In search of the genes of asthma on the island of Tristan da

Asthma. like several common Jiscases such as diabetes and atherosc lerosis. occurs in Camilies and thus probably has a complex polygen ic basis. in which environmental factors al so play a role . In trying to elucidate the genetic mechani sm, studies of comm unities characterized by a high leve l of interbreeding and a high prevalence of asthma should he hel pful. One such community has been described in the mcJical literature. the island of Tri stan da C unha. The University of Toronto Genetics of Asthma Project decided to st udy this commun ity. It sent a tea m to the island to construct a geneology, obtain a history of respiratmy and allergy symptoms by questionnaire . perform allergy skin testi ng and methocholine challenge, and obtain blood for white cell ge netic studies . The initial resu lts of thi s study are presented here. togethe r with a historical perspective on the people ll f Tristan da Cunha .

A sn, l'vl A WA S FIRST NOTED ON TH E ISL AND OF TR 1ST AN DA Cunha by a missionary, KM Barrow.who in 19!0 described the death rnim asthma or a 12-year-old g irl and told of other nonfatal cases of asthma.In 1923, a visiting ship's physician, F Wild. round asthma to he the most common di sease on the island: another .,hip'sphysician.EJ S Wooley, diagnosed asthma in 97 islanJcrs , of which 27 cases were severe.The Norwegian scicntil'ic expedition or  A la recherche des genes de l'asthme sur l'ile de Tristan da Cunha RESUME : L • as thm c. com me plusicurs affections rnura111cs tcllcs que le diabctc ct J'atherosl'l c rose, affcctc ccrtaincs famili es.Cctte patho logic a do ne probablcmcnt unc base polygeniquc cnmplexc it laqucllc s'ajo ute nt des factcurs cnv ironncmentaux .AJ'in d ' elucide r les mccani smcs gc nct iques, des eludes de communautes caracteri sces par un ni veau e leve de croi sc mcnt co nsang uin e t unc forte preva lence d ' asth me devrai cnt s ' avcrcr util es.Une communautc de cc type.J' Jie Jc Triqan da C unha. a e tc dcc ritc dans la litterature mcdi cale.Les rc sponsablcs du Geneti cs o f As thn1a Project de la Un ivers ity of Toronto o nt decide d 'cnvoycr unc equ ipc sur cctte ilc pour y etablir la gencalogic des habitants.obte nir par q ues tionnaire l'histo irc Jes sympt6111cs rcspiratoircs ct des syrnptumcs d'allcrgic.pratiquer des tests de provocatio n ~ la methacho linc c t des tests cutancs d 'allcrg ie.c t ob teni r des cc hantillons sangu in s pour l' c tudc gcncti4u c des lcu cocytes.Les prem iers resu lt ats de cc ttc c tudc sont prcscnt cs c t sont acco mpag ncs d'un e perspective hi storiquc sur la population de T ristan da Cu nha.claimed to have convincing evidence that three ot'thc ori ginal 15 ancestors suffered from asthma.
As a result of the volcanic eruption in 1961, thl' entire populatio n of Trista n da Cunha was e vacuated to Eng land where they remai ned for almost two years.During that time they were subjected to 66 studies sponsored by the T ri stan da Cunha Working Party of th e Medical Research Cou nc il.Virtu a lly every aspect or thei r health.anthropo logy, .,ucitil- ogy , psychology.Jietary habits and even tl1L•ir pel'ltliar English Jialect were investigated.Asthma prevalence was one or the studies conJuctcJ by Citron and Pepys ( I ), who found that about half llf the islanders gave a history of asthma, with wheezing hearJ in 29c1co of the adults and 12 % of the children.Mantle and Pepys C2). in a subsequent study dnne on the isla nd IO years after the islanJers returned.found that 32% of the islanders demonstrated objective evidence of asthma over the 16-month study period.
Some years ago the Uni versit y of Toronto Genetic, of Asthma Project group decided to study the com mu nity of Tri stan da Cunha.The init ial contact was made on February 24.1992 but it was not until March 17. 1993 that the Island Council approved the stuJy.Before Jescribing ho w the project was done. it is lilting to review briefly till' islanJ's geography.history and pertinent events relateJ to the study.

THE PAST AND THE PRESENT
Tristan Ja Cu nha is an island situated in the South At lantic Ocean roughly half way between Cape Town and Buenos Aires.It is roughly circular and covers an area of 98 kn/, risi ng steeply from the sea to the 2060 m peak that revea ls the caldera of the ori ginal vo lcano.T he island emerged from the mid-Atlantic riJge.which L'Xtend s northwarJs to St Helena, the Asce nsion lsl.1nds and the Azores.All the islanders live in a small community on a narrow plateau at the foot of the mountain, which they simply call the S ttlcment.The official name is Ed inburgh, so called after the visit ol HRH Prince Alfred.the first Duke of Edinb urgh , in 1867.The inhabited area is barely 8 kni2.It is Briti sh t;rritory.anJ like Ascension Island further north . is a depcnJency of St Helena.

THE PEOPLE OF TRISTAN DA CUNHA
The island's people stem from sett lers who originated from Scotland.England.Ireland .Holland, Italy , the United States, South Africa and St Helena.Although first sighted by the Portuguese ex plorer Tri , tao d;.i Cunha in 1506, Trista n's first settlers did not arrive unti I 18 I 0. In that year Jonathan Lambert of Salem.Massachusetts arri\'t.:d with three companions and shortly thereafte r declared himself Empero r of Tristan da Cunha.His reign, however.was short-lived because there was only one survivor, Thomas Currie.remaini ng of this group when the Briti.sharrivcJ in 181 (1.
The first people to settle and raise families were th ree soldi ers who staycJ on the island when the Bri tish garri son was withdrawn in 18 17.The best known of these men was a Scot.William Glass, who is regarded as the founder of the present Tristan community.He married a woman fro m Cape Town and they had 16 children.Between 1817 and 1825 four ,hips were wrcd.cJ in Tristan waters and members of their rn~ws stayed for varying periods of time.More permanent \Cltlcrs came in 1821 and 1826 -twu En_,!lishmen , Cotton and Swain.
An important landmark in the history of the people or Tristan occurrcJ in 1827 when a party of IO people e migrated from St Helena to Tristan -li ve women.one of them with four chi ldren.and a single man.The population was sudde nly increased to 24 people -seven men.six women and I I children .hvc of the islanders married women fro m St Helena.Apparently three of these women from St Helena (two sisters, one of whom had a daughter) introduced asthrna to the island.Te n years later.another shipwreck occurred and three of the survirnrs, Green from Holland.Mille r from Denmark, and Daley from the United States, deciJed to sett le and marry into island famili es.Pete r Green became the leader of the com mun ity on the death of William Gla.ss.The next important event was yet another shipwreck in 1892, which res ulted in two Itali ans, Lavarello and Re petto, settling on Tristan.After 1892 many people came and went but in 1908 a new population of settlers appeared when three Irish women.who had married Tri stanians in Cape Town, returned with their families to settle on the island.Since then the only new surname to appear on the island is Patterson .an Englishman who married a Tristanian woman.They returned with two daughters to settle on the island in 1986.

MAJOR EVENTS
The island was relatively prosperous betwee n l 816 and 1885 , with frequent visits by wha lers and several shipwrecks.Duri ng these years there were 17 ships wrecked in Trista n waters.Sh ips bou nd for Ind ia and the Far East L'alled in for fre sh produ ce and watL'.r. which were u. ually bartered for rlour, sugar.te:1.tob:1cco and clothing.Educat ion for the young was a constant problem -only two missionaries (teachers) arrived and spent a kw years on the island during thi s period.
The firs t of three major events that conditioned li fe on Tri sta n happened in 1885.At this time the population was 107.In seeking to barter with a passing ship.an island boat with a crew of 15 men was lost : they included 12 marTi ed and three single men.The di saste r left only four el de rly married rnu ples: the rest were women anJ children on the island .By 1890 some 34 of them had migrated to South Africa.The inevitable question arose -coul d a co mmun ity of 64 people survive on the island?This dilemma haunted the islanders W, ,/colll<' si g ll In//,,• " / .011<'/il'S// 11ulll/" and th e British go vcrnmrnl t"ur the next 15 years .It came to a head in 1904.A pnirosal was made to tra nsfer the w hole purulation to C ape Co lony.provided that all the is lande rs agreed.Of the re main ing I (1 f'amilies.se ven voted in favo ur or relocating and IO vu tcd in favour uf rL'maining .so the oiler was withdra w n.
The second e vent occurred Juring World W a r II.A naval stat ion was established in 1942 a nd the re newed inte rest in the island resul ted in a fi shi ng survey expcuition to study the feasibility of establ ishing a fi sh ing and canning ind ustry.It ren:ived a favo urabl e re port and by 1949 a cann ing factory had been bui lt -it has since bee n the main source of income for the islanders.The men engage in l'i.. hing for cray fish or rock lobster while the wome n and older me n c lea n and pac k the catch at the factory.There arc two fishing traw le rs owneu by the factory .wh ich bring reg ular supplies from C ape Town.Ot her parts o f the na va l station became a hospital and a school.'With all these dcvelupments the Briti sh governme nt appointed an administrator in 1950 w ith overall authority over the island.Doctors.te achers.ag ricul tural and de velopme nt officers arc appointed regularly a nd sent fro m Eng land tu the i.•d:md.Hmvever.local politics are the respo nsi bility of th e Is land Council.which is ckctcd hy th e isl ande rs along with the Head or the Council.the Head man .for a term of th ree years.
The third event was a more shatteri ng experie nce for the islanders.During August 1961 piccl's uf roc k broke from till' mounta inside hl'11ind the Settkrm' nt and earth tremors devd -(1 ped.By Octobl'r a wide fi ssure had opened near the base or thl' lllountain just to the east of the cottages: the heat a nd the smell emerg ing threatened volc anic acti vi ty.Eve ryo ne was evacuated first to the local fiel ds to the west.known as the Potato Patches, and then to Ni gh tinga le Is land 40 km a way .Fro m there they sailed fur C ape Town.As they passed Tristan.they could see the smoke.cinders and lava gushing f'rom lire now active volcano clevdoping al the side of the mountain .T he factory o n the beach was compl etely engulfed, but (inly one cottage was des troyed.From ape Town the islanders were evacuated to Eng land where the y we re accommodated near Southampton _ A rter one year in England most or 20 the islan ders voted to return to Tristan al'tl'r it had been inspected and re ported to be safe.A new fa c tory and harbo ur were built.and since the n the fishin g industry has prospered.Though dee ply upsetti ng. the e vacuati o n led to some benefits fo r th e islanders.The fo rced stay in England introduced th e m to a diffe re nt life sty le.T heir homes we re renovated .and many or the for merly thatched roo t's were rep laced with c orrugated shee ting: run ning water was provided.as was elect ricity with the completion of the factory.

A TOUR OF THE ISLAND
The. mo untain towers above the harbour.and the grayblack .cindery mass o f the volcano wit h its ridge of so liclificJ lava lies to the.cast of th e Settlement.Four kilomet res to the west are the Pot ato Patc hes, whe re eac h o f the 90 fami lic~ rnltivat es the ann ual q1ppl y of potatoes.Scatte red about the Settlemen t and the lowe r hillsides arc sheep and cattle -cach fa m il y is allowed lo sloL•k only nine sheep and two cows.dUL' lo the lim ited grazing la nd .T he school.hu i It in I 975. is sta lled hy the isla nders and provides the chi ldren• s education up to th e age or 15 years .A m useum and cra rt shor di sp lays a his tory of the isla nde rs a nJ has woo le n goods and hanclicra l'l work on sa le.Nearby is the post o ffice w ith a valuable assortmen t of stam ps and first Jay covers: th is provides ano the r source or inco me for the island .The factory.just abo ve till' harbour_ gives employment to many of the isla nders.The prod ucts a rc packed and froze n for sh ip men t to C ape Tow n and ultimate ly the market s o r f'rance.the Un ited S tales a nd Japan .
The ad min is trat ion build ing houses the adrninistrato r•s office.the tre asury.the police stati o n and a video library.It contain., the council chamber -every three years a counc il or eigh t islande rs is elected to adv ise the admin is trator on the maJ..i ng o f by-laws and olh<.:rmatte rs.
Furthe r up the same road is th e hos pital.It was bu ilt in 1972 and i. called the Camng li Hospita l -Camogl i is the sca\ide village neru• Genoa in Italy from wh ich the two shipwrecked Italians originated.T here is a residen t doctor.two nurses a nd occasiona l visits fro m a den ti st and a n optician.
The re arc two ch urc hes -St Ma ry the V irg in .which serves the largest g roup.the Ang li cans, and the tiny chu rch or St Jose ph 's serv ing the smal l Ro man C atholic community.St l\.'la1-y' sis proud to have rL'CeivcJ the first chu rc h orga n from Q ueen Mary .wife or George V; its second and third organ were g iven by Queen E lizabeth II.
T he vill age hal l. which was opened hy Prince Philip in i ')5 7. is the social centre for dances and ga mes: a separate part fo rms the vi llagc pu b.An in teresting construction beh ind the hall is the gong.a gas cylinder with the bottrn11 removed.
The go ng is sounded to announce special eve nt s to the island • crs such as a fishin g day or the clistribut irn1 uf mail.The co m me rcial a nd indu st rial area is centred on and around the site of the former nava l ,talion .A su pe rmarke t provides a wide selection or froze n. l'an ned and some times f'rcsh foo ds tuffs as well as o ther items such as c lot hing.cosmetics, ci gare ttes .alco hol and sort drinks.The government cle pa rt111ents_ ag ric ulture.public wo rks depa rt ment and Can Respir J Vol 2 No 1 Spring 1995 ve hic le ya rd are c lose by.T he nearby radio station main ta ins a regu lar te lecomm unicat ions serv ice with the outside world via Cape Town.Radio Tristan broadcasts four days a week and tra nsmi ts the BBC Worl d Service news.The adm ini strator li ves at the Residency w here the Union Jack is hoisted each day.C lose by are fo ur government bungalows avail able to visi ting official s.
Due to the dangers of swi mming in the harbour and surrounding waters, a swimming pool was built near the village hall in I 986.Next door is Jane's Cafe -open fo r light refreshments each weekday evening.In the fi elds just below the school are three squared off cemeteries, a testament to the history of the island.
Most cottages have a vegetabl e patch and can grow cabbage, lettuce.pumpkin, tomatoes and root crops .Families keep their own hens so they are self-sufficient in eggs.Wool fro m the sheep is knitted into socks, sweaters and other articles.Many of the older women still ca.rd and spi n their own woo l, and some of the older men make model sa ilboats.
T he islanders ra rely leave the island.Some travel fo r further education or work for a peri od abroad bu t the majority ~tay on the isla nd.Presently the em igration from T ri stan is virtually nil.

LANGUAGE
The English dia lect spoken o n Tristan da Cunha is unique .The ir grammar and use o f tenses are confusing to other English speakers."W here you all was?" is their equi valent of •"Where were you all ?".They have a tendency to add a strong h in fro nt of words starti ng with vo we ls.For instance they pronounce "Al bert" as "Halbert" ." Asthma" is pronounced •'hashmere".The "isla nders" are " hi gh landers" ."Cough" is •'tiss ick", "dogs" are "dongs" and "donkeys" are "dornkeys".•'S urf" is •'sarf'."He rbert" is "Ha rbert" and ''learn ing" is "lm11ing".Also, there are some Dutch influ ences, so that "f,u•di'.means "godfather" .and " kappie" is a li ttle girl' s bonnet.The most striking Dutch in fl uence is the use of the torossive pronoun : "this is mine, that's you 'n , those are they'sn".

COMMUNICATIONS
The ma in external link with the island is Cape Town in South Africa.The crayfish company is based the re and its fish ing vesse ls call on Tristan abo ut six times a year -they have accommodations fo r a few passengers , but some space is always ke pt in reserve for urgent medica l cases from Tris tan .The RMS St He lena is the on ly regu lar passenger sh ip -it cal ls at the is la nd on route from England to Cape Town just once a year.The occas iona l cargo or naval sh ip wi ll call , but these are infrequen t and depend upon spec ial cargoes .

CLIMATE AND NATURAL HISTORY
The cli mate is temperate and oceanic with rapid weather changes, a wide temperat ure ra nge of 4°C to 24°C and frequent rain averag ing 165 c m a yea r.T he peak of the island, the original volcanic cone. is u!'tcn covered with snow , but the settlement pla teau is free o f frost and snow.
Can Res p1r J Vo l 2 No 1 Sprin g 1995

Asthma on the island of Tristan da Cunha
The seas around the isla nd are teem ing with fi sh ranging from the common five fin gers and crayfish to mackerel.snoek and steambras.A number of bi rds and mammals arc full y protected, including the Trista n thrush, island cock, the wanderi ng albatross.and various spec ies o f sea ls and the southern right whale.In di fferent parts of the island va rious kinds of penguins have estab lished rookeries.Seals abound in the seas and can be seen lounging on the rocks.O n the upper slopes of the island yell ow-no eel al batross nest in large numbers.
T here are spec tacu lar views from the top o f the first crest of hill s -a pl ateau some 600 m high where sheep graze on the rich vegetat ion.It can be reac hed after a stiff hill cl imb o f about one hour; climbing from there to the peak of the island takes another few hours.Due to the changeable weather conditions all such climbs must have an islander as a gui de.

THE STUDY
Our objectives were to construct a genea logy, obtain a history of respiratory and allergy symptoms by questionnaire, perform allergy kin te ting and methacho line challenge and obtain blood fo r white cell genet ic stud ies.Before our arriva l, the med ical officer on the island, Dr Peter R Sandell , obtai ned a detailed respiratory ymptom quest ionnaire and conducted all ergen kin prick tests to 15 common allerge ns on virt uall y all islanders o lder than five years of age.T he total population of the island in October l 993 was 30 I; data were obtained from 282 subjects.
The members o f the Un iversity o f Toronto Genet ics o f Asthma Proj ect who went to the is land were me and M rs Patricia A McC lean, research assoc iate of the T rihospital Pulmonary Function Laboratories o f the Un ivers ity o r Toron to.We carri ed with us equi pment to perfo rm methacholi ne cha llenges by the Cockcroft method.usi ng a computerized bronchial chal lenge system.We also took with us all the materials req ui red fo r blood sa mp ling and storage.
We left Toronto on September 20, 1993.arriving in Cape Tow n on September 22.We departed for Tristan da C unha on September 23 aboard the SA Agul has, a South African oceanographic research vessel I 00 m long.with a crew of 42.The trip typically takes one week between Cape Town and Tristan da C unha.This part of the Sout h At lantic Ocean is cal led the Roari ng Forties due to the strong winds an d very rough seas.The ship rolled 20 degrees for most of the journey and on the fourth day we experienced a ro ll o f 45 degrees.One person who was o n the deck was prope lled towa rds a low rai ling, unable to stand on the slop ing dec k.If' he had not fal len flat on hi s back he sure ly wou ld have been swept overboard .At that time cabins were flooded .furniture was damaged and it wa~ amazing that no one was injured.The captain late r sa id , " We like to make l'ach voyage memorab le'"• In the early morning of Septem ber 29 we awokL' l1 l the spectacular sight of a mountai n risi ng out of the ocean.The disemba rkat ion from the SA Agu lhas was accomplished by hoi sti ng the passengers in a c rate down to a small motor boat tossing in the waves be low.Tristan's shall ow harbour cannot accommodate large vessels.Once we arrived and tha nk fully ki ssed the land, we were welcomed by the sm il ing islanders a nd a big s ign saying, " Welcome to the Loneliest Isla nd in the W orld". T his is defini tely not an exaggerated claim.We and the other passe ngers who came to work o n the isla nd for a pe riod of about o ne month.be fo re the SA Agulhas was schedu led to ret urn .we r lodged in th ree g uest hou ses.Eac h g uest house was equipped with three bedrooms, a common room, washroom and kitchen.We we re prov ided with a crate of island potatoes.a daily supp ly of fresh (still w arm) milk and one small space heate r to hudd le around \vhilc the wind howled cease lessly outs ide.From then on it was work for I 0 hours a Jay.six Jays a wee k, doing mcthacholine or bronchodil ator challenges using two sets of equ ipment.ThL' cooperation and the level of e nthusiasm or the islanders was overwhelm ing.
The SA J\gulhas was scheduled to pick us up !'mm Tristan <la C unha to rL'turn to Cape Town on October 22.In order lP min im ize the transportation timL' rm the blooJ, which had to bL' kept at 4°C and could he reliabl y stored for no more tha n 12 days, we sampled all the subjcL'ts on one day (Octobe r 20 ).
The following day we transported all the blood samples to a re frigerato r on the S A Agulhas using the ship's he licopter beca use of rough sea conditions.That even ing we hosted a large celebration that was attended by virtually the entire community.We danced at the Prince Phil ip Hall until 3 /\'vi the ne xt day (October 22) whe n we left Tristan da Cunha.
There are many stories to tell of the time we spe nt o n the island, all of the m are extremely pleasa nt, apart from one painful expe rience I had with a kidney sto ne that started moving on the day or the blood collection.Tha nks to strong pain killers I was able to sample blood of 90 subjec ts (40 ml from each person) while Pat McC lean and Peter Sandell managed similar quotas.We an-ived in Cape Town on October 28 and finally in Toronto on October 30.By Novembe r 2. all the DNA was success fully extracted such that not one san1pk was lost.

Genealogy:
We now have virtually complete data describing the family trees , including all th e islanders and e xte nd ing to the very first settlers on the island, starting with W ill ia m Glass .The le vel ol inbreeding is so high that all the isl anders arc cou sins and on average two sihlings a re cous in s according to 50 diffe re nt pathways.
Incidence of asthma: When we rnmbinecJ the results ol ll1L' clinical 4uesti o nnaire in fo rmation with the methacholine or bronchodilator challenge resu lls we found th a t 56 subjec ts (2 l % ) had strong e vidence ol asthma, 96 subjects (35 % ) had partial or questi onable evidence of asthma, and 120 subjects ( 44o/, ) had no evidence o r asthma.T he lattL'r group, howe ve r. includes a cons iderab le numbn of young subjects who may develop as thma in the ruture.
Incidence of atopy: S kin testing showed 1h,1t nearly half of the su~jects had positive skin challenges, especia lly to house dust mites.In teresting ly. a rnnsidcrable number of the atopic individual s (approx imately 40St) we re scn~itive to cat fur extract.Howe ver.all the cats were killed about 20 years ago because or toxoplasrnosi s, and ever since there have l1L•cn no cats on the island.Some or the suhjcct s scn~iliVL' to cal ha\'L' never encounte red a cat in their li ve .

Genetic studies:
All the blood samples were rapidly processed and the le ukocyte DNA success full y ex tracted.Radi(laeti ve DN A probes having molecular seque nces that 11lap individ ual genes were sequenced w ith electrophoretic se paration followed by autoradiography: presently the chromosomes of all subjects have been mapped and linkage analysis is underway.DNA markers representing dirferent si tes ailmg the 23 chromosome pa irs an~ exa m ined for segrega tion ol the marke rs among all subjects .The statistical analys is.rcfen-ed to as linkage anal ysis, idcntilics any marker that cosegregates with the asthma phenotype (de fined as airway hypcrresponsivencss to metha holine ,1ssociatcd with a clinical his tory o f asthl1la) .Because the chromosomal position or eac h marke r is known , demonstration of cosegregat ion of a g ive n marker with the asthma phenotype allows identification of the chromosomal positio11 of a potential asth ma susceptibility gene.
W e hope that thi s unique study will have been worthwhile, and the genc(s) of asthma will be' isolated.

Spring 1995 Asthma on the island of Tristan da Cunha
Can Respir J Vol 2 No 1