J Med Genet: first published as 10.1136/jmg.20.1.37 on 1 February 1983. Downloaded from

Jouirnal ofMedical Genetics, 1983, 20, 37-40

Acetylator phenotypes in Papua

R J A PENKETH*, S F A GIBNEYt, G T NURSEt, AND D A HOPKINSON From * University College Hospital Medical School, London; tPapua New Guinea Institute ofMedical Research; and + MRC Human Biochemical Genetics Unit, London.

SUMMARY Acetylator phenotypes have been determined in 139 unrelated subjects from the hitherto untested populations of , and their relevance to current antituberculous isoniazid chemotherapy is discussed.

Several drugs, including isonicotinyl hydrazide Materials and methods (isoniazid), diamino diphenyl sulphone (dapsone), hydralazine, and some sulphonamides, are meta- Subjects were drawn from hospital wards and from bolised by the liver enzyme acetyl transferase. There various educational institutions where exact con- is individual variation in the rate at which acetylation formity with the protocol of the test could be occurs and two phenotypes, rapid and slow, are guaranteed. The largest single geographical sample usually recognised, which show an autosomal came from the Southern Highlands Province and dominant mode of inheritance. The rapid phenotype consisted of 33 subjects tested in the provincial includes subjects homozygous and heterozygous for capital Mendi. There were 47 subjects from the other copyright. an allele which determines a rapid rate ofacetylation. Highland provinces, Enga, Western Highlands, The slow phenotype comprises subjects homozygous Chimbu, and Eastern Highlands, collected mainly in for an allele which determines slow acetylation of Goroka, and 32 from the coastal provinces, East and these drugs. Populations vary in the frequency of West Sepik, Madang, Morobe, Central, Gulf, and rapid and slow acetylators; for instance, the incidence Western. Of those from the island provinces three of the slow type may be as low as 5 to 10% in came from Manus, two from , nine

Japanese and Eskimos but up to about 60% in from East and West New Britian, and 11 from the http://jmg.bmj.com/ some European, African, and Asiatic Indian North Solomons. These are shown in fig. 1. populations.1-3 Tests were carried out as recommended by Evans8 This paper describes the investigation of the using blood and urine samples. Subjects took acetylator status of 139 Papua New Guineans standard doses of sulphadimidine 500 mg if they carried out during a 10-week period of laboratory weighed less than 50 kg, and 750 mg if their weight and field work. Our objective was to assess the exceeded 50 kg, after an overnight fast. Drinking population incidence of the acetylator phenotypes in was not restricted, but to ensure rapid absorption a hitherto untested population, and to evaluate the the subjects were asked not to eat for 2 hours on September 27, 2021 by guest. Protected relevance of the phenotypes in the control of following the dose. tuberculosis. The acetylator polymorphism is relevant in as much as isoniazid, in combination Results with other drugs, is the mainstay of antituberculous therapy in Papua New Guinea, as in other parts ofthe The results are shown in the table and are plotted world. graphically in fig 2 to show the clear separation Slow acetylators are more likely to develop between the slow and rapid acetylators. There is a peripheral neuropathy on prolonged treatment with striking contrast in the incidence of acetylator isoniazid,4 though this is preventable by pyridoxine phenotypes between the mainland of Papua New supplementation, and rapid acetylators respond less Guinea and the North . well to a once weekly antituberculous regimen of The slow acetylator allele was identified with a isoniazid and companion drugs.1 5-7 frequency of 0-798 ± SE 0-121 in the North Solomons and 0-353 ± SE 0.168 in East New Received for publication 12 May 1982. Britain and not at all in the mainland population. 37 J Med Genet: first published as 10.1136/jmg.20.1.37 on 1 February 1983. Downloaded from

38 R J A Penketh, S F A Gibney, G T Nurse, and D A Hopkinson TABLE Acetylator phenotypes of 139 Papua New Guineansfrom six different geographical areas. Protvince No ofsubjects Rapi(t acetylotors Slow acetylators PloJsni?a Urine Plasnma Urine

Highland Provinces 83 72 7 (80) 88 9 (81) - Coastal Provinces 31 70.4 (29) 87.9 (30) - - Nlanus Island 3 75-1 (3) 89 0 (3) - New Ireland 2 74 - 2 (2) 83 .6 (2) - - 9 67-4 (8) 86.6 (8) 15.0 (1) 59.7 (1) North Solomons I1 61.3 (4) 83.2 (4) 21*7 (7) 63.5 (7) Results expressed as mean percentage sulphadimidine acetylated in plasma or urine. Number of samples tested given in parentheses. Not all subjects were able to provide both a plasnia and a urine sample and such cases were characterised on the basis of one result.

PACIFIC OCEAN Manus g.7o' " .d

0O0 'a -6~~~~ NORTH SOLOMONS PROVINCE

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SOLOMON ISLANDS http://jmg.bmj.com/

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FIG 1 Geographical regionis ofPapua Newv Guinea from which specimens were collected. on September 27, 2021 by guest. Protected

However these estimates are based on relatively and it has been demonstrated that a good cure rate small population sample sizes, particularly in can be obtained in subjects of the rapid acetylator East New Britain. phenotype receiving twice weekly isoniazid and companion drugs. However, subjects of the slow Discussion acetylator phenotype could be maintained on once weekly dosage regimens to obtain a similar cure Failure of antituberculous chemotherapy during the rate. Thus, in the communities where the health care maintenance phase of treatment may be attributed to system is favourable and both phenotypes are lack of supervision and patient motivation. In common, the acetylator status of each patient could principle, the problems may be overcome by super- be evaluated before the start of a supervised inter- vised intermittent therapy with isoniazid and mittent treatment regimen, as has been pioneered in combinations of other antituberculous drugs. Such urban communities in Czechoslovakia.7 regimens have been evaluated in several centres PapuLa New Guinea is fortunate to have a health J Med Genet: first published as 10.1136/jmg.20.1.37 on 1 February 1983. Downloaded from

Acetylator phenotypes in Paplua New Guiniea 39 supply being collected from an aid post every 4 1001 (a) weeks, but this is avoided wherever possible to O 90 - ensure maximum supervision.9 t We found only the rapid acetylator phenotype on 0 the mainland of Papua New Guinea and the inter- a 80- 1- -5. mittent twice weekly isoniazid-streptomycin main- a) tenance regimen seems appropriate here. In New 70- .- 0 Britain and the , however, a 'a .c once weekly isoniazid-streptomycin maintenance D nIi 0 *a bU I 0 0 regimen could be employed. Our results suggest that 0 the slow acetylator phenotype could occur in as 50- many as half the patients. The acetylator phenotype of each patient could easily be determined during the initial intensive therapy period in hospital, since 20 - (b) coincident isoniazid does not affect the results of the sulphadimidine test. The rapid acetylators could then be allocated to the twice weekly and slow acetylators the once weekly isoniazid-streptomycin main- a)- tenance regimen. 10- The striking difference in the slow acetylator gene -5 frequency between the people of the mainland of z Papua New Guinea and the North Solomon Islanders (coupled with the unique physical appear- ance and colour of the latter) can be seen as further *1 AU. evidence of the individuality of the North Solomon- 10 20 30 40 50 60 70 ese when compared with people from other provinces Plasma (°/. acetylated) of Papua New Guinea. This is supported by the copyright. FIG 2 (a) Urine andplasma values for %0 acetylated finding of an extremely high frequency (0.413) of sulphadimidine in 139 subjectsfrom Papua New Guinea. the phosphoglucomutase allele PGM2 in Buka, the Open circles indicate values in five subjectsfrom northernmost of the North Solomons,'0 which is the whom only urine was tested and open triangles indicate highest frequency of this allele yet found in Melan- subjects from whom only plasma was tested. esia. The discovery of the presence of the slow (b) Histogram ofplasma values of acetylated acetylator gene in the island of East New Britain sulphadimidine in the 139 subjects. provides evidence of genetic contact with the North http://jmg.bmj.com/ Solomonese. There is little other evidence of this, though it is possible that the transferrin TfDl allele care system consisting of several hospitals and could have come via East New Britain to the North several hundred aid posts each staffed by an orderly Solomons.'0 trained to recognise and treat or refer common Our investigation of the frequency of acetylator diseases. These Aid Post Orderlies are backed by phenotypes in Papua New Guinea and the neigh- regular patrols, both from the nearby hospitals and bouring island provinces was based on considerations by the Health Extension Officer responsible for the of the antituberculous therapy practised in this area on September 27, 2021 by guest. Protected area. Health Extension Officers receive a 3-year and in particular the efficacy of isoniazid in subjects training which contains most aspects of a medical of rapid phenotype. However, the recent reports of course that are directly relevant to the common associations between acetylator status and other ailments in Papua New Guinea. Thus, most rural genetic markers such as the HLA type, and the communities are within a few miles of an aid post. development of a lupus-like syndrome after medica- Following a diagnosis of tuberculosis, an 8-week tion with drugs such as procainamide,1' hydralazine, period of intensive therapy (streptomycin I g im, and isoniazid suggests that the acetylator poly- 300 mg isoniazid, 150 mg thioacetazone daily) is morphism may have Nwider pharmacological signi- started in hospital. The patients then go on to a ficance. The genetic factors involved in the maintenance regimen of twice weekly isoniazid, with manifestation of such side effects are complex and pyridoxine supplementation, and streptomycin (im) accurate identification of subjects at risk is likely to administered at an aid post. An alternative main- be a difficult practical problem. For example, the tenance regimen involves self administration of occurrence of the lupus-like syndrome seen in combined isoniazid-thioacetazone tablets daily, a hypertensive patients treated with hydralazine J Med Genet: first published as 10.1136/jmg.20.1.37 on 1 February 1983. Downloaded from 40 R J A Penketh, S FA Gibney, G TNurse, and D A Hopkinson appears to be associated with sex (female) and HLA out Papua New Guinea for their help, advice, type (DR4), as well as the acetylator type (slow).'2 accommodation, transport, etc, without which this It will be noted that the distribution of the plasma project would not have been possible. values from the rapid acetylators (fig 2) is bimodal. Subjects showing the relatively higher proportions of References acetylated sulphadimidine may represent homo- Ellard GA. Variations between individuals and popula- zygotes for the 'rapid' gene and the others with tions in the acetylation of isoniazid and its significance for slightly lower values may be heterozygotes for the treatment of pulmonary tuberculosis. Clin Pharmacol Ther 1976;19:610-23. 'rapid' and 'slow' genes. 2 Karim AKMB, Elfellah MS, Evans DAP. Human Further testing using other drugs known to be acetylator polymorphism: estimate of allele frequency in acetylated by this system would perhaps establish Libya and details of global distribution. J Med Genet the validity of this subdivision and lead to more 1981 ;18:325-30. 3 Weber WW, Hein DA. Clinical pharmacokinetics of accurate assessment of the genotype. We have isoniazid. Clin Pharmacokinet 1979 ;4:401-22. assumed that the 'rapid' and 'slow' genes identified 4 Devadatta S, Gangadharam PRJ, Andrews RH, et al. in this Papua New Guinea population are the same Peripheral neuritis due to isoniazid. Bull WHO 1960;23: as those found in other populations throughout 587-98. the world, However, it is conceivable that the 5 Tuberculosis Chemotheraphy Centre, Madras. A con- trolled comparison of a twice-weekly and three once- acetylator polymorphism is, like many other weekly regimens in the initial treatment of pulmonary genetic polymorphisms, rather heterogeneous and tuberculosis. Bull WHO 1970;43:143-206. similar phenotypes may represent a wide range of 6 Tuberculosis Chemotherapy Centre, Madras. A controlled comparison of two fully supervised once-weekly regimens diverse genotypic combinations owing to multiple in the treatment of newly diagnosed pulmonary tuber- allelism. Direct analysis of the structural gene or its culosis. Tubercle 1973;54:23-45. gene product, acetyl transferase, will probably be Fox W. The chemotherapy of pulmonary tuberculosis; a necessary to resolve this question. review. Chest 1979;76:785S. Evans DAP. An improved and simplified method of detecting the acetylator phenotype. J Med Genet 1969;6: We are grateful to staff and students of the Mendi 405-7. High School in the Southern Highlands Province, Health Extension Officer Handbook. Department ofcopyright. the Malaguna Technical College in East New Health, Port Moresby, Papua New Guinea, 1979. Britain, the University of Papua New Guinea 10 McLoughlin K, Blake NM, Hogen PF. Blood group, red cell enzyme and serum protein types in the Buka Islanders, Medical School at Port Moresby, the Goroka Papua New Guinea. Hum Hered 1982 ;32:152-9. Teachers College (UPNG) in the Eastern Highlands, Woosley RL, Drayer DE, Reidenberg MM, Neis AS, and also the Health Extension Officers Training Carr K, Oates JA. Effect of acetylator phenotype on the College at Madang rate at which procainamide induces antinuclear antibodies for their co-operation in and the lupus syndrome. N Engl J Med 1978 ;298 :1157-9. obtaining subjects for testing. We are also grateful 12 Batchelor JR, Welsh KI, Mansilla Tinoco R, et al. http://jmg.bmj.com/ to Dr G A Ellard for his advice, constructive Hydralazine-induced systemic lupus erythematosus: criticism, and encouragement throughout this influence of HLA-DR and sex on susceptibility. Lancet project. Mr Penketh received financial support 1980;i: 1107-9. from the Rodgers fund administered by the Medical Requests for reprints to Dr D A Hopkinson, Research Council, London, and also from the MRC Human Biochemical Genetics Unit, The Trustees of the Bennington Memorial Studentship, Galton Laboratory, University College London, University College London. He is also extremely Wolfson House, 4 Stephenson Way, London grateful to a considerable number of people through- NWI 2HE. on September 27, 2021 by guest. Protected