GoRA. For more information on genetics and on Rheumatoid Arthritis: Genetics of Rheumatoid Arthritis. Published work referred to in the results:

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1 For more informaion on geneics and on Rheumaoid Arhriis: Published work referred o in he resuls: The geneics revoluion and he assaul on rheumaoid arhriis. A review by Michael Seldin, Crisopher Amos, Ryk Ward and Peer Gregersen published in Arhriis and Rheumaism June 1999 p1071 Genes for rheumaoid arhriis offer new insighs ino disease mechanisms: A review by Sally John, Nick Davies and Jane Worhingon in Drug Discovery Today vol2 no p337 Websies: hp:// GoRA Geneics of Rheumaoid Arhriis Issue 1 hp:// hp:// hp:// The GoRA sudy eam would like o hank you for your paricipaion Welcome o he second newsleer for paricipans in he Depression Nework, also know by he acronym DeN. Firsly, GlaxoSmihKline and Washingon Universiy School of Medicine would like o convey our warmes hanks o all paricipans of his sudy: wihou you he research ha we are doing would no have been possible. We would also like o updae you on he curren saus of he sudy and le you know wha has happened since you paricipaed. Jodie Keyworh, Rosie Le Grys, Anne Hinch, Jayne McDermo

2 Inroducion C M Y CM MY CY CMY K Welcome o he firs newsleer for paricipans in he Geneics of Rheumaoid Arhriis sudy, also know as GoRA. Firsly, GlaxoSmihKline and he Molecular Medicine/Rheumaology Deparmen a he Royal Hallamshire Hospial in Sheffield would like o convey our warmes hanks o all paricipans of his sudy; wihou your help he research ha we are doing would no have been possible. We would also like o updae you on he curren saus of he sudy and le you know wha has happened since you paricipaed. Why did we se up he GoRA Sudy? Rheumaoid arhriis (RA) affecs approximaely 1% of he populaion and is a disease of he immune sysem ha causes long erm inflammaion of he joins. RA can also cause inflammaion of he issue around he joins, as well as oher organs in he body. RA is an Auoimmune Disease. This is an illness which is caused when he body issues are misakenly aacked by he body s own immune sysem. The aim of his sudy is o beer undersand he causes of RA and o idenify some of he genes (basic unis of herediy passed from paren o offspring) ha may be involved in RA. This is because here appears o be an inheried componen o many cases of RA. Previous research sudies in Rheumaoid Arhriis (RA) have shown ha here are srong geneic risk facors linked o RA. This means ha if one or boh of your parens have RA, hen hey may pass genes o you ha may increase he chance ha you will also laer go on o develop RA. 2 For example, if one of your parens, or a sibling (one of your brohers or sisers) has RA, your risk of developing RA will be slighly higher (around a 16% chance) han someone ha does no have a family member affeced wih his illness (around a 0.8% chance). The inheriance of RA is complicaed and involves a mixure of geneic and environmenal facors. Even if you have a gene ha increases your chances of developing a disease, his sill doesn mean ha you will develop he disease for cerain. I seems ha facors you encouner in he environmen in combinaion wih your geneics migh be a rigger for developing he disease. These facors could include hings like sress, food, oher medical illnesses, as well as facors in he exernal environmen such as air polluion. Many of hese environmenal riggers are no ye known. This is why we asked you o complee a deailed quesionnaire in he GoRA sudy, which may help us research ino he effecs of he environmen on RA. In he GoRA sudy we have been comparing he genes from people who suffer from RA wih he genes from people who don, and we hope o be able idenify which genes may be associaed wih his illness. Like many common diseases, geneic sudies of RA have shown ha he genes you inheri may increase your chance ( suscepibiliy ) of developing RA, bu i does no mean ha you will definiely go on o develop he illness. This is because RA is a complicaed illness, and involves many suscepibiliy genes and a combinaion of oher environmenal facors.

3 Many of you who paricipaed in he GoRA sudy kindly donaed blood and urine. We are working o analyse hese samples o look for special (chemical/proein) markers in he body. These so-called biomarkers may give us los of useful informaion, including he level of inflammaion in he body, how severe he disease is and even help us o predic how RA may progress in he fuure. This research helps us o undersand how he disease is working and helps us look for beer ways of reaing RA paiens in he fuure. Your genes will always remain he same as you inheri hese from your parens, however hese biomarkers may change over a ime as he RA disease changes (ges beer or ges worse). We asked approximaely 260 RA paiens o come back 1 year afer he firs assessmen o see how heir disease has changed and o measure heir bio-markers. The hand and fee X-Rays ha were aken if you are an RA paien will also help researchers undersand he changes in your disease. Wha has been analysed o dae? Blood samples from 497 RA paiens and 495 healhy voluneers have been analysed so far. Of he 497 RA paiens involved, 136 were males and 361 were females. This was expeced because more women suffer from RA han men (3 imes more women suffer from RA hen men). If you are an RA sufferer and paricipaed in his sudy, you would have been assessed by he sudy docor or nurse. They would have recorded los of deails abou your disease. To be eligible o paricipae you would have been diagnosed wih RA a leas 3 years before you sared he sudy. You would have been asked o give some samples and also an X-Ray would have been aken of your hands and fee. The mean age of an RA subjec enering he sudy was 61 years old. Of he 495 healhy voluneer subjecs who enered he sudy, 146 were males and 349 were females. We have ried o ask for voluneers ha are as similar as possible o he RA paiens in age and gender. If you are a healhy voluneer and paricipaed in his sudy, you would have been assessed by he sudy docor or nurse o check ha you have no medical hisory of RA and oher inflammaory arhriis. You would also have been asked o give some samples. I is imporan for his research ha he healhy voluneers are no relaed by blood o he RA sufferers. This is o make sure ha he wo groups don share he same geneic heriage. However, we have been able o enrol many husbands/wives of RA suffers because his is a marriage relaionship no a blood relaionship. We also did invie a small number of parens and siblings (brohers and sisers) of RA paiens o paricipae, because we can do some separae research looking a how genes are passed hrough families. 3

4 C M Y CM MY CY CMY K If you are a healhy voluneer and paricipaed in his sudy, you would have been assessed by he sudy docor or nurse o check ha you have no medical hisory of RA and oher inflammaory arhriis. You would also have been asked o give some samples. I is imporan for his research ha he healhy voluneers are no relaed by blood o he RA sufferers. This is o make sure ha he wo groups don share he same geneic heriage. However, we have been able o enrol many husbands/wives of RA suffers because his is a marriage relaionship no a blood relaionship. We also did invie a small number of parens and siblings (brohers and sisers) of RA paiens o paricipae, because we can do some separae research looking a how genes are passed hrough families. 4 A e g p f 4 m g I p R e c i d

5 How did we ge he resuls? A chemical called DNA (deoxyribonucleic acid) was exraced from he blood sample you gave. DNA is he geneic informaion ha makes up a gene. Genes are pieces of DNA and mos genes conain he informaion for making a specific proein. Genes are organized ino 46 chromosomes in he nucleus of he cell. The geneic maerial of an organism is called is genome. The human genome conains approximaely 25,000 genes. In our analysis, we compared your DNA wih ha of oher paricipans in his sudy. This was so we could idenify he regions of chromosomes mos likely o be linked o RA. Once hese regions are idenified, we will need o examine hese areas furher o ry and idenify genes conneced wih he disease. These are called suscepibiliy genes and are he genes which are invesigaed individually for heir involvemen in he disease. Changes in he DNA of hese genes could be he key o idenifying wha causes suscepibiliy o RA. 5

6 C M Y CM MY CY CMY K Wha are he resuls? The analysis of he resuls from he firs 497 RA subjecs and 495 conrols has been very promising. 27 new genes have been idenified ha are maybe associaed wih RA. Furher work will enable us o undersand wha his associaion means and how his migh benefi he paiens in he fuure. The analysis of he blood samples aken, has allowed us o find biomarkers which will help indicae he level of disease aciviy in RA subjecs. These biomarkers are used o map he effecs of new drugs ha are being developed for RA paiens. 6 M s i f b Y a y W h a B h O m e R f I r T b b b a h

7 Wha happens nex? The blood samples from he second group of approximaely 500 will be analysed o confirm he resuls from he firs group of subjecs analysed. Furher work is required o deermine he role of he genes idenified and how he genes are associaed wih RA. Through his undersanding of he genes associaed wih RA we he hope o develop new drugs. Of paricular ineres is confirming which genes are responsible in deermining he severiy and progression of RA. A proporion of he RA subjecs in he sudy have been followed up afer 12 monhs and hrough furher assessmen have had informaion gahered o idenify o help predic disease progression via join damage. 7

8 For more informaion on geneics and on Rheumaoid Arhriis: Published work referred o in he resuls: The geneics revoluion and he assaul on rheumaoid arhriis. A review by Michael Seldin, Crisopher Amos, Ryk Ward and Peer Gregersen published in Arhriis and Rheumaism June 1999 p1071 Genes for rheumaoid arhriis offer new insighs ino disease mechanisms: A review by Sally John, Nick Davies and Jane Worhingon in Drug Discovery Today vol2 no p337 Websies: hp:// GoRA Geneics of Rheumaoid Arhriis Issue 1 hp:// hp:// hp:// The GoRA sudy eam would like o hank you for your paricipaion Welcome o he second newsleer for paricipans in he Depression Nework, also know by he acronym DeN. Firsly, GlaxoSmihKline and Washingon Universiy School of Medicine would like o convey our warmes hanks o all paricipans of his sudy: wihou you he research ha we are doing would no have been possible. We would also like o updae you on he curren saus of he sudy and le you know wha has happened since you paricipaed. Jodie Keyworh, Rosie Le Grys, Anne Hinch, Jayne McDermo