We thank White for his interest in our editorial.1 He favours a founder effect over our hypothesis of ‘heterozygote advantage’ in pseudocholinesterase deficiency.2 We did not entirely discount that possibility in our article, but White rests his alternative argument on the belief that ‘unaffected homozygotes (i.e. normals) would have to die in significant numbers before reproductive age’ for heterozygote advantage to be an explanation. We think this belief is incorrect.
The genetic advantage conferred by a genotype can be described by the notion of ‘relative fitness’ (a term, like heterozygote advantage, Fisher helped to coin).3 Fitness is a product of the proportion of the genotype surviving to the next generation and the fecundity of the genotype (so is a measure of both survivability and ability to reproduce). For sickle cell disease, which White cites to support his argument, the relative fitness of the heterozygote (with sickle trait) varies between approximately 1.10–1.15 depending on the prevalence of malaria. This is against a fitness of 1.0 for the normal homozygote and 0 for the abnormal homozygote (with sickle disease).4 Thus, contrary to White's belief, the normal homozygotes are only at most approximately 10–15% disadvantaged in terms of their alleles surviving to the next generation in malaria-prevalent areas. If White's assertion was correct and normal homozygotes were perishing in such large numbers, we would expect the relative fitness of normal homozygotes to be much lower than this.
Indeed, it is not necessary for unaffected homozygotes to perish before reproductive age for heterozygote advantage to be evident. If a modest heterozygote advantage allows individuals to survive and reproduce for longer (as may be the case with our suggestion for pseudocholinesterase deficiency wherein individuals are protected from ischaemic heart disease), this itself can confer a modest increase in fitness. This has been noted in phenylketonuria, in which increased fecundity is observed for heterozygotes.5
White further suggests that heterozygote advantage in pseudocholinesterase deficiency may be negated by exposure to organophosphates in the developing world. Even if this selection pressure were prevalent (and we think it is not), mathematical modelling helps in determining how long it would take for an abnormal allele to disappear from the population.6 The malaria/sickle cell example is again useful. If malaria were eradicated, it would take approximately 20 000 years for the abnormal sickle cell allele to disappear. Even if the sickle heterozygotes found themselves at a slight (10%) disadvantage after eradication of malaria, it would take approximately 4600 years for the abnormal allele to vanish (for details of a computer program, see http://www.zoology.ubc.ca/∼bio301/Bio301/Lectures/Lecture12/Overheads.html). Organophosphates simply have not been around long enough for the proposed heterozygote advantage of pseudocholinesterase deficiency to be reversed or negated.
We are not convinced that White's reference to the article by Acuňa et al. on South American Indians is at odds with our theory.7 This population innately had a low prevalence of pseudocholinesterase deficiency (entirely consistent with their presumably low-fat diet). It was only with the arrival of Europeans that the allele was introduced into this population and it conferred a potential heterozygote advantage, as the Europeans also brought with them a higher fat diet. So the South American situation, entirely different from the case of the Vysyas, nonetheless appears consistent with our hypothesis.1
White's suggestion of examining mortality of cocoa-chewing American Indians by genotype is interesting. However, it has already been established that individuals with lower pseudocholinesterase activities exhibit higher incidence of life-threatening reactions to cocaine and we would expect a repeat of such a study confined to American Indians to yield the same results.8 So this case is perhaps already proven.
Although we may differ with Dr White in some aspects of interpretation, we are very pleased that the editorial has fulfilled one of its aims, which was to generate interest and wider discussion of such issues in the anaesthetic literature.
1. Pandit JJ, Gopa S, Arora J. A hypothesis to explain the high prevalence of pseudocholinesterase deficiency in specific population groups. Eur J Anaesthesiol
2. White SM. Pseudocholinesterase deficiency in specific populations. Eur J Anaesthesiol
3. Pandit JJ. The analysis of variance in anaesthetic research: statistics, history and biography. Anaesthesia
4. Livingstone FB. Population genetics and population ecology. Am Anthropol
5. Saugstad LF. Heterozygote advantage for the phenylketonuria allele. J Med Genet
6. Hesterbeek JAP, van Arendonk JAM. Changes in disease gene frequency over time with differential genotypic fitness and various control strategies. J Anim Sci
7. Acuña M, Eaton L, Ramírez NR, et al. Genetic variants of serum butyrylcholinesterase in Chilean Mapuche Indians. Am J Phys Anthropol
8. Hoffman RS, Henry GC, Howland MA, et al. Association between life-threatening cocaine toxicity and plasma cholinesterase activity. Ann Emerg Med