1 Copenhagen, Denmark 2 Bournemouth, UK
EditorI would like to congratulate Dr Sweeney for the interesting Editorial.1 In it he describes, in some detail, the history of pharmacogenetics. He correctly points out that among the first documented accounts on genetic deficiencies responsible for a varied drug response were glucose-6-phosphate-dehydrogenase and N-acetyltransferase.2 3 However, he fails to report some early observations of far greater clinical impact for us as anaesthetists. About the same time as the genetic deficiencies in glucose-6-phosphate-dehydrogenase and N-acetyltransferase were found, other investigators observed the occurrence of low plasma cholinesterase activity in a number of families, indicating genetic control.47 Historically, the impact of these findings both for clinical anaesthetists and for the anaesthesia research to follow was greater than any of the other early findings reported in the Editorial. Also, Motulsky,8 Vogel9 and Kalow10 all wrote important papers on genes and drugs, and Vogel even invented the word pharmacogenetics. Does all this matter? Yes, because in an editorial about genes and anaesthesia in one of the leading anaesthesia journals in the world, you should be fair to the history of pharmacogenetics in anaesthesia, not least because our speciality has played such a crucial role in this respect. Writing an editorial with the title: Do genes influence outcome from anaesthesia? without mentioning genetic defects in plasma cholinesterase, is unfair to those who worked hard in this field in the early days of pharmacogenetics.
J. Viby-Mogensen
Copenhagen, Denmark
EditorI would like to thank Professor Viby-Mogensen for his relevant and constructive comments and for the opportunity to reply to them. There is no doubt that the contribution of Motulsky,8 Kalow5 and Vogel9 in the 1950s and 1960s to the then emerging science of pharmacogenetics was pivotal. The characterization of the genetic basis for cholinesterase deficiency by Kalow in 1956,5 of which every anaesthetist is cognizant and which is most certainly noteworthy, was of fundamental importance to anaesthesia and to the further development and understanding of the wider implications of genetically determined differences in drug metabolism. The omission of a reference to the work of Vogel may justifiably be considered remiss. In my defence, this was included in my original draft, but I was compelled to omit it along with other important and interesting facets of the subject through lack of space. I have no doubt that some may consider the earlier contributions of Garrod11 and Snyder12 as noteworthy, as well as the important contributions of Vessel and Page.13 Similarly, I could have elaborated more on the early contributions by Eichelbaum and Bertillson14 who did much to improve our understanding of P450 enzymes. I also failed to mention some of the outstanding figures of the genomic era who are equally deserving of mention, such as Nobel prize-winner Karry Mullis, the inventor of the polymerase chain reaction (PCR),15 which facilitated the development of genomics and the related discipline of pharmacogenomics. This opened the door to easy screening for important genetically related disorders of metabolism and, in particular, permits the screening for abnormal enzymes, to which I referred in my Editorial.1 Other interesting areas that I was compelled to overlook, and which I think are of interest to anaesthetists, are the recently described variants of the 5-lipoxygenase gene (ALOX5 gene),16 which controls leukotriene synthesis and the beta 2 adrenergic (beta2AR) gene17 both of which may lead to differing responses of asthmatic patients to treatment. Variants of the ACE (angiotensin converting enzyme) gene18 have been found to be associated with differing responses to treatment with ACE inhibitors. I also omitted the latest and highly interesting discoveries related to the pharmacogenomics of smoking,19 which are known to alter outcome from anaesthesia.
My Editorial was neither intended to be a comprehensive review of the subject nor even a historical perspective, but only to draw attention to some of the more interesting aspects of recent developments in the field, which might induce the reader to explore the ever-expanding body of literature relating not only to pharmacogenomics, but also to the wider area of environmental/gene interactions. As such, it was intended to complement my earlier Editorial,20 which deals with the interesting effects of smoking on recovery from anaesthesia.
B. Sweeney
Bournemouth, UK
References
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