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THE ROLE OF HUMAN GENETICS IN IDENTIFYING CLINICALLY RELEVANT THERAPEUTIC TARGETS FOR SS

THE ROLE OF HUMAN GENETICS IN IDENTIFYING CLINICALLY RELEVANT THERAPEUTIC TARGETS FOR SS. Steven Taylor CEO, Sjögren’s Syndrome Foundation. WELCOME. Elaine Alexander, MD, PhD Chair, SSF Medical and Scientific Advisory Board.

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THE ROLE OF HUMAN GENETICS IN IDENTIFYING CLINICALLY RELEVANT THERAPEUTIC TARGETS FOR SS

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  1. THE ROLE OF HUMAN GENETICS IN IDENTIFYING CLINICALLY RELEVANT THERAPEUTIC TARGETS FOR SS

  2. Steven TaylorCEO, Sjögren’s Syndrome Foundation WELCOME

  3. Elaine Alexander, MD, PhDChair, SSF Medical and Scientific Advisory Board THE ROLE OF HUMAN GENETICS IN IDENTIFYING CLINICALLY RELEVANT THERAPEUTIC TARGETS FOR SS

  4. GENOME-WIDE ASSOCIATION (GWA) STUDIES In which hundreds of thousands of single-nucleotide polymorphisms (SNPs) are tested for association with a disease in hundreds or thousands of persons have revolutionized the search for genetic influences on complex traits (i.e. cancer, heart disease, etc.).

  5. Complex disorders, in contrast to single-gene disorders, are caused by many genetic and environmental factors working together, each having a relatively small effect and few, if any, are absolutely required for disease to occur. In the past 5 years, GWA studies have identified SNPs implicating hundreds of robustly replicated loci (i.e., specific genomic locations) for common traits. GENOME-WIDE ASSOCIATION (GWA) STUDIES

  6. The identified variants have low associated risks and account for little disease heritability. Potential explanations: Rare variants, which are not captured by current GWA studies Structural variants, which are poorly captured by current studies Other forms of genomic variation or interactions between genes or between genes and environmental factors WHAT HAVE WE LEARNED FROM GWA STUDIES ABOUT RISK IN COMPLEX DISEASES?

  7. Despite their value in locating the vicinity of potential disease-causing genomic variants, few of the SNPs identified in GWA studies have clear functional implications that are relevant to disease mechanisms. Narrowing an implicated locus to a single variant that directly causes disease susceptibility by disrupting the expression or function of a protein has proven elusive to date. This will be a key step in improving our understanding of the mechanisms of disease and in designing effective strategies for risk assessment, management, and treatment. WHAT DO GWA STUDIES TELL US ABOUT DISEASE MECHANISMS?

  8. Complex disease: A multi-factorial condition caused by the interaction of multiple genes and environmental factors SS is a multi-system disorder Differentially expressed in different individuals Variable number of affected organs per individual Multiple types of organs (exocrine, endocrine, systemic) Potential different pathophysiologic processes in different organs SJÖGREN’S SYNDROME (SS) IS A COMPLEX DISEASE

  9. Kathy Moser, PhDOklahoma Medical Research Center The Genetic Basis of Human Sjögren’s Syndrome Corinne Richard-Miceli, MD, PhDHôpital Bicêtre, Paris Genetic and epigenetic contribution to pSS susceptibility Lindsey Criswell, MD, MPHUniversity of California, San Francisco Epigenetics and Other Influences on Gene Expression HOW HAVE AND WILL OUR PANELISTS APPROACH GWA STUDIES IN SS THAT LEAD TO INDENTIFICATION OF DISEASE MECHANISMS?

  10. The urgent and ultimate goal in SS is discovering, if not a cure, at least more effective, safe therapies. Identification of disease mechanisms, pathways, targets is essential to the therapeutic development process for complex diseases, including SS. How do the panelists envision their research translating GWA study observations into identification of potential therapeutic targets? HOW HAVE AND WILL OUR PANELISTS APPROACH GWA STUDIES IN SS THAT LEAD TO INDENTIFICATION OF DISEASE MECHANISMS?

  11. THE ROLE OF HUMAN GENETICS IN IDENTIFYING CLINICALLY RELEVANT THERAPEUTIC TARGETS FOR SS Moderator Peter K. Gregersen, MD Center for Genomics and Human Genetics Feinstein Institute for Medical Research

  12. The Genetic Basis of Human Sjögren’s Syndrome Kathy L. Moser, PhD Associate Member Director, OMRF Sjogren’s Research Clinic Director, Lupus Family Registry and Repository Arthritis and Clinical Immunology Program Oklahoma Medical Research Foundation Oklahoma City, Oklahoma

  13. Complex Etiology of SS: genetics + environment The genetics of SS are largely unexplored: Twin concordance estimates unavailable Genome-wide linkage studies in families not performed ~ 30 candidate genes evaluated to date ~20 show at least minimal evidence for association Relatively small (<200), case-control association studies Most convincing associations found with HLA molecules involved in antigen recognition, plus IRF5 and STAT4 involved in interferon/T cell signaling

  14. The Human Genome Genome: 3 billion basepairs of DNA Chromosomes: 23 pairs (autosomes + X,Y) Size varies 1-22, large to small Chromo 1 has ~ 3,000 genes Y chromo has ~231 genes Locus: General term for a location in the genome Gene: Functional unit of heredity 20-22,000 genes Ave. gene is ~3000 bps Variation: Humans are ~99.9% the same Variation occurs ~1/800 bps Major and minor variants (>12 K) SNPS: single nucleotide polymorphisms (>30 M) Sequencing ~ 2 X or more variants Disease genes: Identified for >2,200 disorders Technology: Genotype >1 M SNPs per experiment ...CGAATTCCGAATT... ...GCTTAAGGCTTAA...

  15. Impact of Genome Wide Association Studies on Gene Discovery MS CD T1D RA SLE Psor 1996 INS 2001 Very few confirmed associations prior to 2006 IBD5 CARD15 SH2D2A 2003 CTLA4 2004 PTPN22 PTPN22 PAD14 2005 IL2Ra IL7R IRF5 PTPN22 2006 IFIH1 ICAM-1 IL23R PHOX2B ATG16L1 FCRL3 1st GWAS 2007 2008 2009 2010

  16. Impact of Genome Wide Association Studies on Gene Discovery MS CD T1D RA SLE Psor 1996 INS 2001 IBD5 CARD15 SH2D2A 2003 CTLA4 2004 PTPN22 PTPN22 PAD14 2005 IL2Ra IL7R IRF5 PTPN22 2006 IFIH1 ICAM-1 IL23R PHOX2B ATG16L1 FCRL3 1st GWAS 2007 C12orf30 KIAA350 Tenr-IL2 PTPN2 IL12B IRGM 5p13 3p21 TNFAIP3 ITGAV CARD8 IL7R IL23R ADAM33 ERBB3 CD226 IL7R NKX2-3 ATG16L1 PTPN2 10q21 STAT4 TRAF1 FOXJ1 IL2Ra CD58 IL12B CD40 TNFAIP3 SPP1 BLK PTPN21 CLEC16A PRKCQ NOD2 ATG16L1 ZNF365 MST1 ORMDL3 5q33.3 XKR6 2008 C12orf30 BACH2 PTPN11 NKX2-3 JAK2 PTPN2 CCR6 ITLN1 PTPN22 STAT4 BANK1 PHRF1 6q21 C8orf12 CTLA4 PTPN1 IRGM PTGER4 IL12B STAT3 CTSH C11orf30 TRAF1 ITGAM PXK NMNAT2 ICA1 SCUBE1 IFIH1 ERBB3 IL23R ICOSLG MUC19 TNFSF15 CDKAL1 OLIG3 K1F1B UBE2L3 TNFSF4 LYN 8p23.1 1q25.1 7q11.23 DLK1 RIO3 C10orf59 IL2RA IL2 CD69 REL TNFRSF1A CYP27B1 ETS1 HIC2 PRDM1 WDFY4 IL23A 2009 MEG3 TYK2 SHBB3 IL27 ORMDL3 IL10 CTLA4 CD6 STAT4 IKZF1 ATG5 SLC15A4 IL13 STAT2 IL10 RTL1 INS PTPN2 C6orf173 GLIS3 UBASH3A BLK IRF8 JAZF1 RASGRP3 LRRC18 TNIP1 TNFAIP3 UHRF1BP1 TNIP1 2010 CCR6 AFF3 ANKRD55 IRF5 SPRED2 METTL1 DQA1 ETS1 IRF8 CD44 RBPJ IL2RA IL6ST CCL21 CD40 STAT3 CBLB

  17. Impact of Genome Wide Association Studies on Gene Discovery MS CD T1D RA SLE Psor 1996 INS Genes associated with multiple ADs: PTPN22 2001 IBD5 CARD15 SH2D2A 2003 CTLA4 2004 PTPN22 PTPN22 PAD14 2005 IL2Ra IL7R IRF5 PTPN22 2006 IFIH1 ICAM-1 IL23R PHOX2B ATG16L1 FCRL3 1st GWAS 2007 C12orf30 KIAA350 Tenr-IL2 PTPN2 IL12B IRGM 5p13 3p21 TNFAIP3 ITGAV CARD8 IL7R IL23R ADAM33 ERBB3 CD226 IL7R NKX2-3 ATG16L1 PTPN2 10q21 STAT4 TRAF1 FOXJ1 IL2Ra CD58 IL12B CD40 TNFAIP3 SPP1 BLK PTPN21 CLEC16A PRKCQ NOD2 ATG16L1 ZNF365 MST1 ORMDL3 5q33.3 XKR6 2008 C12orf30 BACH2 PTPN11 NKX2-3 JAK2 PTPN2 CCR6 TRAF1 ITLN1 STAT4 BANK1 PHRF1 6q21 C8orf12 CTLA4 PTPN1 IRGM PTGER4 IL12B STAT3 CTSH C11orf30 ITGAM K1F1B PXK NMNAT2 ICA1 SCUBE1 IFIH1 ERBB3 IL23R ICOSLG MUC19 TNFSF15 CDKAL1 OLIG3 1q25.1 UBE2L3 TNFSF4 LYN 8p23.1 DLK1 RIO3 C10orf59 IL2RA IL2 CD69 REL TNFRSF1A CYP27B1 ETS1 HIC2 PRDM1 WDFY4 IL23A TNIP1 2009 MEG3 TYK2 SHBB3 IL27 ORMDL3 IL10 CTLA4 CD6 IKZF1 ATG5 SLC15A4 IL13 STAT2 7q11.23 IL10 RTL1 INS PTPN2 C6orf173 GLIS3 UBASH3A BLK IRF8 JAZF1 RASGRP3 LRRC18 TNIP1 TNFAIP3 UHRF1BP1 2010 CCR6 AFF3 ANKRD55 IRF5 SPRED2 METTL1 DQA1 ETS1 IRF8 CD44 RBPJ IL2RA IL6ST CCL21 CD40 STAT3 CBLB

  18. Impact of Genome Wide Association Studies on Gene Discovery MS CD T1D RA SLE Psor 1996 INS Genes associated with multiple ADs: PTPN22 IRF5 2001 IBD5 CARD15 SH2D2A 2003 CTLA4 2004 PTPN22 PTPN22 PAD14 2005 IL2Ra IL7R IRF5 PTPN22 2006 IFIH1 ICAM-1 IL23R PHOX2B ATG16L1 FCRL3 1st GWAS 2007 C12orf30 KIAA350 Tenr-IL2 PTPN2 IL12B IRGM 5p13 3p21 TNFAIP3 ITGAV CARD8 IL7R IL23R ADAM33 ERBB3 CD226 IL7R NKX2-3 ATG16L1 PTPN2 10q21 STAT4 TRAF1 FOXJ1 IL2Ra CD58 IL12B CD40 TNFAIP3 SPP1 BLK CLEC16A PRKCQ NOD2 ATG16L1 ZNF365 MST1 PTPN21 ORMDL3 5q33.3 XKR6 2008 C12orf30 BACH2 PTPN11 NKX2-3 JAK2 PTPN2 CCR6 TRAF1 ITLN1 STAT4 BANK1 PHRF1 6q21 C8orf12 CTLA4 IRGM PTGER4 IL12B STAT3 CTSH C11orf30 ITGAM K1F1B PXK PTPN1 NMNAT2 ICA1 SCUBE1 IFIH1 ERBB3 IL23R ICOSLG MUC19 TNFSF15 CDKAL1 OLIG3 1q25.1 UBE2L3 TNFSF4 LYN 8p23.1 DLK1 RIO3 C10orf59 IL2RA IL2 CD69 REL TNFRSF1A CYP27B1 ETS1 HIC2 PRDM1 WDFY4 IL23A TNIP1 2009 MEG3 TYK2 SHBB3 IL27 ORMDL3 IL10 CTLA4 CD6 IKZF1 ATG5 SLC15A4 IL13 STAT2 7q11.23 IL10 RTL1 INS PTPN2 C6orf173 GLIS3 UBASH3A BLK IRF8 JAZF1 RASGRP3 LRRC18 TNIP1 TNFAIP3 UHRF1BP1 2010 CCR6 AFF3 ANKRD55 IRF5 SPRED2 METTL1 DQA1 ETS1 IRF8 CD44 RBPJ IL2RA IL6ST CCL21 CD40 STAT3 CBLB

  19. Impact of Genome Wide Association Studies on Gene Discovery MS CD T1D RA SLE Psor 1996 INS Genes associated with multiple ADs: PTPN22 IRF5 STAT4 2001 IBD5 CARD15 SH2D2A 2003 CTLA4 2004 PTPN22 PTPN22 PAD14 2005 IL2Ra IL7R IRF5 PTPN22 2006 IFIH1 ICAM-1 IL23R PHOX2B ATG16L1 FCRL3 1st GWAS 2007 C12orf30 KIAA350 Tenr-IL2 PTPN2 IL12B IRGM 5p13 3p21 TNFAIP3 ITGAV CARD8 IL7R IL23R ADAM33 ERBB3 CD226 IL7R NKX2-3 ATG16L1 PTPN2 10q21 STAT4 TRAF1 FOXJ1 IL2Ra CD58 IL12B CD40 TNFAIP3 SPP1 BLK CLEC16A PRKCQ NOD2 ATG16L1 ZNF365 MST1 PTPN21 ORMDL3 5q33.3 XKR6 2008 C12orf30 BACH2 PTPN11 NKX2-3 JAK2 PTPN2 CCR6 TRAF1 ITLN1 STAT4 BANK1 PHRF1 6q21 C8orf12 CTLA4 IRGM PTGER4 IL12B STAT3 CTSH C11orf30 ITGAM K1F1B PXK PTPN1 NMNAT2 ICA1 SCUBE1 IFIH1 ERBB3 IL23R ICOSLG MUC19 TNFSF15 CDKAL1 OLIG3 1q25.1 UBE2L3 TNFSF4 LYN 8p23.1 DLK1 RIO3 C10orf59 IL2RA IL2 CD69 REL TNFRSF1A CYP27B1 ETS1 HIC2 PRDM1 WDFY4 IL23A TNIP1 2009 MEG3 TYK2 SHBB3 IL27 ORMDL3 IL10 CTLA4 CD6 IKZF1 ATG5 SLC15A4 IL13 STAT2 7q11.23 IL10 RTL1 INS PTPN2 C6orf173 GLIS3 UBASH3A BLK IRF8 JAZF1 RASGRP3 LRRC18 TNIP1 TNFAIP3 UHRF1BP1 2010 CCR6 AFF3 ANKRD55 IRF5 SPRED2 METTL1 DQA1 ETS1 IRF8 CD44 RBPJ IL2RA IL6ST CCL21 CD40 STAT3 CBLB

  20. Impact of Genome Wide Association Studies on Gene Discovery MS CD T1D RA SLE Psor 1996 INS Genes associated with multiple ADs: PTPN22 IRF5 STAT4 TNIP1 …and others 2001 IBD5 CARD15 SH2D2A 2003 CTLA4 2004 PTPN22 PTPN22 PAD14 2005 IL2Ra IL7R IRF5 PTPN22 2006 IFIH1 ICAM-1 IL23R PHOX2B ATG16L1 FCRL3 1st GWAS 2007 C12orf30 KIAA350 Tenr-IL2 PTPN2 IL12B IRGM 5p13 3p21 TNFAIP3 ITGAV CARD8 IL7R IL23R ADAM33 ERBB3 CD226 IL7R NKX2-3 ATG16L1 PTPN2 10q21 STAT4 TRAF1 FOXJ1 IL2Ra CD58 IL12B CD40 TNFAIP3 SPP1 BLK CLEC16A PRKCQ NOD2 ATG16L1 ZNF365 MST1 PTPN21 ORMDL3 5q33.3 XKR6 2008 C12orf30 BACH2 PTPN11 NKX2-3 JAK2 PTPN2 CCR6 TRAF1 ITLN1 STAT4 BANK1 PHRF1 6q21 C8orf12 CTLA4 IRGM PTGER4 IL12B STAT3 CTSH C11orf30 ITGAM K1F1B PXK PTPN1 NMNAT2 ICA1 SCUBE1 IFIH1 ERBB3 IL23R ICOSLG MUC19 TNFSF15 CDKAL1 OLIG3 1q25.1 UBE2L3 TNFSF4 LYN 8p23.1 DLK1 RIO3 C10orf59 IL2RA IL2 CD69 REL TNFRSF1A CYP27B1 ETS1 HIC2 PRDM1 WDFY4 IL23A TNIP1 2009 MEG3 TYK2 SHBB3 IL27 ORMDL3 IL10 CTLA4 CD6 IKZF1 ATG5 SLC15A4 IL13 STAT2 7q11.23 IL10 RTL1 INS PTPN2 C6orf173 GLIS3 UBASH3A BLK IRF8 JAZF1 RASGRP3 LRRC18 TNIP1 TNFAIP3 UHRF1BP1 2010 CCR6 AFF3 ANKRD55 IRF5 SPRED2 METTL1 DQA1 ETS1 IRF8 CD44 RBPJ IL2RA IL6ST CCL21 CD40 STAT3 CBLB

  21. Genetic Pathways in SLE C4B IRAK1 PXK C4A ATG5 PDCD1 TNFAIP3 ITGAM C2 FcγR2B CRP ICA1 SPP1 STAT4 STAT4 HLA-DR HLA-DR SCUBE1 PTPN22 C1q TNFSF4 TREX1 UBE2L3 ITGAM FcγR3A NMNAT2 FcγR3B BANK1 IRAK1 MECP2 TNFAIP3 STAT4 XKR6 IRF5 KIAA1542 BLK LYN Cells Pathways Genes DNA methylation T Cell signaling TNF/NFκB signaling TLR/IFN signaling Cellular adhesion B Cell signaling Ubiquitination Phagocytosis Complement Apoptosis Unknown Innate Immune Response Dendritic cells Macrophages Lymphocyte Activation/Function Autoreactive T cells Autoreactive B cells Immune Complex Clearance Macrophages Neutrophils Other Association of ~35 genes robustly confirmed, more on the way (Reviewed by Moser et al, Genes Immunity SLE Genetics Special Issue, 2009)

  22. Genome-Wide Association Study in SS Goals: Identify SNPs that are associated with SS and subphenotypes Initial GWAS dataset:313 SS patients, 435 controls Genotyping: Illumina OMNI1-Quad array; >1.1 million SNP markers

  23. Association Analysis Example for a single nucleotide polymorphism (SNP) 1) Count alleles CASES (n=6): CONTROLS (n=6): Allele “A” Allele “B” 0 1 1 2 2 2 0 0 1 1 2 2 2) As copies of allele B are added, does the risk of developing disease increase?

  24. SS Study Methods • Standard pre-analysis quality control (QC): • call rates, missingness, HWP, MAF, PCA • GWAS dataset following application of QC: • Subjects: 272 SS cases and 387 controls • SNPs: ~750,000 • no inflation in the test statistic (λGS=1) • Performed logistic regression (PLINK): • additive, recessive and dominant genetic models • models adjusted for gender and PC1-4 • Independent replication: • Subjects: 250 SS cases and 200 controls • DNA pooling (50 subjects each) • OMNI arrays

  25. Summary of All Results 45 SNPs surpassed genome-wide significance (P<5x10-8) all within the Major Histocompatibility Complex (MHC) 659 surpassed “suggestive” threshold (P<10-4) 593 within the MHC 66 outside MHC MHC Significant Suggestive MSC

  26. Future Directions Additional GWAS follow-up in SS: Ongoing replication studies ~2000 cases and ~2000 controls ~195,000 SNPs Increase power to reach genome-wide significance: Expand GWAS (discovery + replication) Integrative analyses: genetic + expression +clinical data Continue to build sample sizes SSF funding utilized to expand GWAS (yr 1) and replication (yr 2) studies, thus increasing power

  27. SGENE: The Sjogren’s Genetics Network • International group interested in contributing DNA samples and clinical data for genetic studies • Currently: • 15 contributing sites (plus subsites) • >2000 SS cases (AECG criteria), 2000 controls • Developing consistent clinical dataset • OMRF: coordinating center • Goal: • Overall: 15,000+ cases • If interested: • moserk@omrf.org

  28. Expectations for SS Genetics multiple genes (> 100 genes?) genes will include those involved in both the immune system and target organs genes will vary with subphenotypes genes will vary with population background environment will be important genetics will provide insight into key pathways and pathogenic mechanisms

  29. Genetic and epigenetic contribution to pSSsusceptibility Corinne Miceli-Richard & Xavier Mariette, Rheumatology, Bicêtre Hospital, INSERM U1012, Paris-Sud University, France

  30. Our group • Translational research on pSS susceptibility: • Genetic association studies • Functional study of associated SNPs (effect on mRNA expression levels) • Epigenetic dysregulation (IRF5 – CD40L) • Largely involved in clinical trials on pSS (and other autoimmune disease: lupus - RA) • TNF blockers in pSS (TRIPSS trial) • Hydroxychloroquine in pSS (Phase III trial) • Belimumab in pSS (Phase II trial)

  31. Results in the lab BAFF is a good link between innate and adaptative immunity • BAFF is increased in serum of patients with Sjögren’s syndrome, correlated with autoantibody level • BAFF is present in the target organ of autoimmunity • There is an Interferon signature in salivary glands of patients with Sjögren’s syndrome • BAFF is secreted by resident salivary epithelial cells after • IFN stimulation • viral infection

  32. Results in the lab - Genetics • Polymorphism of BAFF is not associated with Sjögren’s syndrome, but is associated with the serum level of the cytokine • No association ofSjögren’s syndrome with Tyk2, IFNAR-1 and IFNAR-2 polymorphisms • Association of Sjögren’s syndrome with IRF5 rs2004640 and CGGGG insdel polymorphisms of IRF5 – functional consequences on IRF5 mRNA expression – search for an epigenetic dysregulation of IRF5 • STAT4 polymorphism association with pSS with an unexpected high correlation with IFN type I induced genes

  33. IRF5 and Sjögren – rs2004640 Controls (n=154)

  34. IRF5 Promoter CGGGG in/del in Sjögren’s syndrome N=385 N=439 GRR 3R/3R vs 3R/4R or 4R/4R: P=6.6 10-6 – OR 2.00CI 95 (1.5;2.7)

  35. The promoter CGGGG in/del association is functional in Sjögren’s syndrome Réovirus infection Salivary gland Epithelial cells PBMCs Miceli-Richard, A&R, 2009,

  36. Correlations with other IFN type I induced genes B A Miceli-Richard, A&R, 2009

  37. Epigeneticregulation of IRF5 ? • Working hypothesis: • The promoter of IRF5 is located within a CpG island •  DNAmethylation abnormalities in SS ? (as demonstrated in lupus) •  interaction between genetic polymorphism and epigenetic dysregulation ? CpG island From http://www.ncbi.nlm.nih.gov/mapview

  38. Epigeneticdysregulation • No significant methylation of IRF5 CGGGG repeat region in various cell types: • B cells • T cells • Salivary gland epithelial cells • Same IRF5 methylation profiles between patients and controls • IRF5 demethylation do not account for IRF5 up-regulation in pSS patients Gestermann N et al, manuscript in preparation

  39. STAT4: association study in pSS Gestermann et al, Genes Immun 2010

  40. STAT4: functional study Gestermann et al, Genes Immun 2010

  41. STAT4 and type I IFN induced genes Gestermann et al, Genes Immun 2010

  42. Association studies • Two French cohorts of pSS patients: • Bicêtre cohort: • 244 pSS patients referred for sicca symptoms to the Rheumatology Department of Bicêtre Hospital and. • ASSESS cohort: • 413 patients with pSS who are going to be followed for 5 years in order to identify predictive factors for lymphomas and other systemic complications • All patients fulfil the European-American Consensus Group (EACG) criteria for pSS • Two cohorts of European (French) ancestry controls (N=473)

  43. Future prospects • Objective: identify new therapeutic targets in pSS • Association study on pSS candidate gene with functional study of associated genes • Participation in the GWAS approaches in collaboration with K. Moser (SGENE project) • Epigenetic studies with whole genome methylation profile studies (collaboration with Jorg Tost – Genopole Evry - France)

  44. Lindsey Criswell, MD, MPHUniversity of California, San Francisco EPIGENETICS AND OTHER INFLUENCES ON GENE EXPRESSION

  45. Proportion of heritability explained by established loci

  46. What explains the missing heritability? Large # variants with small effects Rare variants with larger effects Structural variants copy number variants (CNVs) Epigenetic modifications DNA methylation, histone modification Gene-gene and gene-environment interactions Imprecise phenotyping & disease heterogeneity

  47. “The new science of epigenetics reveals how the choices you make can change your genes – and those of your kids”

  48. CH3 + CH3 5’ 3’ 5’ 3’ C G C G C C G C G C Unmethylated- gene expressed Methylated- gene silenced Epigenetics: inherited changes in gene expression caused by mechanisms other than DNA base sequence changes Qui, Nature 2006

  49. DNA methylation in action Is inherited, but is dynamic Thin, no DM obese, +DM obese, +DM // // Demethylating agent (e.g. BPA) High methyl diet • In humans • implicated in cancer • Angelman/Prader-Willi • X-inactivation Jirtle, Sciencewatch.com 2009 (Waterland, Mol Cell Bio 2003)

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