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Search for genes predisposing to atopic diseases
THE LANCET
COMMENTARY
Epidemiology of PNH See page 573 Paroxysmal nocturnal haemoglobinuria (PNH) was one of the first haematological diseases to be described accurately from clinical symptoms alone1 and has been readily diagnosed by reliable laboratory means for nearly 60 years.2 Yet, because of its rarity and its great clinical variability, we can still learn from epidemiological reviews such as that of Socié and his associates in France in this week’s issue, and that of Hillmen et al in Great Britain.3 These authors have confirmed that PNH is a disease that knows no age limits but we learn that onset at a later age is an adverse prognostic factor. We have a clearer idea about the very high incidence of venous thrombosis in the older age-groups (perhaps 50%) in these European populations but do not learn why the incidence is so much lower in Asian populations.4,5 The relation to aplastic anaemia is even more clear than when Dacie and Lewis first pointed it out,6 in part because therapy for aplastic anaemia is now more successful with the use of antithymocyte globulin, and this success brings out the abnormal cells of PNH.7 The precise relation between PNH and aplastic anaemia at a cellular level remains elusive. The evolution to leukaemia is described by Socié et al but the incidence is somewhat lower than noted in Asian series. The major advantage of a large study such as these is that it can give statistical validity to prognostication. Earlier studies had cited a mean survival rate of 8 years from diagnosis, a grim prospect for a newly diagnosed young patient.8 Socié and colleagues’ study estimates the mean survival at 15 years. The increase may be due to earlier diagnosis, to better medical care, to the greater proportion of patients starting with aplastic anaemia (a positive prognostic sign), or a combination of these and other reasons. Equally encouraging is the finding of Hillmen et al that a third of those patients surviving more than 10 years (about half of all patients in their series) had a spontaneous clinical remission.3 Nevertheless, it is clear that the patient with PNH may face unhappy events and the ability of the French epidemiological study to help shape decisions is a major advantage. PNH can be cured by successful bone-marrow transplantation but until that procedure becomes more risk-free than it is at present, the selection of patients for whom the risk of continuing to have the disease is greater than the risk of bone-marrow transplantation is a crucial exercise. It is clear that major venous thrombosis is the factor most related to poor prognosis, with a relative risk of 10·0; even careful anticoagulant therapy is not very effective in ameliorating its effect. Bone-marrow transplantation may offer relief from the relentless progression of hepatic venous thrombosis,9 so it should be considered in appropriate candidates with serious thrombotic complications. The evolution to bone-marrow failure is also an adverse factor that can be cured by bonemarrow transplantation, which becomes the only hope for those patients whose disease evolves to acute leukaemia or myelodysplastic syndrome. Unfortunately, not every patient with PNH is a candidate for bone-marrow transplantation. Those aged over 50 not only have a poorer prognosis with respect to PNH but are ineligible for bone-marrow transplantation because older patients cannot tolerate the effects of the 560
therapy. In this age of small families, histocompatible siblings are commonly not available, and transplantation with the marrow of unrelated donors, no matter how carefully matched, or of partly matched relatives is so fraught with difficulties as to discourage all but the desperate. The gene that is defective in PNH is known,10 and perhaps gene therapy will in the long run be possible, but not soon. Thus, for the most part, we will have to continue our efforts to optimise the treatment of PNH by other means and to collect prospective data on the results. Comparison with studies such as this will let us know whether we are doing better than we have done in the past.
Wendell F Rosse Department of Medicine, Hematology-Oncology Division, Duke University Medical Center, Durham, NC 27710, USA 1
Gull WW. A case of intermittent haematinuria, with remarks. Guy’s Hosp Reports 1866; 12: 381–92. 2 Ham TH. Chronic hemolytic anemia with paroxysmal nocturnal hemoglobinuria. A study of the mechanism of hemolysis in relation to acid-base equilibrium. N Engl J Med 1938; 217: 915–17. 3 Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995; 333: 1253–58. 4 Kruatrachue M, Wasi P, Nanakorn S. Paroxysmal nocturnal haemoglobinuria in Thailand with special reference to an association with aplastic anemia. Br J Haematol 1978; 39: 267–76. 5 Fujioka S, Takayoshi T. Prognostic features of paroxysmal nocturnal hemoglobinuria in Japan. Acta Haematol Japan 1989; 52: 1386–94. 6 Lewis SM, Dacie JV. The aplastic anaemia-paroxysmal nocturnal haemoglobinuria syndrome. Br J Haematol 1967; 13: 2336–51. 7 Schubert J, Bogt HG, Zielinska-Skowronek M, et al. Development of the glycosylphosphatidylinositol-anchoring defect characteristic for paroxysmal nocturnal hemoglobinuria in patients with aplastic anaemia. Blood 1994; 83: 2323–28. 8 Dacie JV, Lewis SM. Paroxysmal nocturnal haemoglobinuria: clinical manifestations, haematology, and nature of the disease. Series Hematol 1972; 5: 3–23. 9 Graham ML, Rosse WF, Halperin EC, Miller CR, Ware RE. Resolution of Budd-Chiari syndrome following bone marrow transplantation for paroxysmal nocturnal haemoglobinuria. Br J Haematol 1996; 92: 707–10. 10 Takeda J, Miyata T, Kawagoe K, et al. Deficiency of the GPE anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell 1993; 73: 703–11.
Search for genes predisposing to atopic diseases See page 581 The search for genes responsible for complex diseases seems to be characterised by many claims but few confirmations. Factors such as absence of a clear phenotype, genetic heterogeneity, and interactions between several major and a few minor genes may account for this difficulty. Atopic hypersensitivity is a complex disorder with different clinical expressions (asthma, rhinitis or hayfever, and eczema) that share as a common phenotype excessive synthesis of immunoglobulin E (IgE), which leads to a generalised and prolonged hyperresponsiveness to common environmental antigens, including pollen and housedust mite. Genetic analysis of atopy is strongly hampered by its high prevalence (approximately 50% among young western adults), lack of knowledge about the mode of inheritance and the number of the factors involved, incomplete penetrance of the genes, and the influence of environmental and medical factors. Loci suggested as harbouring candidate susceptibility genes have initially been identified by affected sibling-pair analysis, a method
Vol 348 • August 31, 1996
THE LANCET
COMMENTARY FceRl-b and the 5q31.1-locus both lead to a general increase of IgE responsiveness. By contrast, linkage of the T-cell receptor a/d-complex at chromosome 14 to specific IgE responses was found.7 The broad array of variable (V) and junctional (J) elements within this locus may be involved in the generation of its response specificity. In this issue of The Lancet Mao et al describe an association between a genetic marker within the mast-cellchymase (MCC) gene and eczema, but not with allergic asthma and rhinitis. When triggered by IgE most mast cells in the skin express MCC, but only a small fraction of bronchial and pulmonary mast cells do so. Thus, organspecific expression of a general atopic predisposition is not determined only by environmental conditions—eg, the exposure of particular organs to allergens—but also by genetic factors. This finding is important. Nevertheless, when confirmed in further studies, it will not make any easier the prediction of the clinical course in individual patients.
H Scheffer Department of Medical Genetics, University of Groningen, 9713 AW Groningen, Netherlands
not requiring assumptions about factors affecting inheritance. A possibly better approach for the identification of genetic factors involved in multifactorial disorders is the study of patients from a homogeneous population for haplotypes identical by descent and indicative of a shared predisposing factor. Several studies point to a locus, or better a fairly extended region, at chromosome 5q containing a number of genes coding for interleukins and other growth factors.1 Linkage of chromosome 5 markers with a gene controlling total serum IgE concentration has been demonstrated.2 The conclusion was that IL-4 (or a nearby gene in this cluster) plays a part in regulating IgE production. B-cells become activated by IL-4 released by T helper lymphocytes type 2. Such activation causes the Ig heavychain class to switch to the e-isotype. Postma et al found strong correlations of total IgE concentrations within pairs of siblings concordant for bronchial hyperresponsiveness, but not in their study group as a whole.3 They also found linkage of bronchial hyperresponsiveness to 5q and concluded that a gene regulating bronchial hyperresponsiveness lies near a locus regulating serum IgE concentrations on 5q. It is conceivable, however, that the 5q-locus regulating serum IgE levels is also directly, though only partly, responsible for bronchial hyperresponsiveness. Although the initial localisation of an atopy locus at 11q134 was disputed,5 a common sequence variant Ile181Leu in the gene for the b-subunit of FceRl (FceRlb) was identified showing a significant association with positive IgE responses.6 The inheritance of this variant is maternally dominant. Such inheritance can be explained either by paternal imprinting, or by maternal modification. through the placenta or breastmilk, of developing immune responses. The Ile181Leu substitution may either be a true mutation responsible for atopy in a subset of patients, or a sequence variant in allelic association with a true mutation in a regulatory sequence of FceRl-b. The bchain is involved in single transduction. Mutations in this chain may modulate receptor signalling, either by making the receptor more sensitive to ligand, or by enhancing IL4 production by mast cells.
Vol 348 • August 31, 1996
1
2
3
4
5
6
7
Le Beau MM, Espinosa R, Neuman WL, et al. Cytogenetic and molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases. Proc Natl Acad Soc 1993; 90: 5484–88. Marsh DG, Neely JD, Breazeale DR, et al. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science 1994; 264: 1152–56. Postma DS, Bleecker ER, Amelung PJ, et al. Genetic susceptibility to asthma: bronchial hyperresponsiveness coinherited with a major gene for atopy. N Engl J Med 1995; 333: 894–900. Cookson WOCM, Sharp PA, Faux JA, Hopkin JM. Linkage between immunoglobulin E responses underlying asthma and rhinitis and chromosome 11q. Lancet 1989; 338: 1292–95. Amelung PJ, Panhuysen CIM, Postma DS, et al. Atopy and bronchial hyperresponsiveness: exclusion of linkage to markers on chromosomes 11q and 6p. Clin Exp Allergy 1992; 22: 1077–84. Shirakawa T, Li A, Dubowitz M, et al. Association between atopy and variants of the b subunit of the high affinity immunoglobulin E receptor. Nat Genet 1994; 7: 125–30. Moffatt MF, Hill MR, Cornelis F, et al. Genetic linkage of T-cell receptor a/d comples to specific IgE responses. Lancet 1994; 343: 1597–600
Management of Barrett’s oesophagus See page 584 Despite intensive efforts, the contribution of gastroesophageal reflux to the development of columnarlined (Barrett’s) oesophagus remains unclear.1 The incidence of this condition seems to be rising, perhaps the result of improved detection due to increased use of upper endoscopy in the diagnosis and management of gastrointestinal disease.1 The association of Barrett’s oesophagus and adenocarcinoma is well established, and the risk of neoplastic transformation in these patients is estimated to be about 40 times greater than that in the general population.2 The loss of the tumour-suppressor gene p53 and the 5q chromosome are molecular events that have been identified in carcinomas arising within Barrett’s oesophagus.2 To date, Barrett’s oesophagus has been managed by routine endoscopic surveillance and a standard biopsy protocol for the detection of dysplasia. More recent experience with laser-induced autofluorescence suggests that high-grade dysplasia can be distinguished on the basis of its spectral pattern.3 Surgical 561
COMMENTARY
Epidemiology of PNH See page 573 Paroxysmal nocturnal haemoglobinuria (PNH) was one of the first haematological diseases to be described accurately from clinical symptoms alone1 and has been readily diagnosed by reliable laboratory means for nearly 60 years.2 Yet, because of its rarity and its great clinical variability, we can still learn from epidemiological reviews such as that of Socié and his associates in France in this week’s issue, and that of Hillmen et al in Great Britain.3 These authors have confirmed that PNH is a disease that knows no age limits but we learn that onset at a later age is an adverse prognostic factor. We have a clearer idea about the very high incidence of venous thrombosis in the older age-groups (perhaps 50%) in these European populations but do not learn why the incidence is so much lower in Asian populations.4,5 The relation to aplastic anaemia is even more clear than when Dacie and Lewis first pointed it out,6 in part because therapy for aplastic anaemia is now more successful with the use of antithymocyte globulin, and this success brings out the abnormal cells of PNH.7 The precise relation between PNH and aplastic anaemia at a cellular level remains elusive. The evolution to leukaemia is described by Socié et al but the incidence is somewhat lower than noted in Asian series. The major advantage of a large study such as these is that it can give statistical validity to prognostication. Earlier studies had cited a mean survival rate of 8 years from diagnosis, a grim prospect for a newly diagnosed young patient.8 Socié and colleagues’ study estimates the mean survival at 15 years. The increase may be due to earlier diagnosis, to better medical care, to the greater proportion of patients starting with aplastic anaemia (a positive prognostic sign), or a combination of these and other reasons. Equally encouraging is the finding of Hillmen et al that a third of those patients surviving more than 10 years (about half of all patients in their series) had a spontaneous clinical remission.3 Nevertheless, it is clear that the patient with PNH may face unhappy events and the ability of the French epidemiological study to help shape decisions is a major advantage. PNH can be cured by successful bone-marrow transplantation but until that procedure becomes more risk-free than it is at present, the selection of patients for whom the risk of continuing to have the disease is greater than the risk of bone-marrow transplantation is a crucial exercise. It is clear that major venous thrombosis is the factor most related to poor prognosis, with a relative risk of 10·0; even careful anticoagulant therapy is not very effective in ameliorating its effect. Bone-marrow transplantation may offer relief from the relentless progression of hepatic venous thrombosis,9 so it should be considered in appropriate candidates with serious thrombotic complications. The evolution to bone-marrow failure is also an adverse factor that can be cured by bonemarrow transplantation, which becomes the only hope for those patients whose disease evolves to acute leukaemia or myelodysplastic syndrome. Unfortunately, not every patient with PNH is a candidate for bone-marrow transplantation. Those aged over 50 not only have a poorer prognosis with respect to PNH but are ineligible for bone-marrow transplantation because older patients cannot tolerate the effects of the 560
therapy. In this age of small families, histocompatible siblings are commonly not available, and transplantation with the marrow of unrelated donors, no matter how carefully matched, or of partly matched relatives is so fraught with difficulties as to discourage all but the desperate. The gene that is defective in PNH is known,10 and perhaps gene therapy will in the long run be possible, but not soon. Thus, for the most part, we will have to continue our efforts to optimise the treatment of PNH by other means and to collect prospective data on the results. Comparison with studies such as this will let us know whether we are doing better than we have done in the past.
Wendell F Rosse Department of Medicine, Hematology-Oncology Division, Duke University Medical Center, Durham, NC 27710, USA 1
Gull WW. A case of intermittent haematinuria, with remarks. Guy’s Hosp Reports 1866; 12: 381–92. 2 Ham TH. Chronic hemolytic anemia with paroxysmal nocturnal hemoglobinuria. A study of the mechanism of hemolysis in relation to acid-base equilibrium. N Engl J Med 1938; 217: 915–17. 3 Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995; 333: 1253–58. 4 Kruatrachue M, Wasi P, Nanakorn S. Paroxysmal nocturnal haemoglobinuria in Thailand with special reference to an association with aplastic anemia. Br J Haematol 1978; 39: 267–76. 5 Fujioka S, Takayoshi T. Prognostic features of paroxysmal nocturnal hemoglobinuria in Japan. Acta Haematol Japan 1989; 52: 1386–94. 6 Lewis SM, Dacie JV. The aplastic anaemia-paroxysmal nocturnal haemoglobinuria syndrome. Br J Haematol 1967; 13: 2336–51. 7 Schubert J, Bogt HG, Zielinska-Skowronek M, et al. Development of the glycosylphosphatidylinositol-anchoring defect characteristic for paroxysmal nocturnal hemoglobinuria in patients with aplastic anaemia. Blood 1994; 83: 2323–28. 8 Dacie JV, Lewis SM. Paroxysmal nocturnal haemoglobinuria: clinical manifestations, haematology, and nature of the disease. Series Hematol 1972; 5: 3–23. 9 Graham ML, Rosse WF, Halperin EC, Miller CR, Ware RE. Resolution of Budd-Chiari syndrome following bone marrow transplantation for paroxysmal nocturnal haemoglobinuria. Br J Haematol 1996; 92: 707–10. 10 Takeda J, Miyata T, Kawagoe K, et al. Deficiency of the GPE anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell 1993; 73: 703–11.
Search for genes predisposing to atopic diseases See page 581 The search for genes responsible for complex diseases seems to be characterised by many claims but few confirmations. Factors such as absence of a clear phenotype, genetic heterogeneity, and interactions between several major and a few minor genes may account for this difficulty. Atopic hypersensitivity is a complex disorder with different clinical expressions (asthma, rhinitis or hayfever, and eczema) that share as a common phenotype excessive synthesis of immunoglobulin E (IgE), which leads to a generalised and prolonged hyperresponsiveness to common environmental antigens, including pollen and housedust mite. Genetic analysis of atopy is strongly hampered by its high prevalence (approximately 50% among young western adults), lack of knowledge about the mode of inheritance and the number of the factors involved, incomplete penetrance of the genes, and the influence of environmental and medical factors. Loci suggested as harbouring candidate susceptibility genes have initially been identified by affected sibling-pair analysis, a method
Vol 348 • August 31, 1996
THE LANCET
COMMENTARY FceRl-b and the 5q31.1-locus both lead to a general increase of IgE responsiveness. By contrast, linkage of the T-cell receptor a/d-complex at chromosome 14 to specific IgE responses was found.7 The broad array of variable (V) and junctional (J) elements within this locus may be involved in the generation of its response specificity. In this issue of The Lancet Mao et al describe an association between a genetic marker within the mast-cellchymase (MCC) gene and eczema, but not with allergic asthma and rhinitis. When triggered by IgE most mast cells in the skin express MCC, but only a small fraction of bronchial and pulmonary mast cells do so. Thus, organspecific expression of a general atopic predisposition is not determined only by environmental conditions—eg, the exposure of particular organs to allergens—but also by genetic factors. This finding is important. Nevertheless, when confirmed in further studies, it will not make any easier the prediction of the clinical course in individual patients.
H Scheffer Department of Medical Genetics, University of Groningen, 9713 AW Groningen, Netherlands
not requiring assumptions about factors affecting inheritance. A possibly better approach for the identification of genetic factors involved in multifactorial disorders is the study of patients from a homogeneous population for haplotypes identical by descent and indicative of a shared predisposing factor. Several studies point to a locus, or better a fairly extended region, at chromosome 5q containing a number of genes coding for interleukins and other growth factors.1 Linkage of chromosome 5 markers with a gene controlling total serum IgE concentration has been demonstrated.2 The conclusion was that IL-4 (or a nearby gene in this cluster) plays a part in regulating IgE production. B-cells become activated by IL-4 released by T helper lymphocytes type 2. Such activation causes the Ig heavychain class to switch to the e-isotype. Postma et al found strong correlations of total IgE concentrations within pairs of siblings concordant for bronchial hyperresponsiveness, but not in their study group as a whole.3 They also found linkage of bronchial hyperresponsiveness to 5q and concluded that a gene regulating bronchial hyperresponsiveness lies near a locus regulating serum IgE concentrations on 5q. It is conceivable, however, that the 5q-locus regulating serum IgE levels is also directly, though only partly, responsible for bronchial hyperresponsiveness. Although the initial localisation of an atopy locus at 11q134 was disputed,5 a common sequence variant Ile181Leu in the gene for the b-subunit of FceRl (FceRlb) was identified showing a significant association with positive IgE responses.6 The inheritance of this variant is maternally dominant. Such inheritance can be explained either by paternal imprinting, or by maternal modification. through the placenta or breastmilk, of developing immune responses. The Ile181Leu substitution may either be a true mutation responsible for atopy in a subset of patients, or a sequence variant in allelic association with a true mutation in a regulatory sequence of FceRl-b. The bchain is involved in single transduction. Mutations in this chain may modulate receptor signalling, either by making the receptor more sensitive to ligand, or by enhancing IL4 production by mast cells.
Vol 348 • August 31, 1996
1
2
3
4
5
6
7
Le Beau MM, Espinosa R, Neuman WL, et al. Cytogenetic and molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases. Proc Natl Acad Soc 1993; 90: 5484–88. Marsh DG, Neely JD, Breazeale DR, et al. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science 1994; 264: 1152–56. Postma DS, Bleecker ER, Amelung PJ, et al. Genetic susceptibility to asthma: bronchial hyperresponsiveness coinherited with a major gene for atopy. N Engl J Med 1995; 333: 894–900. Cookson WOCM, Sharp PA, Faux JA, Hopkin JM. Linkage between immunoglobulin E responses underlying asthma and rhinitis and chromosome 11q. Lancet 1989; 338: 1292–95. Amelung PJ, Panhuysen CIM, Postma DS, et al. Atopy and bronchial hyperresponsiveness: exclusion of linkage to markers on chromosomes 11q and 6p. Clin Exp Allergy 1992; 22: 1077–84. Shirakawa T, Li A, Dubowitz M, et al. Association between atopy and variants of the b subunit of the high affinity immunoglobulin E receptor. Nat Genet 1994; 7: 125–30. Moffatt MF, Hill MR, Cornelis F, et al. Genetic linkage of T-cell receptor a/d comples to specific IgE responses. Lancet 1994; 343: 1597–600
Management of Barrett’s oesophagus See page 584 Despite intensive efforts, the contribution of gastroesophageal reflux to the development of columnarlined (Barrett’s) oesophagus remains unclear.1 The incidence of this condition seems to be rising, perhaps the result of improved detection due to increased use of upper endoscopy in the diagnosis and management of gastrointestinal disease.1 The association of Barrett’s oesophagus and adenocarcinoma is well established, and the risk of neoplastic transformation in these patients is estimated to be about 40 times greater than that in the general population.2 The loss of the tumour-suppressor gene p53 and the 5q chromosome are molecular events that have been identified in carcinomas arising within Barrett’s oesophagus.2 To date, Barrett’s oesophagus has been managed by routine endoscopic surveillance and a standard biopsy protocol for the detection of dysplasia. More recent experience with laser-induced autofluorescence suggests that high-grade dysplasia can be distinguished on the basis of its spectral pattern.3 Surgical 561