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ELECTRONIC ARTICLE: S. Nadya J. Kazzi, U. Olivia Kim, Michael W. Quasney, and Irina Buhimschi Polymorphism of Tumor Necrosis Factor- and Risk and Severity of Bronchopulmonary Dysplasia Among Very Low Birth Weight Infants Pediatrics 2004; 114: e243-e248 [Abstract] [Full text] [PDF]

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An Important Pitfall In Neonatal Genetic Association Studies

David R Harding   (20 January 2005)

An Important Pitfall In Neonatal Genetic Association Studies 20 January 2005
David R Harding, Consultant Neonatologist St. Michael's Hospital, Bristol Send letter to journal: Re: An Important Pitfall In Neonatal Genetic Association Studies david.harding{at}bristol.ac.uk David R Harding	The pro-inflammatory response contributes to the development of bronchopulmonary dysplasia (BPD) in the very low birthweight (VLBW) infant. It is logical therefore that a genetic polymorphism that down regulates the inflammatory response should be found to be associated with a reduced occurrence rate of BPD in the VLBW infant (1). This interesting work is however flawed in design and this flaw alters the conclusion that can be drawn. Gene and environment association studies relate the magnitude of a biochemical, physiological or pathological response to an environmental stimulus (preferably uniform) with variation in a candidate gene. The response of an individual exposed to an insult (in this case preterm birth and its sequele, including RDS, mechanical ventilation and sepsis) depends not only on the nature and magnitude of the stimulus but also on the subject's physical and genetic characteristics. It is extremely important therefore in a gene-environment interaction study involving the preterm infant, who is exposed to a multitude of insults, that the subjects are as homogeneous as possible i.e. of the same race (and arguably gender). Associations of phenotype with race will confound the association with genotype if polymorphism frequency also varies with race, or the effect of the polymorphism is altered by the racial background that it finds itself in, or if the phenotype is affected by other genes associated with race. Functionally significant single nucleotide polymorphisms (SNPs) of cytokine genes have been shown for instance to account for (assuming causality rather than association) differences in kidney (allograft) transplant survival and to vary in frequency in different racial groups (e.g. white, black and Hispanic (2)). The patients described by Kazzi et al (1) comprised 24 white patients, 93 African-American babies and 3 Hispanic infants which are spread over three genotypes per polymorphism. Racial breakdown of the polymorphic variants are not described, and the study is too small to demonstate such difference (if they exist in the preterm population). Thus while fully agreeing in theory with the conclusion that determination of genotype in VLBW infants may provide clinicians with a useful tool for identifying infants at risk of BPD and allow us to target therapies at the higher risk patients (1) it must be stressed that before such work can be attempted large epidemiological studies should be performed in specific racial groups to model the possible effects of functional SNPs upon phenotyope. 1: Kazzi SN, Kim UO, Quasney MW, Buhimschi I. Polymorphism of tumor necrosis factor-alpha and risk and severity of bronchopulmonary dysplasia among very low birth weight infants. Pediatrics. 2004;114:e243-8. 2: Hoffmann SC, Stanley EM, Cox ED, DiMercurio BS, Koziol DE, Harlan DM, Kirk AD, Blair PJ. Ethnicity greatly influences cytokine gene polymorphism distribution. Am J Transplant. 2002;2:560-7.