Genetics of COPD Prof. Ian P Hall

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1 Genetics of COPD 1 Prof. Ian P. Hall Dean, Faculty of Medicine and Health Sciences The University of Nottingham Medical School Ian.Hall@nottingham.ac.uk Chronic obstructive pulmonary disease (COPD) 900,000 diagnosed patients in the UK 30,000 deaths/year in the UK 500m/year direct NHS costs 1.1 million adults in the USA (00) 7,000 hospital admissions in USA 10,970 deaths in USA th leading cause of death Will rise in importance due to increased prevalence in developing world Definition of COPD Irreversible airflow obstruction GOLD criteria for severity Histopathological changes: emphysema or chronic bronchitis (small-medium airway obstruction with remodelling) 3 1

2 Is COPD genetically determined? Heritability of FEV1 ~0% Family/twin based studies Alpha 1 antitrypsin deficiency Phenotypes of COPD Emphysema vs. airways disease Potential for additional sub-phenotypes to be defined HRCT patterns of disease Exacerbation frequency (not well correlated with lung function) Revised GOLD criteria 5 Current risk prediction for COPD Smoking history Environmental exposures (e.g., wood smoke exposure, cadmium) Family history Alpha 1 antitrypsin deficiency (~1% in UK of all cases of COPD) Some cases of asthma develop an element of irreversible airflow obstruction

3 How well does smoking behaviour predict lung function in alpha 1 antitrypsin deficiency? 7 Relation between forced expiratory volume in 1 second (FEV1) and pack-years of cigarette smoking in 31 smokers with the protease inhibitor ZZ genotype, AAT Genetic Modifier Study, FEV 1, % Predicted Pack-Years 8Castaldi et al., Am. J. Epidemiol. 170: 05-13, 009; doi:.93/aje/kwp1 Nottingham smokers 9 3

4 Conclusions ZZ alpha 1 antitrypsin deficiency associated with enhanced lung function decline Predictive models explain at best 50% of variance in FEV1 decline Value of genetics Define new treatment targets Define genetic factors which predict disease sub-phenotypes, and/or severity Define genetic factors which can be used to predict treatment response (pharmacogenetics) Alter concepts of disease pathogenesis 11 Approaches to COPD genetics Family based approaches Linkage studies Difficult to perform due to age of onset of disease, availability of family members with DNA and clear phenotype information Candidate gene studies Case control approaches Difficult to match for smoking exposure Genome wide association studies 1 COPD cases vs. controls Lung function using FEV1, FEV1/FVC or FVC as end points Sub-phenotypes within COPD Severity (e.g., GOLD) Emphysema (HRCT) Exacerbations and other end points

5 Genome wide association studies Association studies covering complete genome, typically >500k single nucleotide polymorphisms (SNPs) Different platforms available from main manufacturers Most based on common SNPs, but recent platforms with rare or intermediate frequency variants May not tag other variants well, such as copy number variants (CNVs) 13 Genomic variation of likely relevance to disease: Sequence Structural 1 Manolio et al., Nature 1, ,

6 Meta-analysis of GWAS on lung function 1 FEV1 GSTCD HHIP -log(p-value) 8 TNS1 HTR Chromosome -log(p-value) 1 8 HHIP AGER FEV1/FVC THSD Chromosome Repapi et al., Nature Genetics 0 Lung function meta-analysis across SpiroMeta & CHARGE consortia STAGE 1 (Genome-wide association studies) n=8,01 STAGE (follow up of SNPs only) n=,737 STAGE (follow up of up to 3 SNPs) n=1,7 17 SpiroMeta-CHARGE GWAS -log(p-value) MECOM FEV 1 Manhattan plot CDC13 ZKSCAN3 Corf11 -log(p-value) Chromosome 0 18 FEV 1/FVC Manhattan plot 1 1 HDAC CCDC38 CFDP1 MFAP NCR3 CDC13 MMP15 1 TGFB RARB SPATA9 KCNE ARMC LRP Chromosome Soler Artigas et al., Nature Genetics 011, online first Sept 5th

7 Associations with COPD Effect sizes FEV1 and FEV1/FVC units COPD odds ratio 0 1 rs5715 rs515 rs1508 rs rs07000 rs A allele A allele T allele A allele C allele A allele (Freq 0.39) (Freq 0.9) (Freq 0.0) (Freq 0.59) (Freq 0.9) (Freq 0.15) TNS1 GSTCD HHIP HTR AGER THSD 19 Soler Artigas et al., Am J Respir Crit Care Med., 011 Key genes associated with lung function and COPD (bold)*, and the 15q5 locus associated with smoking and COPD 0 COPD Lung function MFAP Near TGFB HDAC RARB MECOM SPATA9 ARMC NCR3 IREB/ CHRNA3/ CHRNA5/ CHRNB Smoking SpiroMeta - CHARGE consortium (n=8,01) ZKSCAN3 CDC13 Corf11 LRP1 CCDC38 MMP15 CFDP1 KCNE SpiroMeta consortium (n=0,88) TNS1 THSD GSTCD FHS* HTR (n=7,91) AGER HHIP CHARGE consortium (n=0,890) FAM13A ADAM19 GPR1 PITCH1 * Soler Artigas et al., Am J Respir Crit Care Med., 011 Castaldi et al., Am J Respir Cell Mol Biol., Genetic architecture of lung function Of the associations at loci: None driven by tobacco addiction All independent of smoking Up to 7.5% of variance in FEV1/FVC ~19/ loci probably affect lung development Overlap with loci for other traits: Height: Near HHIP: height ; FEV1/FVC GPR1: height ; FEV1/FVC MFAP: height ; FEV1/FVC Lung cancer: NCR3 and ZKSCAN3 (reduced lung function and increased risk of lung cancer) Myocardial infarction: KCNE 7

8 Key question How do we prioritise functional studies given the expanding list of genes involved in lung function determination? Pragmatic? Based on effect size? Based on knowledge of gene role? Based on ability to target? 3 Strategy for functional studies Define key genetic variants Re-sequencing in extreme populations/00 genomes Define functional role of wild type gene Mouse models (knock out or overexpression) Overexpression in relevant human cell systems/sirna Define functional effects of genetic variants Recombinant expression, or better studies in ex vivo/in vivo tissue from individuals of known genotype eqtl type approaches Examine genotype/phenotype correlations Large relevant populations Expression profiling 8

9 RAGE receptor for advanced glycation end products (p1.3) Also known as AGER Member of Ig superfamily Many splice variants (1+) Potential involvement in: Cell proliferation Apoptosis Migration Invasion Wound healing Cell adherence 5 HMGB1 S0 s AGE s Zhang, et al., 009 Riehl et al., 009 SNPs in RAGE are associated with lung function RAGE gene at p1 in MHC Key variant codes for a Gly/Ser substitution in exon 3 Regional association plot showing association of RAGE with FEV1/FVC (p = 3.07x -15 ) RAGE in Lung RAGE staining is increased in COPD lung x x0 x 7 Miller et al., unpublished x0 Wu et al., Resp Med. 5: 39-33, 011 9

10 Summary: RAGE Top GWAS hit codes for a coding region variant (Gly/Ser exon 3) RAGE expression in lung correlates with COPD Association between rs07000 and lung function Association between srage (serum) and rs07000 Does rs07000 alter balance of RAGE/sRAGE levels? 8 Summary Genetic factors underlie the risk of developing COPD Alpha 1 antitrypsin deficiency is a rare but important cause of early onset emphysema in smokers Genome wide association studies of lung function have recently identified a large number of genes which contribute to FEV1 and/or FEV1/FVC ratio Many of these genes may also contribute to risk of developing COPD Functional studies to define the mechanisms underlying these associations with COPD are at an early stage Genetic information could potentially be used in risk prediction and may also define novel therapeutic targets 9 Acknowledgements Therapeutics and Molecular Medicine team at University of Nottingham Martin Tobin and colleagues 30

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