产午夜福利视频| 国产欧美日韩综合在线一区二区| 美国免费a级毛片| 欧美乱妇无乱码| 中文字幕av电影在线播放| 国产xxxxx性猛交| 亚洲精品久久国产高清桃花| 国产成人精品久久二区二区免费| 巨乳人妻的诱惑在线观看| 久久久久国内视频| 美国免费a级毛片| 男女下面进入的视频免费午夜 | 麻豆国产av国片精品| 国产免费男女视频| 亚洲久久久国产精品| 亚洲免费av在线视频| 久久香蕉精品热| 亚洲狠狠婷婷综合久久图片| 亚洲欧美日韩高清在线视频| 国产精品久久久av美女十八| 制服诱惑二区| 九色亚洲精品在线播放| 国产av精品麻豆| 最新美女视频免费是黄的| 波多野结衣高清无吗| 亚洲国产欧美一区二区综合| 欧美日本视频| 国产黄a三级三级三级人| 欧美另类亚洲清纯唯美| 久久欧美精品欧美久久欧美| www.www免费av| 香蕉久久夜色| 黄色视频不卡| 国产日韩一区二区三区精品不卡| 久久狼人影院| 99精品久久久久人妻精品| 久久久久国产精品人妻aⅴ院| 中文字幕人妻丝袜一区二区| 在线播放国产精品三级| 亚洲国产精品999在线| a在线观看视频网站| 无限看片的www在线观看| 免费av毛片视频| 非洲黑人性xxxx精品又粗又长| 亚洲一区中文字幕在线| 日韩欧美免费精品| 一级毛片高清免费大全| 国产一卡二卡三卡精品| 人人妻人人澡人人看| 在线播放国产精品三级| 女性被躁到高潮视频| 午夜福利高清视频| av有码第一页| 国内精品久久久久久久电影| 亚洲精品中文字幕在线视频| 亚洲精品久久国产高清桃花| 免费无遮挡裸体视频| 色综合站精品国产| 淫妇啪啪啪对白视频| 精品国产一区二区三区四区第35| 亚洲一区高清亚洲精品| 好男人电影高清在线观看| 视频在线观看一区二区三区| 岛国在线观看网站| 欧美日韩亚洲综合一区二区三区_| 精品第一国产精品| 精品国产一区二区三区四区第35| 性欧美人与动物交配| 久久婷婷成人综合色麻豆| 两个人视频免费观看高清| 中文字幕av电影在线播放| 国产精品久久久人人做人人爽| 女人精品久久久久毛片| 黑人巨大精品欧美一区二区蜜桃| 亚洲色图 男人天堂 中文字幕| 欧美精品啪啪一区二区三区| 中文字幕另类日韩欧美亚洲嫩草| 亚洲国产欧美网| 中文字幕人妻丝袜一区二区| 久久人妻av系列| 97人妻精品一区二区三区麻豆 | 亚洲免费av在线视频| 国产一区二区三区视频了| 免费看美女性在线毛片视频| 国产成人免费无遮挡视频| www.自偷自拍.com| 国产亚洲av嫩草精品影院| 亚洲av片天天在线观看| 黄色女人牲交| 精品欧美国产一区二区三| 国产精品乱码一区二三区的特点 | 可以免费在线观看a视频的电影网站| 超碰成人久久| 日韩视频一区二区在线观看| 久久伊人香网站| 成人特级黄色片久久久久久久| 久久久久久大精品| 久久伊人香网站| 少妇粗大呻吟视频| 国产三级在线视频| 亚洲人成电影观看| 国产亚洲精品综合一区在线观看 | 国产片内射在线| 国产精品乱码一区二三区的特点 | 国产激情久久老熟女| 欧美不卡视频在线免费观看 | 亚洲专区国产一区二区| 亚洲,欧美精品.| 婷婷丁香在线五月| 日韩中文字幕欧美一区二区| 露出奶头的视频| 国产麻豆69| 老熟妇乱子伦视频在线观看| 99在线人妻在线中文字幕| 无人区码免费观看不卡| 丝袜在线中文字幕| 免费观看人在逋| 美女扒开内裤让男人捅视频| 天天躁狠狠躁夜夜躁狠狠躁| 午夜精品在线福利| 亚洲国产日韩欧美精品在线观看 | 久久伊人香网站| 侵犯人妻中文字幕一二三四区| av视频在线观看入口| 国产亚洲欧美精品永久| 国产高清视频在线播放一区| 91麻豆精品激情在线观看国产| av视频在线观看入口| tocl精华| 国产熟女xx| 每晚都被弄得嗷嗷叫到高潮| 日韩成人在线观看一区二区三区| 久久久久久国产a免费观看| 18禁美女被吸乳视频| 夜夜夜夜夜久久久久| 亚洲天堂国产精品一区在线| 日日摸夜夜添夜夜添小说| 黄色 视频免费看| 日韩欧美一区视频在线观看| 女生性感内裤真人,穿戴方法视频| 嫩草影院精品99| 免费高清在线观看日韩| 久9热在线精品视频| 欧洲精品卡2卡3卡4卡5卡区| 一边摸一边抽搐一进一出视频| 久久香蕉精品热| 欧美老熟妇乱子伦牲交| 一级片免费观看大全| 国内精品久久久久精免费| 曰老女人黄片| 悠悠久久av| 久久人妻福利社区极品人妻图片| 国产成人影院久久av| 国产人伦9x9x在线观看| 成人特级黄色片久久久久久久| 欧美午夜高清在线| a级毛片在线看网站| 亚洲 欧美一区二区三区| 一边摸一边做爽爽视频免费| 亚洲视频免费观看视频| 后天国语完整版免费观看| 精品日产1卡2卡| 亚洲色图综合在线观看| 国产三级在线视频| 日本免费a在线| 欧洲精品卡2卡3卡4卡5卡区| 国产精品乱码一区二三区的特点 | 岛国视频午夜一区免费看| 日韩高清综合在线| 在线播放国产精品三级| 老司机靠b影院| 亚洲成人国产一区在线观看| 亚洲五月天丁香| 国产在线精品亚洲第一网站| 麻豆成人av在线观看| 久久精品aⅴ一区二区三区四区| 国产高清有码在线观看视频 | 欧美丝袜亚洲另类 | 好男人电影高清在线观看| 欧美激情 高清一区二区三区| 亚洲五月天丁香| 两个人看的免费小视频| 欧美精品亚洲一区二区| 亚洲精品一区av在线观看| 免费av毛片视频| 欧美日韩一级在线毛片| 最新在线观看一区二区三区| 国产1区2区3区精品| 侵犯人妻中文字幕一二三四区| 午夜a级毛片| 久久久国产成人免费| 亚洲 欧美一区二区三区| 欧美成人午夜精品| 久久精品国产清高在天天线| 日本一区二区免费在线视频| 啦啦啦韩国在线观看视频| 成人国产综合亚洲| 亚洲精品一区av在线观看| 午夜免费激情av| 日本三级黄在线观看| 亚洲色图av天堂| 乱人伦中国视频| 亚洲一码二码三码区别大吗| 一进一出抽搐动态| 在线播放国产精品三级| 欧美日韩瑟瑟在线播放| 国产精品综合久久久久久久免费 | 在线永久观看黄色视频| 国产精品久久久久久精品电影 | 成人国产一区最新在线观看| 精品乱码久久久久久99久播| 欧美成人一区二区免费高清观看 | 日韩中文字幕欧美一区二区| 一级a爱片免费观看的视频| 国产色视频综合| 国产人伦9x9x在线观看| 少妇粗大呻吟视频| 国产一区二区激情短视频| www.www免费av| √禁漫天堂资源中文www| 看黄色毛片网站| 丰满的人妻完整版| 久久人妻福利社区极品人妻图片| 欧美日韩亚洲国产一区二区在线观看| 身体一侧抽搐| 色综合亚洲欧美另类图片| 久久精品91无色码中文字幕| 久久伊人香网站| 日韩精品青青久久久久久| 欧美日韩中文字幕国产精品一区二区三区 | 久热这里只有精品99| 国内毛片毛片毛片毛片毛片| 亚洲人成伊人成综合网2020| 黑人操中国人逼视频| 免费在线观看完整版高清| 十八禁人妻一区二区| 国产在线精品亚洲第一网站| 国产亚洲精品第一综合不卡| 国产一区二区三区在线臀色熟女| 可以在线观看的亚洲视频| 日日爽夜夜爽网站| 午夜福利一区二区在线看| 国产精华一区二区三区| 国产1区2区3区精品| 国产蜜桃级精品一区二区三区| 又大又爽又粗| 大陆偷拍与自拍| 青草久久国产| www日本在线高清视频| 少妇被粗大的猛进出69影院| АⅤ资源中文在线天堂| 亚洲五月婷婷丁香| 最近最新中文字幕大全电影3 | 黄色视频不卡| 中文字幕人妻熟女乱码| 成年版毛片免费区| 国产一卡二卡三卡精品| 色精品久久人妻99蜜桃| 美女扒开内裤让男人捅视频| 日韩免费av在线播放| 国产精品日韩av在线免费观看 | 国产成人精品久久二区二区免费| 亚洲精品一区av在线观看| 午夜影院日韩av| 国产91精品成人一区二区三区| 亚洲在线自拍视频| 黄色a级毛片大全视频| 国产av在哪里看| 国产成人精品久久二区二区91| 国产成人欧美在线观看| 久久久久久人人人人人| 丝袜美腿诱惑在线| 国产亚洲av嫩草精品影院| 国产99久久九九免费精品| 悠悠久久av| 久久久久久国产a免费观看| 高清在线国产一区| 老司机福利观看| 99久久99久久久精品蜜桃| 亚洲国产毛片av蜜桃av| 成年人黄色毛片网站| 看免费av毛片| 自线自在国产av| av有码第一页| 国产高清videossex| 精品国产亚洲在线| 涩涩av久久男人的天堂| 一本久久中文字幕| 国产精品一区二区免费欧美| 亚洲国产高清在线一区二区三 | 在线观看免费视频网站a站| 18禁裸乳无遮挡免费网站照片 | 香蕉丝袜av| 女警被强在线播放| 91九色精品人成在线观看| 精品一品国产午夜福利视频| 一区在线观看完整版| 一本综合久久免费| 日本五十路高清| 在线观看午夜福利视频| xxx96com| 亚洲人成网站在线播放欧美日韩| 91av网站免费观看| 久久久久国产一级毛片高清牌| 亚洲色图av天堂| 亚洲性夜色夜夜综合| 亚洲av电影不卡..在线观看| 亚洲人成网站在线播放欧美日韩| 日韩欧美免费精品| 在线播放国产精品三级| 黄网站色视频无遮挡免费观看| 在线免费观看的www视频| 国产精品久久久久久人妻精品电影| 老司机午夜十八禁免费视频| 免费在线观看视频国产中文字幕亚洲| 亚洲国产精品sss在线观看| 欧美成人性av电影在线观看| 女人爽到高潮嗷嗷叫在线视频| 国产精品久久久人人做人人爽| 性少妇av在线| 天天一区二区日本电影三级 | 亚洲人成77777在线视频| 精品久久蜜臀av无| www.自偷自拍.com| 国产成人精品久久二区二区91| 精品第一国产精品| 国产欧美日韩一区二区三| 好男人在线观看高清免费视频 | 在线播放国产精品三级| 色哟哟哟哟哟哟| 中国美女看黄片| 国产亚洲精品综合一区在线观看 | 一区二区日韩欧美中文字幕| 国产精品久久视频播放| 亚洲专区国产一区二区| 视频区欧美日本亚洲| 欧美黄色淫秽网站| 欧美日本亚洲视频在线播放| 69av精品久久久久久| 色尼玛亚洲综合影院| 自线自在国产av| 日本vs欧美在线观看视频| 亚洲国产精品合色在线| 亚洲熟妇熟女久久| 窝窝影院91人妻| 巨乳人妻的诱惑在线观看| 可以免费在线观看a视频的电影网站| 亚洲专区国产一区二区| 中国美女看黄片| 搡老熟女国产l中国老女人| 欧美午夜高清在线| 中文字幕最新亚洲高清| 亚洲精品在线观看二区| 电影成人av| 侵犯人妻中文字幕一二三四区| 国产一区二区三区综合在线观看| 可以免费在线观看a视频的电影网站| 亚洲精品一区av在线观看| 亚洲成av人片免费观看| 精品国产超薄肉色丝袜足j| 亚洲中文av在线| 国产精品永久免费网站| 国产精品久久久人人做人人爽| 亚洲欧美激情综合另类| 9热在线视频观看99| 一级片免费观看大全| 亚洲av片天天在线观看| 90打野战视频偷拍视频| 日日爽夜夜爽网站| 国产高清激情床上av| 欧洲精品卡2卡3卡4卡5卡区| www.自偷自拍.com| 亚洲人成伊人成综合网2020| 日韩中文字幕欧美一区二区| a在线观看视频网站| 午夜日韩欧美国产| 他把我摸到了高潮在线观看| 91麻豆av在线| 亚洲全国av大片| 国产精品久久久久久人妻精品电影| 欧美激情久久久久久爽电影 | 国产亚洲精品久久久久5区| 老司机深夜福利视频在线观看| av欧美777| 亚洲精品国产一区二区精华液| av中文乱码字幕在线| 在线av久久热| 天天躁夜夜躁狠狠躁躁| 黄色片一级片一级黄色片| 亚洲国产高清在线一区二区三 | 精品国内亚洲2022精品成人| 人人妻,人人澡人人爽秒播| 亚洲成a人片在线一区二区| 色哟哟哟哟哟哟| 国产麻豆成人av免费视频| 色播在线永久视频| 中文字幕另类日韩欧美亚洲嫩草| e午夜精品久久久久久久| 国产一区在线观看成人免费| 桃色一区二区三区在线观看| 国产精品久久久av美女十八| 久久九九热精品免费| 两性午夜刺激爽爽歪歪视频在线观看 | 变态另类丝袜制服| 很黄的视频免费| 成人三级做爰电影| 久久欧美精品欧美久久欧美| 在线观看午夜福利视频| 国产一区二区三区视频了| 亚洲精品久久国产高清桃花| 国产午夜福利久久久久久| 免费看十八禁软件| 亚洲成人久久性| 国产亚洲av嫩草精品影院| 大型黄色视频在线免费观看| 欧美成狂野欧美在线观看| 韩国精品一区二区三区| www.www免费av| 在线观看舔阴道视频| 亚洲一码二码三码区别大吗| 91九色精品人成在线观看| 满18在线观看网站| 免费在线观看视频国产中文字幕亚洲| 亚洲一码二码三码区别大吗| 91在线观看av| 日韩av在线大香蕉|