- Email: [email protected]
ACE inhibitors, cough, and genetics
patients. Sexual complications (4% in males, 8% are
rare
but must be known
in females) by patients considering
prophylactic proctocolectomy. Cancer3’ and dysplasia5 have been reported in the reservoir after ileoanal anastomosis. Dysplasia would be more frequent in patients with pouchitis and is estimated at 1 % five years after the construction of the ileal reservoir. Patients can take part in decision-making about cancer prophylaxis but they must know that prophylactic coloproctectomy is not warranted for ulcerative colitis if the recommendations of Langholz et al are followed. Stanislas Chaussade, Rosine Guimbaud, Daniel Couturier Hepatogastroenterology Service, Hôpital Cochin, 75674 Paris, France
1
Langholz E, Munkholm P, Davidsen M, Binder V. Colorectal cancer risk and mortality in ulcerative colitis. Gastroenterology 1992; 103:
2
Keighley MRB, Grobler S, Bain I. An audit of restorative proctocolectomy. Gut 1993; 34: 681-84. Puthu D, Rajan N, Rao R, Rao L, Venugopal P. Carcinoma of the rectal pouch following restorative proctocolectomy. Dis Col Rect 1992;
1444-51.
3
4
5
35: 257-60. Stem H, Walfish S, Mullen B, McLeod R, Cohen Z. Cancer in ileoanal reservoir: a new late complication? Gut 1991; 32: 167-74. Löfberg R, Liljequist L, Lindquist K, Veress B, Reinholt FP, Tribukait B. Dysplasia and DNA aneuploidy in a pelvic pouch. Dis Col Rect 1991; 34: 280-84.
38%) (table). In patients with cough, allele D frequencies were similar in cases classified dubious (0-60), plausible (0-68), and likely (0-54), and in men (0-60) and women (0-64). No trend towards an increased frequency of the I allele in patients with cough was observed, even in those in whom the adverse reaction was most likely to have been attributable to the ACE inhibitor. Two other tests of the same assocation have been reported. One prospectively studied patients selected on the basis of ACE inhibitor cough and a positive capsaicin test.S No trend towards a difference in genotype frequencies was observed but only 18 patients with cough were analysed. A positive result was obtained by Furuya et al in retrospectively selected Japanese patients, there being no DD homozygotes among the 31 patients with cough. Perhaps the I and D alleles in Japan do not bear exactly the same haplotype of the ACE gene as they do in Europe and are associated with some other difference in the expression of this gene. Another explanation could be the presence of an epistatic factor influencing ACE gene expression, differentially expressed in Japanese and European
populations. Carmen Kreft-Jais, Laurent Laforest, Alain Bonnardeaux, Cécile Dumont, Pierre-François Plouin, Xavier Jeunemaitre Department of Arterial Hypertension, Hôpital Broussais, 75674 Paris, France; and INSERM U36, Paris
1
ACE
inhibitors, cough, and genetics
SiR-The persistent dry cough observed with angiotensin-1enzyme (ACE) inhibitors may be related to the accumulation of kinins or substance P due to decreased ACE activity.1 The strong relation between the ACE liD genetic polymorphism and plasma ACE levels2 justifies the search for an association between this polymorphism and ACE inhibitor cough. Indeed, the retrospective study by Furuya et al (Feb 5, p 354) shows an association between the I allele and cough in Japanese patients with hypertension and/or chronic heart failure. We have not been able to confirm this in a retrospective analysis of French patients with hypertension. Of 75 hypertensives (mean age 53 [SD 10] years) with a
2
converting
spontaneously reported persistent dry cough, 61 were on enalapril, 8 captopril, and 6 other ACE inhibitors. The likelihood of the ACE inhibitor causing the cough was rated as dubious (29), plausible (35), likely (11) on four criterianamely, time to onset of cough, characteristics of the cough, time to disappearance (+ if 2 weeks), and effect of rechallenge (5 positive out of 9 tested). ACE genotyping3 was also done in 71 non-coughing hypertensives (47 [9] years) treated with enalapril 20 mg for 6 months and in 206 unselected hypertensives (53 [10] years) referred to our hypertension clinic but not specifically assessed for ACE inhibitor cough. Genotype frequencies in the control groups were in HardyWeinberg equilibrium and similar to those previously observed in normotensive and hypertensive whites.4 No significant difference in ACE genotypes was observed between the different groups, with a very similar frequency of DD homozygotes in patients with and without cough (40% vs
*A= 206 hypertensive controls, B=71 non-coughing hypertensive controls on enalapril,I, C= 75 patients with cough. In C the genotype numbers for II/ID/and DD were 5/13/11 for a dubious association with ACE inhibitors, 5/14/16 for a plausible one, and 2/6/3 for a likely association.
Table: ACE genotypes and alleles In patients with and without cough 740
3
Israili ZH, Hall WD.
Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy: a review of the literature and pathophysiology. Ann Intern Med 1992; 117: 234-42. Tiret L, Rigat B, Visvikis S, et al. Evidence from combined segregation and linkage analysis that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet 1992; 51: 197-205. Rigat B, Hubert C, Corvol P, Soubrier F. PCR detection of the insertion/deletion polymorphism of the angiotensin I converting enzyme gene (DCP1) dipeptidyl carboxypeptidase 1). Nucleic Acids Res 1992; 20: 1433.
4
5
Harrap SB, Davidson HR, Cornor JM, et al. The angiotensin Iconverting enzyme gene and predisposition to high blood pressure, Hypertension 1993; 21: 455-60. Yeo WW, Higgins KS, Morice AH, Jackson PR, Peack JR, Ramsay LE. Investigation of the relation between ACE gene polymorphisms and ACE inhibition cough. Br J Clin Pharmacol 1993; 35: 66P.
SiR-Furuya and colleagues’ data appear to support our suggestion1 that cough with ACE inhibitors may be related to the ACE gene polymorphism, patients of genotype II showing an excess of cough while those of DD are protected. The high frequency of the allele I in Japanese patients might predispose them genetically to a high incidence of ACE inhibitor cough. A higher incidence of cough has been reported in the Chinese,2 among whom the population prevalence of the I allele is high.3 However, our observations do not support a relation between ACE genotype and ACE inhibitor cough. We have determined the ACE genotypes of 31 hypertensive patients who had a persistent and otherwise unexplained cough whilst taking enalapril, probably being related to the drug." The ACE genotypes of these patients and of 221 local controls are shown in the table. The patients with ACE inhibitor cough showed no excess of genotype II; nor did DD protect against
*British patients with
(B+, 31) or without (B-, 221) cough; Japanese patients with (J+, 31) (J - , 71) cough. Table 1: ACE genotypes and alleles In patients with ACE Inhibitor cough and controls or without
cough. The distribution of genotypes Furuya’s Japanese patients with ACE differ significantly (p < 0-05).
in our British and inhibitor cough did
I G Chadwick, W W Yeo, K S Higgins, P R Jackson, L E Ramsay, A H Morice Section of Pharmacology and Therapeutics, Floor L, University Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
1 Yeo WW, Ramsay LE, Morice AH. ACE inhibitor cough: a genetic link? Lancet 1991; 337: 187. 2 Chan WK, Chan TYK, Luk WK, Leung VKS, Li TH, Critchley JAJH. A high incidence of cough in Chinese subjects treated with angiotensin-converting enzyme inhibitors. Eur J Clin Pharmacol 1993; 44: 299-300. 3 Lee EJD. Population kinetics of the angiotensin-converting enzyme in Chinese. Br J Clin Pharmacol 1994; 37: 212-14. 4 Yeo WW, Foster G, Ramsay LE. Prevalence of persistent cough during long term treatment with enalapril: controlled study with nifedipine. Q J Med 1991; 81: 763-70.
mimic the testosterone effect. If the macrophage is the key effector, the absence of KS in congenital immunodeficiency syndromes would no longer be perplexing. The epidemiology of AIDS-associated KS, which suggests a sexually transmitted infectious agent other than HIV, may reflect a macrophagesuppressing disease prevalent in the male homosexual cohort, rather than sexual transmission of the KS agent. Thus, the KS agent could be the ubiquitous common denominator for all four presentations of KS, which reflect these different mechanisms of macrophage dysfunction.
Kathryn A O’Connell Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
1
Nowotny A, Keler T, Pham PH, et al. Isolation of a nonendotoxic antitumor preparation from Serratia marcescens. J Biol Response Mod
2
Urban RW, Edwards BS, Segal W. Tumor-immunotherapeutic efficacy of Serratia marcescens polyribosomes. Cancer Res 1980; 40: 1501-05. McCall C, Weimer L, Baldwin S, et al. A membrane vesicle/ribosome preparation from Serratia marcescens elicits peritoneal exudate cells expressing both tumoricidal and bactericidal activity. Inflammation 1992; 16: 355-69. Coley WB. Contribution to the knowledge of sarcoma. Ann Surg 1891;
1987; 7: 296-308.
3
Resolution of Kaposi’s sarcoma SiR-Resolution of AIDS-related Kaposi’s sarcoma (KS) in a severely T-cell-deficient patient with concurrent opportunistic infections is highly unlikely. I report one such
4 5
case.
An HIV-positive homosexual male with Pneumocystis carinii pneumonia (PCP) and KS of the penis declined chemotherapy and radiation for the KS, which progressed to a large tumour mass causing functional impairment despite cryotherapy and intralesional vinblastine, which were discontinued after several months. In the three years since diagnosis, the CD4 count has declined to zero and he has been maintained on various combinations of zidovudine, stavudine, acyclovir, foscarnet, ganciclovir for cytomegalovirus (CMV) retinitis, fluconazole, rifabutin, pentamidine, clarithromycin, erythropoietin, and filgrastim. Seven months ago he had the first of three episodes of Serratia marcescens sepsis treated with ceftazidime. Examination two weeks after a 26-day course of cefotaxime for the third episode revealed no clinically evident KS, which has remained in remission (three months follow-up) despite recurrent PCP and progressing CMV retinitis. Could Serratia marcescens have initiated destruction of KS by mobilising the macrophage, a cell known to acquire tumoricidal capacity when fully activated? Various preparations derived from Serratia marcescens are reported to have antineoplastic properties/.2 and induce long-lasting tumoricidal macrophage activation in mice.3 The idea that bacterial infection can awaken defences against tumours was proposed by Coley in 1891.4 Since bacteriologically derived biological response modifiers upregulate a plethora of cytokines, some of which have been implicated in the pathophysiology of KS and AIDS, possible therapeutic application would necessitate cautious investigation. Moreover, research into the role of the macrophage in KS may reveal a unifying conceptual framework for this disease. T-cell abnormalities do not occur in classic and endemic African KS; epidemiological features implicate hormonal and genetic factors. KS in this group could reflect infection by the putative KS agent superimposed on macrophage dysfunction induced by testosterone and certain environmental factors. Indeed, macrophage dysfunction has been implicated in testosteroneassociated susceptibility to some infections in genetically defined mice.S Similarly, the hypothesised lymphatic toxicity of volcanic soil in endemic KS6 could instead reflect silicainduced macrophage depletion. Male predominance is minimal in iatrogenic KS associated with corticosteroids, which, as potent inhibitors of macrophage function,7 may
6 7
8
15: 199-220. Yamamoto Y, Saito H, Setogawa T, et al. Sex differences in host resistance to Mycobacterium marinum infection in mice. Infect Immun 1991; 59: 4089-96. Ziegler JL. Endemic Kaposi’s sarcoma in Africa and local volcanic soils. Lancet 1993; 342: 1348-51. Hibbs JB. Heterocytolysis by macrophages activated by Bacillus Calmette-Guérin: lysosome exocytosis into tumor cells. Science 1974; 184: 468-71. Beral V, Peterman TA, Berkelman RL, Jaffe HW. Kaposi’s sarcoma among persons with AIDS: a sexually transmitted infection? Lancet 1990; 335: 123-28.
Aldehyde dehydrogenase genotypes In Japanese alcoholics SIR-The inactive form of liver mitochondrial aldehyde dehydrogenase (ALDH2), encoded by the gene LDT2*//2*2 or ALDH2*2/2*2, is considered a genetic deterrent of heavy drinking and alcoholism among Asians.1,2 However, this biological effect on drinking behaviour is strongly influenced by sociocultural factors. Rapid increases in Japanese per caput alcohol consumption and alcohol-related problems in recent decades suggest modification of the suppressive effect of inactive ALDH2 on alcohol use. To examine this hypothesis, we investigated ALDH2 genotype patterns in 1300 alcoholics admitted to the National Institute on Alcoholism in three different years. The subjects were randomly selected from 1791 alcoholics admitted in 1979 (370 males, 30 females; mean [SD] age 46 [ 10] years), 1986 [366 males, 34 females; age 48 [9]), and 1992 (455 males, 45 females; age 49 [11]). All met the DSM-III-R diagnostic criteria3 for alcohol dependence or alcohol abuse. Life-time alcohol consumption based on self-reports of alcoholics with inactive ALDH2 tended to be lower than that in those with active ALDH2. However, no important difference
*p<0 001,1979 vs 1986; tp <0 025,1986 vs 1992, by chi-square test. Table : ALDH2 genotype patterns among alcoholics In three different years (%)
741
rare
but must be known
in females) by patients considering
prophylactic proctocolectomy. Cancer3’ and dysplasia5 have been reported in the reservoir after ileoanal anastomosis. Dysplasia would be more frequent in patients with pouchitis and is estimated at 1 % five years after the construction of the ileal reservoir. Patients can take part in decision-making about cancer prophylaxis but they must know that prophylactic coloproctectomy is not warranted for ulcerative colitis if the recommendations of Langholz et al are followed. Stanislas Chaussade, Rosine Guimbaud, Daniel Couturier Hepatogastroenterology Service, Hôpital Cochin, 75674 Paris, France
1
Langholz E, Munkholm P, Davidsen M, Binder V. Colorectal cancer risk and mortality in ulcerative colitis. Gastroenterology 1992; 103:
2
Keighley MRB, Grobler S, Bain I. An audit of restorative proctocolectomy. Gut 1993; 34: 681-84. Puthu D, Rajan N, Rao R, Rao L, Venugopal P. Carcinoma of the rectal pouch following restorative proctocolectomy. Dis Col Rect 1992;
1444-51.
3
4
5
35: 257-60. Stem H, Walfish S, Mullen B, McLeod R, Cohen Z. Cancer in ileoanal reservoir: a new late complication? Gut 1991; 32: 167-74. Löfberg R, Liljequist L, Lindquist K, Veress B, Reinholt FP, Tribukait B. Dysplasia and DNA aneuploidy in a pelvic pouch. Dis Col Rect 1991; 34: 280-84.
38%) (table). In patients with cough, allele D frequencies were similar in cases classified dubious (0-60), plausible (0-68), and likely (0-54), and in men (0-60) and women (0-64). No trend towards an increased frequency of the I allele in patients with cough was observed, even in those in whom the adverse reaction was most likely to have been attributable to the ACE inhibitor. Two other tests of the same assocation have been reported. One prospectively studied patients selected on the basis of ACE inhibitor cough and a positive capsaicin test.S No trend towards a difference in genotype frequencies was observed but only 18 patients with cough were analysed. A positive result was obtained by Furuya et al in retrospectively selected Japanese patients, there being no DD homozygotes among the 31 patients with cough. Perhaps the I and D alleles in Japan do not bear exactly the same haplotype of the ACE gene as they do in Europe and are associated with some other difference in the expression of this gene. Another explanation could be the presence of an epistatic factor influencing ACE gene expression, differentially expressed in Japanese and European
populations. Carmen Kreft-Jais, Laurent Laforest, Alain Bonnardeaux, Cécile Dumont, Pierre-François Plouin, Xavier Jeunemaitre Department of Arterial Hypertension, Hôpital Broussais, 75674 Paris, France; and INSERM U36, Paris
1
ACE
inhibitors, cough, and genetics
SiR-The persistent dry cough observed with angiotensin-1enzyme (ACE) inhibitors may be related to the accumulation of kinins or substance P due to decreased ACE activity.1 The strong relation between the ACE liD genetic polymorphism and plasma ACE levels2 justifies the search for an association between this polymorphism and ACE inhibitor cough. Indeed, the retrospective study by Furuya et al (Feb 5, p 354) shows an association between the I allele and cough in Japanese patients with hypertension and/or chronic heart failure. We have not been able to confirm this in a retrospective analysis of French patients with hypertension. Of 75 hypertensives (mean age 53 [SD 10] years) with a
2
converting
spontaneously reported persistent dry cough, 61 were on enalapril, 8 captopril, and 6 other ACE inhibitors. The likelihood of the ACE inhibitor causing the cough was rated as dubious (29), plausible (35), likely (11) on four criterianamely, time to onset of cough, characteristics of the cough, time to disappearance (+ if 2 weeks), and effect of rechallenge (5 positive out of 9 tested). ACE genotyping3 was also done in 71 non-coughing hypertensives (47 [9] years) treated with enalapril 20 mg for 6 months and in 206 unselected hypertensives (53 [10] years) referred to our hypertension clinic but not specifically assessed for ACE inhibitor cough. Genotype frequencies in the control groups were in HardyWeinberg equilibrium and similar to those previously observed in normotensive and hypertensive whites.4 No significant difference in ACE genotypes was observed between the different groups, with a very similar frequency of DD homozygotes in patients with and without cough (40% vs
*A= 206 hypertensive controls, B=71 non-coughing hypertensive controls on enalapril,I, C= 75 patients with cough. In C the genotype numbers for II/ID/and DD were 5/13/11 for a dubious association with ACE inhibitors, 5/14/16 for a plausible one, and 2/6/3 for a likely association.
Table: ACE genotypes and alleles In patients with and without cough 740
3
Israili ZH, Hall WD.
Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy: a review of the literature and pathophysiology. Ann Intern Med 1992; 117: 234-42. Tiret L, Rigat B, Visvikis S, et al. Evidence from combined segregation and linkage analysis that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet 1992; 51: 197-205. Rigat B, Hubert C, Corvol P, Soubrier F. PCR detection of the insertion/deletion polymorphism of the angiotensin I converting enzyme gene (DCP1) dipeptidyl carboxypeptidase 1). Nucleic Acids Res 1992; 20: 1433.
4
5
Harrap SB, Davidson HR, Cornor JM, et al. The angiotensin Iconverting enzyme gene and predisposition to high blood pressure, Hypertension 1993; 21: 455-60. Yeo WW, Higgins KS, Morice AH, Jackson PR, Peack JR, Ramsay LE. Investigation of the relation between ACE gene polymorphisms and ACE inhibition cough. Br J Clin Pharmacol 1993; 35: 66P.
SiR-Furuya and colleagues’ data appear to support our suggestion1 that cough with ACE inhibitors may be related to the ACE gene polymorphism, patients of genotype II showing an excess of cough while those of DD are protected. The high frequency of the allele I in Japanese patients might predispose them genetically to a high incidence of ACE inhibitor cough. A higher incidence of cough has been reported in the Chinese,2 among whom the population prevalence of the I allele is high.3 However, our observations do not support a relation between ACE genotype and ACE inhibitor cough. We have determined the ACE genotypes of 31 hypertensive patients who had a persistent and otherwise unexplained cough whilst taking enalapril, probably being related to the drug." The ACE genotypes of these patients and of 221 local controls are shown in the table. The patients with ACE inhibitor cough showed no excess of genotype II; nor did DD protect against
*British patients with
(B+, 31) or without (B-, 221) cough; Japanese patients with (J+, 31) (J - , 71) cough. Table 1: ACE genotypes and alleles In patients with ACE Inhibitor cough and controls or without
cough. The distribution of genotypes Furuya’s Japanese patients with ACE differ significantly (p < 0-05).
in our British and inhibitor cough did
I G Chadwick, W W Yeo, K S Higgins, P R Jackson, L E Ramsay, A H Morice Section of Pharmacology and Therapeutics, Floor L, University Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
1 Yeo WW, Ramsay LE, Morice AH. ACE inhibitor cough: a genetic link? Lancet 1991; 337: 187. 2 Chan WK, Chan TYK, Luk WK, Leung VKS, Li TH, Critchley JAJH. A high incidence of cough in Chinese subjects treated with angiotensin-converting enzyme inhibitors. Eur J Clin Pharmacol 1993; 44: 299-300. 3 Lee EJD. Population kinetics of the angiotensin-converting enzyme in Chinese. Br J Clin Pharmacol 1994; 37: 212-14. 4 Yeo WW, Foster G, Ramsay LE. Prevalence of persistent cough during long term treatment with enalapril: controlled study with nifedipine. Q J Med 1991; 81: 763-70.
mimic the testosterone effect. If the macrophage is the key effector, the absence of KS in congenital immunodeficiency syndromes would no longer be perplexing. The epidemiology of AIDS-associated KS, which suggests a sexually transmitted infectious agent other than HIV, may reflect a macrophagesuppressing disease prevalent in the male homosexual cohort, rather than sexual transmission of the KS agent. Thus, the KS agent could be the ubiquitous common denominator for all four presentations of KS, which reflect these different mechanisms of macrophage dysfunction.
Kathryn A O’Connell Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
1
Nowotny A, Keler T, Pham PH, et al. Isolation of a nonendotoxic antitumor preparation from Serratia marcescens. J Biol Response Mod
2
Urban RW, Edwards BS, Segal W. Tumor-immunotherapeutic efficacy of Serratia marcescens polyribosomes. Cancer Res 1980; 40: 1501-05. McCall C, Weimer L, Baldwin S, et al. A membrane vesicle/ribosome preparation from Serratia marcescens elicits peritoneal exudate cells expressing both tumoricidal and bactericidal activity. Inflammation 1992; 16: 355-69. Coley WB. Contribution to the knowledge of sarcoma. Ann Surg 1891;
1987; 7: 296-308.
3
Resolution of Kaposi’s sarcoma SiR-Resolution of AIDS-related Kaposi’s sarcoma (KS) in a severely T-cell-deficient patient with concurrent opportunistic infections is highly unlikely. I report one such
4 5
case.
An HIV-positive homosexual male with Pneumocystis carinii pneumonia (PCP) and KS of the penis declined chemotherapy and radiation for the KS, which progressed to a large tumour mass causing functional impairment despite cryotherapy and intralesional vinblastine, which were discontinued after several months. In the three years since diagnosis, the CD4 count has declined to zero and he has been maintained on various combinations of zidovudine, stavudine, acyclovir, foscarnet, ganciclovir for cytomegalovirus (CMV) retinitis, fluconazole, rifabutin, pentamidine, clarithromycin, erythropoietin, and filgrastim. Seven months ago he had the first of three episodes of Serratia marcescens sepsis treated with ceftazidime. Examination two weeks after a 26-day course of cefotaxime for the third episode revealed no clinically evident KS, which has remained in remission (three months follow-up) despite recurrent PCP and progressing CMV retinitis. Could Serratia marcescens have initiated destruction of KS by mobilising the macrophage, a cell known to acquire tumoricidal capacity when fully activated? Various preparations derived from Serratia marcescens are reported to have antineoplastic properties/.2 and induce long-lasting tumoricidal macrophage activation in mice.3 The idea that bacterial infection can awaken defences against tumours was proposed by Coley in 1891.4 Since bacteriologically derived biological response modifiers upregulate a plethora of cytokines, some of which have been implicated in the pathophysiology of KS and AIDS, possible therapeutic application would necessitate cautious investigation. Moreover, research into the role of the macrophage in KS may reveal a unifying conceptual framework for this disease. T-cell abnormalities do not occur in classic and endemic African KS; epidemiological features implicate hormonal and genetic factors. KS in this group could reflect infection by the putative KS agent superimposed on macrophage dysfunction induced by testosterone and certain environmental factors. Indeed, macrophage dysfunction has been implicated in testosteroneassociated susceptibility to some infections in genetically defined mice.S Similarly, the hypothesised lymphatic toxicity of volcanic soil in endemic KS6 could instead reflect silicainduced macrophage depletion. Male predominance is minimal in iatrogenic KS associated with corticosteroids, which, as potent inhibitors of macrophage function,7 may
6 7
8
15: 199-220. Yamamoto Y, Saito H, Setogawa T, et al. Sex differences in host resistance to Mycobacterium marinum infection in mice. Infect Immun 1991; 59: 4089-96. Ziegler JL. Endemic Kaposi’s sarcoma in Africa and local volcanic soils. Lancet 1993; 342: 1348-51. Hibbs JB. Heterocytolysis by macrophages activated by Bacillus Calmette-Guérin: lysosome exocytosis into tumor cells. Science 1974; 184: 468-71. Beral V, Peterman TA, Berkelman RL, Jaffe HW. Kaposi’s sarcoma among persons with AIDS: a sexually transmitted infection? Lancet 1990; 335: 123-28.
Aldehyde dehydrogenase genotypes In Japanese alcoholics SIR-The inactive form of liver mitochondrial aldehyde dehydrogenase (ALDH2), encoded by the gene LDT2*//2*2 or ALDH2*2/2*2, is considered a genetic deterrent of heavy drinking and alcoholism among Asians.1,2 However, this biological effect on drinking behaviour is strongly influenced by sociocultural factors. Rapid increases in Japanese per caput alcohol consumption and alcohol-related problems in recent decades suggest modification of the suppressive effect of inactive ALDH2 on alcohol use. To examine this hypothesis, we investigated ALDH2 genotype patterns in 1300 alcoholics admitted to the National Institute on Alcoholism in three different years. The subjects were randomly selected from 1791 alcoholics admitted in 1979 (370 males, 30 females; mean [SD] age 46 [ 10] years), 1986 [366 males, 34 females; age 48 [9]), and 1992 (455 males, 45 females; age 49 [11]). All met the DSM-III-R diagnostic criteria3 for alcohol dependence or alcohol abuse. Life-time alcohol consumption based on self-reports of alcoholics with inactive ALDH2 tended to be lower than that in those with active ALDH2. However, no important difference
*p<0 001,1979 vs 1986; tp <0 025,1986 vs 1992, by chi-square test. Table : ALDH2 genotype patterns among alcoholics In three different years (%)
741