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Fetal origins hypothesis in India
CORRESPONDENCE
Fetal origins hypothesis in India Sir—I was disturbed to learn from John Challis (June 2, p 1798)1 that thousands of young women in India are involved in research into the fetal origins hypothesis. It is of great concern that less-developed countries are diverting their much less abundant research funds in pursuit of this elusive holy grail. The most persuasive evidence against the hypothesis is the fact that birthweight in less-developed countries is much lower than that in moredeveloped countries and this difference has been associated with an almost total absence of coronary heart disease (CHD) and type 2 diabetes mellitus. These diseases appear only when lessdeveloped countries take on the diet of more-developed countries, but incidence grows at a much faster rate. Thus if there is any association between neonatal weight and these disorders, unknown constitutional factors associated with heaviness in some infants may be protective against the dietary factors responsible for syndrome X.2,3 However, this effect may also be an artefact if the nutritional intake of underweight infants is different quantitatively, qualitatively, or both, relative to heavier infants during catchup growth, or differs for day-to-day thermoregulation.4 The relevance of neonatal nutrition was confirmed by workers who noted that breastmilk consumption in premature babies was associated with lower later blood pressure.5 It may be no coincidence that the disorders associated with syndrome X— hypertension, type 2 diabetes, and CHD—are also associated with the fetal origins hypothesis. Thus, this hypothesis might simply be another manifestation of that ubiquitous nutritional disorder, syndrome X. Patrick J Bradley PO Box 5397, Wollongong, New South Wales 2500, Australia 1
2 3
4
5
Challis J. Glucose tolerance in adults after prenatal exposure to famine. Lancet 2001; 357: 1798. Bradley PJ. Weight in infancy and death from ischaemic heart disease. Lancet 1989; 2: 985. Bradley PJ. The influence of parental somatic features on childhood weight has been extensively studied. BMJ 1995; 310: 1468. Pittet PG. Direct calorimeter with fast response time using the gradient-layer principle: some illustrations of its utilization in human studies. In: Bjorntorp P, Cairella M, Howard AN, eds. Recent advances in obesity research, III. London: John Libbey, 1981: 146–52. Singhal A, Cole TJ, Lucas A. Early nutrition in preterm infants and later blood pressure: two cohorts after randomised trials. Lancet 2001; 357: 413.
THE LANCET • Vol 358 • September 15, 2001
A non-sense mutation and protection from severe malaria
3
4
Sir—Arnab Pain and colleagues (May 12, p 1502)1 show that the T188G Cd36 mutation does not confer protection from cerebral malaria, and yet they assert that this mutation is associated with protection from severe malaria. They make no mention of the frequency in the 693 African children of genetic markers that do offer some protection against falciparum malaria, namely the qualitative and quantitative hereditary erythrocytopathies (mutations respectively for haemoglobin S and glucose-6 phosphate dehydrogenase [G6PD] deficiency).2–5 The Kilifi community belongs to a Kenyan group called the Miji Kenda (literal translation, nine tribes). It would greatly help polymorphism interpretations if we were told the incidence among the Miji Kenda in general and especially among the 693 Kilifi children, of thalassaemia ( and ␣), sickle cell trait, and G6PD deficiency. A further feature of Pain and colleagues’ report that worries me is the possible misinterpretation or reaction of clinicians and publichealth officials. For example, at least one UK family physician has misadvised a Ghanaian patient who was homozygous (SS) for the sickle cell gene and going on holiday to west Africa. The doctor claimed the patient should have no problem with malaria because one “S” is protective, so SS must be doubly protective. On return to the UK, the patient had a devastating sickle-cell crisis precipitated by malaria. I sincerely hope that no national or international newspaper will run some such headline as “New gene found to protect against severe malaria” at a time when what is urgently needed in the Cape coast and in Kenya is attention to public-health measures such as environmental cleanliness (eg, getting rid of open drains), use of mosquito nets, and a massive governmental and non-governmental effort to get rid of social pathology in the urban and rural areas. Felix I D Konotey-Ahulu University of Cape Coast, Faculty of Science, Private Mail Box, Cape Coast, Ghana (e-mail: [email protected]) 1
2
Pain A, Urban BC, Oscar K, et al. A nonsense mutation in Cd36 gene is associated with protection from severe malaria. Lancet 2001; 357: 1502–03. Commey JOO, Mills-Tetteh D, Phillips BJ.
5
Cerebral malaria in Accra, Ghana. Ghana Med J 1980; 19: 68–72. Pasvol G, Weatherall DJ. The red cell and malaria parasite. Br J Haematol 1980; 46: 165–70. Luzzatto L. Genetics of red cells and susceptibility to malaria. Blood 1979; 54: 961–76. Ringelhann B, Konotey-Ahulu FID. Hemoglobinopathies and thalassaemias in Mediterranean areas and in West Africa: historical and other perspectives 1910–1997—A century review. Atti del’Accademia della Science di Ferrara 1996; 74: 267–307.
Authors’ reply Sir—We did indeed state that the mutation does not protect from cerebral malaria but is associated with protection overall from severe malaria. There is no contradiction between these two statements, since protection is notable in the syndromes of severe malaria other than cerebral malaria, namely respiratory distress, severe anaemia, and hypoglycaemia. This effect is unusual for a mutation that confers protection from severe malaria, but we speculate that it reflects the complex role of interactions with Cd36 in this disease. The Kilifi community has been extensively studied for genetic polymorphisms and protection for severe malaria in separate studies, including for example tumour necrosis factor polymorphisms and G6PD deficiency.1,2 As KonoteyAhulu mentions, the Kilifi community is composed of the Miji Kenda ethnic groups. To eliminate any spurious association, we carefully matched subgroups of Miji Kenda. More than 70% of the population studied are of the Giriama subgroup and we were able to match closely cases and controls for those from this group and the smaller numbers of other groups. Finally, we do share KonoteyAhulu’s concern that the publichealth needs of communities in pandemic areas be addressed. Indeed he will be aware of the very large amount of work at Kilifi that focuses on practical public-health measures such as insecticide-treated bed nets and community-based treatment of childhood illness.3–5 Our findings in no way suggest that this genetic polymorphism in the Cd36 gene, or indeed any others, could be used to guide advice on individual prophylaxis or treatment of malaria. However, these genetic studies are simply a way of trying to understand the pathophysiology of disease, and are designed to unravel the
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Fetal origins hypothesis in India Sir—I was disturbed to learn from John Challis (June 2, p 1798)1 that thousands of young women in India are involved in research into the fetal origins hypothesis. It is of great concern that less-developed countries are diverting their much less abundant research funds in pursuit of this elusive holy grail. The most persuasive evidence against the hypothesis is the fact that birthweight in less-developed countries is much lower than that in moredeveloped countries and this difference has been associated with an almost total absence of coronary heart disease (CHD) and type 2 diabetes mellitus. These diseases appear only when lessdeveloped countries take on the diet of more-developed countries, but incidence grows at a much faster rate. Thus if there is any association between neonatal weight and these disorders, unknown constitutional factors associated with heaviness in some infants may be protective against the dietary factors responsible for syndrome X.2,3 However, this effect may also be an artefact if the nutritional intake of underweight infants is different quantitatively, qualitatively, or both, relative to heavier infants during catchup growth, or differs for day-to-day thermoregulation.4 The relevance of neonatal nutrition was confirmed by workers who noted that breastmilk consumption in premature babies was associated with lower later blood pressure.5 It may be no coincidence that the disorders associated with syndrome X— hypertension, type 2 diabetes, and CHD—are also associated with the fetal origins hypothesis. Thus, this hypothesis might simply be another manifestation of that ubiquitous nutritional disorder, syndrome X. Patrick J Bradley PO Box 5397, Wollongong, New South Wales 2500, Australia 1
2 3
4
5
Challis J. Glucose tolerance in adults after prenatal exposure to famine. Lancet 2001; 357: 1798. Bradley PJ. Weight in infancy and death from ischaemic heart disease. Lancet 1989; 2: 985. Bradley PJ. The influence of parental somatic features on childhood weight has been extensively studied. BMJ 1995; 310: 1468. Pittet PG. Direct calorimeter with fast response time using the gradient-layer principle: some illustrations of its utilization in human studies. In: Bjorntorp P, Cairella M, Howard AN, eds. Recent advances in obesity research, III. London: John Libbey, 1981: 146–52. Singhal A, Cole TJ, Lucas A. Early nutrition in preterm infants and later blood pressure: two cohorts after randomised trials. Lancet 2001; 357: 413.
THE LANCET • Vol 358 • September 15, 2001
A non-sense mutation and protection from severe malaria
3
4
Sir—Arnab Pain and colleagues (May 12, p 1502)1 show that the T188G Cd36 mutation does not confer protection from cerebral malaria, and yet they assert that this mutation is associated with protection from severe malaria. They make no mention of the frequency in the 693 African children of genetic markers that do offer some protection against falciparum malaria, namely the qualitative and quantitative hereditary erythrocytopathies (mutations respectively for haemoglobin S and glucose-6 phosphate dehydrogenase [G6PD] deficiency).2–5 The Kilifi community belongs to a Kenyan group called the Miji Kenda (literal translation, nine tribes). It would greatly help polymorphism interpretations if we were told the incidence among the Miji Kenda in general and especially among the 693 Kilifi children, of thalassaemia ( and ␣), sickle cell trait, and G6PD deficiency. A further feature of Pain and colleagues’ report that worries me is the possible misinterpretation or reaction of clinicians and publichealth officials. For example, at least one UK family physician has misadvised a Ghanaian patient who was homozygous (SS) for the sickle cell gene and going on holiday to west Africa. The doctor claimed the patient should have no problem with malaria because one “S” is protective, so SS must be doubly protective. On return to the UK, the patient had a devastating sickle-cell crisis precipitated by malaria. I sincerely hope that no national or international newspaper will run some such headline as “New gene found to protect against severe malaria” at a time when what is urgently needed in the Cape coast and in Kenya is attention to public-health measures such as environmental cleanliness (eg, getting rid of open drains), use of mosquito nets, and a massive governmental and non-governmental effort to get rid of social pathology in the urban and rural areas. Felix I D Konotey-Ahulu University of Cape Coast, Faculty of Science, Private Mail Box, Cape Coast, Ghana (e-mail: [email protected]) 1
2
Pain A, Urban BC, Oscar K, et al. A nonsense mutation in Cd36 gene is associated with protection from severe malaria. Lancet 2001; 357: 1502–03. Commey JOO, Mills-Tetteh D, Phillips BJ.
5
Cerebral malaria in Accra, Ghana. Ghana Med J 1980; 19: 68–72. Pasvol G, Weatherall DJ. The red cell and malaria parasite. Br J Haematol 1980; 46: 165–70. Luzzatto L. Genetics of red cells and susceptibility to malaria. Blood 1979; 54: 961–76. Ringelhann B, Konotey-Ahulu FID. Hemoglobinopathies and thalassaemias in Mediterranean areas and in West Africa: historical and other perspectives 1910–1997—A century review. Atti del’Accademia della Science di Ferrara 1996; 74: 267–307.
Authors’ reply Sir—We did indeed state that the mutation does not protect from cerebral malaria but is associated with protection overall from severe malaria. There is no contradiction between these two statements, since protection is notable in the syndromes of severe malaria other than cerebral malaria, namely respiratory distress, severe anaemia, and hypoglycaemia. This effect is unusual for a mutation that confers protection from severe malaria, but we speculate that it reflects the complex role of interactions with Cd36 in this disease. The Kilifi community has been extensively studied for genetic polymorphisms and protection for severe malaria in separate studies, including for example tumour necrosis factor polymorphisms and G6PD deficiency.1,2 As KonoteyAhulu mentions, the Kilifi community is composed of the Miji Kenda ethnic groups. To eliminate any spurious association, we carefully matched subgroups of Miji Kenda. More than 70% of the population studied are of the Giriama subgroup and we were able to match closely cases and controls for those from this group and the smaller numbers of other groups. Finally, we do share KonoteyAhulu’s concern that the publichealth needs of communities in pandemic areas be addressed. Indeed he will be aware of the very large amount of work at Kilifi that focuses on practical public-health measures such as insecticide-treated bed nets and community-based treatment of childhood illness.3–5 Our findings in no way suggest that this genetic polymorphism in the Cd36 gene, or indeed any others, could be used to guide advice on individual prophylaxis or treatment of malaria. However, these genetic studies are simply a way of trying to understand the pathophysiology of disease, and are designed to unravel the
927