The Genetic Epidemiology of Rheumatoid Arthritis. Lindsey A. Criswell AURA meeting, 2016

Transcription

1 The Genetic Epidemiology of Rheumatoid Arthritis Lindsey A. Criswell AURA meeting, 2016

2 Overview Recent successes in gene identification genome wide association studies (GWAS) clues to etiologic pathways Cumulative effects of genetic risk loci Clinical utility of genetic information identification of therapeutic targets Contribution of rare genetic variants Importance of epigenetic factors molecular link to environmental risk

3 Autoimmune Diseases are Genetically Complex

4 Population Frequencies & Familial Clustering of Human Autoimmune Diseases Disease Population Frequency (%) Sibling Risk (%) Psoriasis RA Type 1 diabetes Graves Multiple sclerosis SLE λ s

5

6

7 July, 2010

8

9 NEJM, 2007 GWAS in NARAC and EIRA ~1,500 CCP+ RA cases ~1,800 controls

10 TNF anti-tnf therapy is a powerful RA treatment TRAF1 NF-κB inflammation apoptosis Heyninck and Beyaert (2005) Trends Biochem Sci

11 Nat Genet, ,022 RA cases & 7,386 controls (C-Rel: OR = 1.25, p = 3.1 x )

12 May, ,307 RA cases and 28,975 controls (7 novel RA risk loci) 67 authors, 31 institutions (6 countries), plus 2 large UK consortia

13 May 2010: >30 RA genes HLA DR4 Together explain ~35% of genetic risk of disease PADI4 PTPN22 CTLA4 TNFAIP3 STAT4 TRAF1- C5 IL2-IL21 CD40 CCL21 CD244 IL2RB TNFRSF14 PRKCQ PIP4K2C IL2RA AFF3 REL BLK TAGAP CD28 TRAF6 PTPRC FCGR2A PRDM1 CD2-CD58 7 more loci

14 Non-HLA risk loci associated with RA Annu Rev Genom Hum Genet, 2016

15 RA risk loci cumulative proportion of variance in disease risk Nat Rev Rheumatol, 2013

16 Ann Rheum Dis, non-hla risk lock, 5 HLA risk loci and gender 11,366 RA cases 15,489 healthy controls Receiver Operator Characteristic (ROC) curves to compare predictive models

17 Distribution of genetic risk score in CCP+ RA cases & controls OR (high vs. low) > 27 OR (high vs. med.) > 6 Ann Rheum Dis, 2015

18 Comparison of predictive models using ROC curve analysis Gender only vs. GRS + gender (p < ) Ann Rheum Dis, 2015

19

20 GWAS in RA: summary Highly successful strategy for identifying RA risk loci (> 100 to date) large sample sizes international collaboration decreased costs for genotyping Collectively, moderate predictive power Current challenges most risk loci not in coding region identification of causal variants difficult functional mechanisms of variants unclear

21 Genetics and RA therapies

22 RA risk loci map to the TCR, TNF and CD40 signaling pathways Nat Rev Rheum, 2013

23 May 2013 No approved drugs that inhibit CD40 signaling Define biologic consequences of CD40 risk variant Screened > 1,900 chemicals and FDA-approved drugs Identified 2 novel chemical inhibitors

24 Nature, 2014 Transethnic GWAS > 100, novel loci (101 total) Functional annotation & prioritization of risk genes Overlap of RA risk genes & drug targets (RA & other)

25 Genetic Predictors of Treatment Response Anti-TNF treatment of RA PTPRC (CD45) RA risk allele (OR 0.55, p=0.0001) 1,283 RA patients from 9 RA cohorts GWAS of 2,743 RA patients from 4 studies association with CD84, p<10-7 (etanercept, n=733) Tocilizumab treatment of RA humanized monoclonal Ab targeting IL-6 receptor GWAS of 1,683 RA patients from 6 clinical trials 8 loci, not related to IL-6 pathway or RA risk C-lectins (CLEC2D & CD69)

26 Nat Genet, 2013

27 Rare variants and familial disease

28 June, 2015

29 Case History ID: 30 yo female with history of JIA, advanced ILD Chief complaint: coughing up blood Past Medical History: JIA: joint 2 yrs (knees, ankles, hands/fingers) ILD: developed shortness of breath, diagnosed ILD Family History: sister and deceased aunt with similar history Social History: non-smoker System review: achy joints, no URI symptoms but slight fever Exam: O 2, breathing fast, coughing up scant blood

30 A rare autoimmune disorder of inflammatory arthritis & lung disease

31 4 COPA mutations in 5 families all in highly conserved WD40 domain Watkins L. et al, Nature Genetics

32 Coatomer Subunit Alpha (COPA) Subunit of Coat Protein Complex I (COPI) Enables protein transport between the Golgi and ER No disease associations reported in COPA or COPI Mutant COPA ER stress, upregulation of Th17 priming cytokines Novel molecular link between vesicular transport protein and autoimmunity Nat Rev Mol Cell Biol, 2013 Nat Genet, 2015

33 Genetics and seronegative RA

34 EIRA GWAS for RA

35 Meta-analysis of 3 European datasets (ACPA-) (Ann Rheum Dis, 2015) Meta-analysis of 3 Japanese datasets negative (Arthritis Res Ther, 2015)

36 Contribution of epigenetic factors

37 The new science of epigenetics reveals how the choices you make can change your genes and those of your kids

38 Interplay between environmental factors, genetics and epigenetics in SLE Rheum Dis Clin NA, 2014

39

40 Cellular pathways linking environmental factors with epigenetic gene control Discovery Med, 2011

41 DNA Methylation controls gene expression & is both inherited and affected by environment increased gene expression: Methylation occurs at a CpG site a cytosine (C) followed by a guanine (G) decreased gene expression images:

42 Maintenance of DNA Methylation Oxidative Stress Bruce Richardson, Lupus 2014

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

44 Methylation patterns distinguish RA/OA/normal samples in fibroblast-like synoviocytes (FLS) Genome Med, 2013

45 FLS associations replicate in CD4+ naive T cells Cell Type (direction in FLS) Number of Candidate CpGs Raw p-value* <0.05 FDR q-value <0.05 CD14+ Monocytes (Hypo) 8, CD14+ Monocytes (Hyper) 5, CD19+ B cells (Hypo) 8, CD19+ B cells (Hyper) 5, CD4+ Memory T cells (Hypo) 8, CD4+ Memory T cells (Hyper) 5, CD4+ Naive T cells (Hypo) 8, CD4+ Naive T cells (Hyper) 5,532 2,569 1,056 *1-sided Wilcoxon rank sum tests

46 FLS methylation score in CD4+ naive T cells predicts RA FLS Methylation SE GRS Predictor Area Under Curve (95% CI) Comparison: Model vs. Methylation Model FLS Methylation Score 72% (61%-83%) NA HLA-DRB1 shared epitope 66% (56%-76%) p=0.47 Genetic Risk Score (GRS) 58% (46%-71%) p=0.12

47

48 2015

49 Summary Tremendous progress defining the genetic contribution to RA, but more work needed identify causal variants & define biologic mechanisms Clues to etiologic pathways, therapeutic targets Currently defined genetic risk loci have moderate predictive power Epigenetic factors may contribute to RA risk and serve as link to the environment

50 Peter Gregersen Robert Plenge Soumya Raychaudhuri

51 NARAC meeting, 1997

52

53