Methodologic quality and genotyping reproducibility in studies of tumor necrosis factor -308 G-->A single nucleotide polymorphism and bacterial sepsis: implications for studies of complex traits

Failure to confirm genotype may have led to conclusions that this polymorphism is not associated with sepsis or outcome. Our observations have implications for the conduct and evaluation of studies of complex genetic disease.

Studies of genetic associations with common diseases, such as between cytokine gene polymorphisms and severe bacterial sepsis, have reached conflicting conclusions. Failure to follow methodologic standards may have contributed to discordant findings. The -308 G-->A transition in the tumor necrosis factor-alpha promoter has been genotyped by a variety of

We observed that methodologic quality was not uniform and that reproducibility of genotyping was infrequently met. In our subjects, we found that 4 of 46 heterozygotes analyzed by restriction fragment length polymorphism were actually GG-homozygotes (9% misclassified) according to alternative genotyping methods. Conclusions: Failure to confirm genotype may have led to conclusions that this polymorphism is not associated with sepsis or outcome. Our observations have implications for the conduct and evaluation of studies of complex genetic disease.