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S P Kar,
M F Seldin,
W Chen,
E Lu,
G M Hirschfield,
P Invernizzi,
J Heathcote,
D Cusi,
Piero L Almasio,
Domenico Alvaro, [......],
Mario Strazzabosco,
Sonia Tarallo,
Mirko Tarocchi,
Claudio Tiribelli,
Pierluigi Toniutto,
Maria Vinci,
Massimo Zuin,
M E Gershwin,
K A Siminovitch,
C I Amos
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ABSTRACT: Genome-wide association studies (GWAS) have successfully identified several loci associated with primary biliary cirrhosis (PBC) risk. Pathway analysis complements conventional GWAS analysis. We applied the recently developed linear combination test for pathways to datasets drawn from independent PBC GWAS in Italian and Canadian subjects. Of the Kyoto Encyclopedia of Genes and Genomes and BioCarta pathways tested, 25 pathways in the Italian dataset (449 cases, 940 controls) and 26 pathways in the Canadian dataset (530 cases, 398 controls) were associated with PBC susceptibility (P<0.05). After correcting for multiple comparisons, only the eight most significant pathways in the Italian dataset had FDR <0.25 with tumor necrosis factor/stress-related signaling emerging as the top pathway (P=7.38 × 10(-4), FDR=0.18). Two pathways, phosphatidylinositol signaling and hedgehog signaling, were replicated in both datasets (P<0.05), and subjected to two additional complementary pathway tests. Both pathway signals remained significant in the Italian dataset on modified gene set enrichment analysis (P<0.05). In both GWAS, variants nominally associated with PBC were significantly overrepresented in the phosphatidylinositol pathway (Fisher exact P<0.05). These results point to established and novel pathway-level associations with inherited predisposition to PBC that, on further independent replication and functional validation, may provide fresh insights into PBC etiology.Genes and Immunity advance online publication, 7 February 2013; doi:10.1038/gene.2013.1.
Genes and immunity 02/2013; · 4.22 Impact Factor
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Ana Lleo,
Sabine Oertelt-Prigione, Ilaria Bianchi,
Lisa Caliari,
Palma Finelli,
Monica Miozzo,
Roberta Lazzari,
Annarosa Floreani,
Francesca Donato,
Massimo Colombo,
M Eric Gershwin,
Mauro Podda,
Pietro Invernizzi
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ABSTRACT: Sex chromosome abnormalities have been advocated to be involved in the striking female prevalence of primary biliary cirrhosis (PBC) and women with PBC manifest an increased X chromosome loss in peripheral blood mononuclear cells compared to age-matched healthy women. Our knowledge of the etiopathogenesis of autoimmunity in male patients remains, however, limited. Next to the possible role of androgens and their imbalances, the Y chromosome appears as a potential candidate for influence of the immune function in men. Herein we analyzed a population of male patients with primary biliary cirrhosis (n = 26) and healthy controls (n = 88) to define a potential association of disease and the loss of the Y chromosome. We demonstrate that Y chromosome loss indeed is higher in PBC males compared to healthy controls, and this phenomenon increases with aging. We were, thus, able to confirm the existence of an analogous mechanism in the male population to previously identified X haploinsufficiency in female patients with organ-specific autoimmune disease. We propose that this commonality might represent a relevant feature in the etiopathogenesis of autoimmune diseases that should be further investigated.
Journal of Autoimmunity 01/2013; · 7.37 Impact Factor
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Brian D Juran,
Gideon M Hirschfield,
Pietro Invernizzi,
Elizabeth J Atkinson,
Yafang Li,
Gang Xie,
Roman Kosoy,
Michael Ransom,
Ye Sun, Ilaria Bianchi, [......],
Cynthia Levy,
Andre Franke,
Peter K Gregersen,
Fabrizio Bossa,
M Eric Gershwin,
Mariza Deandrade,
Christopher I Amos,
Konstantinos N Lazaridis,
Michael F Seldin,
Katherine A Siminovitch
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ABSTRACT: To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies.
Human Molecular Genetics 08/2012; · 7.64 Impact Factor
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Luca Persani,
Marco Bonomi,
Ana Lleo,
Simone Pasini,
Fabiola Civardi, Ilaria Bianchi,
Irene Campi,
Palma Finelli,
Monica Miozzo,
Chiara Castronovo,
Silvia Sirchia,
M Eric Gershwin,
Pietro Invernizzi
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ABSTRACT: Multiple mechanisms have been proposed to explain the peculiar distribution of autoimmune thyroiditis (AIT) among women and men. Most attention has been focused on the detection of the role of estrogens and the X chromosome. Specifically, a potential role for X haploinsufficiency has been proposed in the female patient population and an association with the disease has been confirmed. Our knowledge of the etiopathogenesis of autoimmunity in male patients remains, however, limited. Next to the possible role of androgens and their imbalances, the Y chromosome appears as a potential candidate for influence of the immune function in men. Herein we analyzed a population of male patients with AIT (n=31) and healthy controls (n=88) to define a potential association of disease and the loss of the Y chromosome. Y chromosome loss increases in AIT compared to unaffected subjects; these phenomenon increases with aging as expected, however, the degree of loss is significantly increased in the patient population compared to the healthy controls. We were, thus, able to confirm the existence of an analogous mechanism in the male population to previously identified X haploinsufficiency in female patients with AIT. We propose that this commonality might represent a relevant feature in the etiopathogenesis of AIT that should be further investigated.
Journal of Autoimmunity 12/2011; 38(2-3):J193-6. · 7.37 Impact Factor
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ABSTRACT: The X chromosome is known to contain the largest number of immune-related genes of the whole human genome. For this reason, X chromosome has recently become subject of great interest and attention and numerous studies have been aimed at understanding the role of genes on the X chromosome in triggering and maintaining the autoimmune aggression. Autoimmune diseases are indeed a growing heath burden affecting cumulatively up to 10% of the general population. It is intriguing that most X-linked primary immune deficiencies carry significant autoimmune manifestations, thus illustrating the critical role played by products of single gene located on the X chromosome in the onset, function and homeostasis of the immune system. Again, the plethora of autoimmune stigmata observed in patients with Turner syndrome, a disease due to the lack of one X chromosome or the presence of major X chromosome deletions, indicate that X-linked genes play a unique and major role in autoimmunity. There have been several reports on a role of X chromosome gene dosage through inactivation or duplication in women with autoimmune diseases, for example through a higher rate of circulating cells with a single X chromosome (i.e. with X monosomy). Finally, a challenge for researchers in the coming years will be to dissect the role for the large number of X-linked microRNAs from the perspective of autoimmune disease development. Taken together, X chromosome might well constitute the common trait of the susceptibility to autoimmune diseases, other than to explain the female preponderance of these conditions. This review will focus on the available evidence on X chromosome changes and discuss their potential implications and limitations.
Journal of Autoimmunity 12/2011; 38(2-3):J187-92. · 7.37 Impact Factor
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ABSTRACT: Autoimmune diseases include more than 70 different disorders affecting over 5% of the population of the Western countries. They are mainly characterized by female predominance and have great impact on the quality of life of affected subjects. It is generally accepted that ADs are the result of a complex interaction between genetic and environmental factors; however the mechanisms involved in the loss of tolerance remain unknown. Studying the distribution of these conditions across various global regions and ethnic groups by means of geoepidemiology might readily provide epidemiological data and also advance our understanding of their pathogenesis. Indeed, geoepidemiology demonstrates that genetic susceptibility interacts with lifestyle and environmental factors, which include socioeconomic status, infectious agents (triggering or protective agents), environmental pollutants, and vitamin D (dependent on sunlight exposure), in determining the risk of developing autoimmunity and in the understanding of their female prevalence. To properly understand the geoepidemiology of human autoimmunity, it is important to consider the many pleiotropic factors which lead to its initiation. In most studies the focus has been on genetics and environment. However, in this review the focus is primarily on gender. Overall, autoimmune diseases are well known to have female predominance, but there is significant variation in geographic area. Further, the mechanisms that influence female predominance are relatively unknown. Hence the attempt in this review is to focus on these critical issues.
Autoimmunity reviews 11/2011; 11(6-7):A386-92. · 6.37 Impact Factor
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Xiangdong Liu,
Pietro Invernizzi,
Yue Lu,
Roman Kosoy,
Yan Lu, Ilaria Bianchi,
Mauro Podda,
Chun Xu,
Gang Xie,
Fabio Macciardi, [......],
Agostino Colli,
Giancarlo Spinzi,
Renzo Montanari,
Peter K Gregersen,
E Jenny Heathcote,
Gideon M Hirschfield,
Katherine A Siminovitch,
Christopher I Amos,
M Eric Gershwin,
Michael F Seldin
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ABSTRACT: A genome-wide association screen for primary biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB (P = 7.9 x 10(-11), odds ratio (OR) = 1.46), IRF5-TNPO3 (P = 2.8 x 10(-10), OR = 1.63) and 17q12-21 (P = 1.7 x 10(-10), OR = 1.38).
Nature Genetics 08/2010; 42(8):658-60. · 35.53 Impact Factor
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Bihui Zhong,
Pavel Strnad,
Carlo Selmi,
Pietro Invernizzi,
Guo-Zhong Tao,
Angela Caleffi,
Minhu Chen, Ilaria Bianchi,
Mauro Podda,
Antonello Pietrangelo,
M Eric Gershwin,
M Bishr Omary
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ABSTRACT: Keratins (K) 8 and 18 variants predispose carriers to the development of end-stage liver disease and patients with chronic hepatitis C to disease progression. Hepatocytes express K8/K18, whereas biliary epithelia express K8/K18/K19. K8-null mice, which are predisposed to liver injury, spontaneously develop anti-mitochondrial antibodies (AMA) and have altered hepatocyte mitochondrial size and function. There is no known association of K19 with human disease and no known association of K8/K18/K19 with human autoimmune liver disease. We tested the hypothesis that K8/K18/K19 variants associate with primary biliary cirrhosis (PBC), an autoimmune cholestatic liver disease characterized by the presence of serum AMA. In doing so, we analyzed the entire exonic regions of K8/K18/K19 in 201 Italian patients and 200 control blood bank donors. Five disease-associated keratin heterozygous variants were identified in patients versus controls (K8 G62C/R341H/V380I, K18 R411H, and K19 G17S). Four variants were novel and included K19 G17S/V229M/N184N and K18 R411H. Overall, heterozygous disease-associated keratin variants were found in 17 of 201 (8.5%) PBC patients and 4 of 200 (2%) blood bank donors (P < 0.004, odds ratio = 4.53, 95% confidence interval = 1.5-13.7). Of the K19 variants, K19 G17S was found in three patients but not in controls and all K8 R341H (eight patients and three controls) associated with concurrent presence of the previously described intronic K8 IVS7+10delC deletion. Notably, keratin variants associated with disease severity (12.4% variants in Ludwig stage III/IV versus 4.2% in stages I/II; P < 0.04, odds ratio = 3.25, 95% confidence interval = 1.02-10.40), but not with the presence of AMA. CONCLUSION: K8/K18/K19 variants are overrepresented in Italian PBC patients and associate with liver disease progression. Therefore, we hypothesize that K8/K18/K19 variants may serve as genetic modifiers in PBC.
Hepatology 09/2009; 50(2):546-54. · 11.66 Impact Factor
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Grazia Anna Niro,
Francesca Poli,
Angelo Andriulli, Ilaria Bianchi,
Francesca Bernuzzi,
Lisa Caliari,
Rosanna Fontana,
Domenica Gioffreda,
Maria Rosa Valvano,
Mauro Podda,
Pietro Invernizzi
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ABSTRACT: Specific HLA alleles and immunoregulatory genes have been evaluated in primary biliary cirrhosis (PBC), but data are discordant. We determined whether TNF-alpha promoter polymorphisms (G-308A and G-238A) and alleles of HLA class II (HLA-DRB1) might be associated either with PBC occurrence and severity in Italian populations from two distinct areas. The distribution of TNF1 (G/G) genotype did not differ either between patients and controls or between patients from Northern and Southern Italy. Contrariwise, the HLA-DRB1*08 appeared positively linked to the occurrence of disease (8.4% in patients vs. 2.5% in controls, P = 0.003), whereas the HLA-DRB1*13 appeared to be protective, being more frequent in controls (12.8%) than in patients (7%) (P = 0.038). Neither positively nor negatively associated alleles of the two genomic loci had an effect on disease progression. We report a distinct genetic risk of developing PBC in the Italian population, with no interaction between the HLA and TNF alleles.
Annals of the New York Academy of Sciences 09/2009; 1173:557-63. · 3.15 Impact Factor
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Grazia Anna Niro,
Francesca Poli,
Angelo Andriulli, Ilaria Bianchi,
Francesca Bernuzzi,
Lisa Caliari,
Rosanna Fontana,
Domenica Gioffreda,
Maria Rosa Valvano,
Mauro Podda,
Pietro Invernizzi
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ABSTRACT: Specific HLA alleles and immunoregulatory genes have been evaluated in primary biliary cirrhosis (PBC), but data are discordant. We determined whether TNF- promoter polymorphisms (G-308A and G-238A) and alleles of HLA class II (HLA-DRB1) might be associated either with PBC occurrence and severity in Italian populations from two distinct areas. The distribution of TNF1 (G/G) genotype did not differ either between patients and controls or between patients from Northern and Southern Italy. Contrariwise, the HLA-DRB1*08 appeared positively linked to the occurrence of disease (8.4% in patients vs. 2.5% in controls, P= 0.003), whereas the HLA-DRB1*13 appeared to be protective, being more frequent in controls (12.8%) than in patients (7%) (P= 0.038). Neither positively nor negatively associated alleles of the two genomic loci had an effect on disease progression. We report a distinct genetic risk of developing PBC in the Italian population, with no interaction between the HLA and TNF alleles.
Annals of the New York Academy of Sciences 08/2009; 1173(1):557 - 563. · 3.15 Impact Factor
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Atsushi Tanaka,
Saeko Nezu,
Satoko Uegaki,
Kentaro Kikuchi,
Akitaka Shibuya,
Hiroshi Miyakawa,
Shin-ichi Takahashi, Ilaria Bianchi,
Paola Zermiani,
Mauro Podda,
Hiromasa Ohira,
Pietro Invernizzi,
Hajime Takikawa
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ABSTRACT: Vitamin D receptor (VDR) agonists have recently been identified as potent immunomodulators capable of inhibiting Th1-mediated immune response, leading us to consider the hypothesis that functional VDR polymorphisms might contribute to enhanced risk for developing primary biliary cirrhosis (PBC), a Th1-mediated autoimmune disease. In the current study, we aimed at elucidating the genetic association of VDR polymorphisms with susceptibility to PBC in Japanese and Italian populations.
We enrolled 334 PBC patients (195 Japanese and 139 Italians), as well as 334 age- and sex-matched controls (179 Japanese and 156 Italians). VDR genotyping was performed by PCR-RFLP, using BsmI, ApaI and TaqI endonucleases.
The genotype BB of BsmI polymorphism was significantly associated with PBC (OR = 1.80 [95% CI; 1.19-2.73], p = 0.005). The association of the genotype BB was observed in Japanese (OR = 13.77, p = 0.001), and Italians (OR = 1.83, p = 0.019), respectively, although not significant in Italians after Bonferroni correction. The frequency of the B allele at the BsmI polymorphism was significantly higher in PBC patients (OR = 1.27 [95% CI; 1.02-1.59], p = 0.040).
The genotype 'BB' as well as 'B' allele at BsmI polymorphism of the VDR gene contribute to the risk of PBC development.
Journal of Hepatology 04/2009; 50(6):1202-9. · 9.26 Impact Factor
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ABSTRACT: Cytokines are soluble peptides secreted by several kinds of cells, they mediate many immune and inflammatory reactions, and
regulate several biochemical processes in and around the cells that produce them. They may act on different cell types (pleiotropic
effects) and have overlapping effects (redundancy); furthermore, their action may be local or systemic. In most tissues, including
the liver, constitutive production of cytokines is absent or minimal. However, as physiologic and pathologic stimuli activate
cells, the production of these molecules increases, and they orchestrate the tissue’s response to the stimulus. Phenotype
of the immune response is a function of the repertoire of cytokines produced in the early phases (1).
12/2006: pages 83-93;
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ABSTRACT: The mechanisms that cause the female predominance of primary biliary cirrhosis (PBC) are uncertain, but the X chromosome includes genes involved in immunological tolerance. We assessed the rate of X monosomy in peripheral white blood cells from 100 women with PBC, 50 with chronic hepatitis C, and 50 healthy controls, by fluorescence in-situ hybridisation. Frequency of X monosomy increased with age in all groups, but was significantly higher in women with PBC than in controls (p<0.0001); age-adjusted back-transformed mean frequencies were 0.050 (95% CI 0.046-0.055) in women with PBC, 0.032 (0.028-0.036) in those with chronic hepatitis C, and 0.028 (0.025-0.032) in controls. We suggest that haploinsufficiency for specific X-linked genes leads to female susceptibility to PBC.
The Lancet 02/2004; 363(9408):533-5. · 38.28 Impact Factor
