Limitations of Genetic Findings That Are Not in Hardy-Weinberg Equilibrium
Body, Simon C. M.B., Ch.B., M.P.H.†; Schwinn, Debra A. M.D.
To the Editor:—
Zaugg et al.1
report an association between the Arg389Gly (rs1801253) single nucleotide polymorphism of the β1
-adrenergic receptor and adverse cardiac outcomes occurring within 1 yr of spinal anesthesia in patients with clinically important coronary artery disease. Although quite interesting, this report may be flawed by an important statistical methodology error.
The reported genotypes of rs1801253 are not in Hardy-Weinberg equilibrium (P
= 4.2 × 10−7
) and have a lower than expected number of heterozygotes. Publicly available genotyping demonstrates that the Arg389Gly genetic variant is generally found to be in Hardy-Weinberg equilibrium.*
The most frequent cause of reduced heterozygote expression is genotyping error caused by low amplification of one of the two alleles in the genotyping process. Examination of genotyping intensity plots will frequently, but not always, identify such errors. With such a markedly abnormal result, the authors would be advised to regenotype this single nucleotide polymorphism using another genotyping platform, preferably by an independent laboratory, to confirm their findings.
The reader is referred to an informative description of Hardy-Weinberg equilibrium in the same issue of Anesthesiology for an explanation of this important quality control measure in genotyping studies.2
Guidance for quality control and reporting the results of genotyping studies have recently been provided.3
Specifically, measures to assess the quality of genotype data should include (1) excluding single nucleotide polymorphisms with low genotyping frequencies, (2) excluding single nucleotide polymorphisms not in Hardy-Weinberg equilibrium, (3) performing genotyping on known study sample duplicates or publicly available samples to confirm accuracy of the genotyping methods, and (4) other methodologic and statistical techniques to ensure data quality. Accordingly, the association reported by Zaugg et al.
should be regarded with considerable caution until confirmation in other cohorts.
Simon C. Body, M.B., Ch.B., M.P.H.,†
Debra A. Schwinn, M.D.
†Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. firstname.lastname@example.org
1. Zaugg M, Bestmann L, Wacker J, Lucchinetti E, Boltres A, Schulz C, Hersberger M, Kälin G, Furrer L, Hofer C, Blumenthal S, Müller A, Zollinger A, Spahn DR, Borgeat A: Adrenergic receptor genotype but not perioperative Bisoprolol therapy may determine cardiovascular outcome in at-risk patients undergoing surgery with spinal block: The Swiss Beta Blocker in Spinal Anesthesia (BBSA) study: A double-blinded, placebo-controlled, multicenter trial with 1-year follow-up. Anesthesiology 2007; 107:33–44
2. Lötsch J: Basic genetic statistics are necessary in studies of functional associations. Anesthesiology 2007; 107:168–9
3. NCI-NH GRI Working Group on Replication in Association Studies, Chanock SJ, Manolio T, Boehnke M, Boerwinkle E, Hunter DJ, Thomas G, Hirschhorn JN, Abecasis G, Altshuler D, Bailey-Wilson JE, Brooks LD, Cardon LR, Daly M, Donnelly P, Fraumeni JF, Freimer NB, Gerhard DS, Gunter C, Guttmacher AE, Guyer MS, Harris EL, Hoh J, Hoover R, Kong CA, Merikangas KR, Morton CC, Palmer LJ, Phimister EG, Rice JP, Roberts J, Rotimi C, Tucker MA, Vogan KJ, Wacholder S, Wijsman EM, Winn DM, Collins FS: Replicating genotype-phenotype associations. Nature 2007; 447:655–60
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