We have noted the comments made by Doi, Noiri, and Tokunaga (1) in this issue of Diabetes Care. To our knowledge, our study (2) is the first to look at Caucasoid patients with type 1 diabetes. Previous studies have reported on type 2 diabetes. Unlike these previous studies, we have a unique group of patients with no microvascular disease after 20 years’ duration of diabetes (mean duration of diabetes 32.7 years). In our study, this group of uncomplicated patients had a distribution of p22phox alleles and genotypes similar to that of the normal healthy control subjects. They were very different from those of the patients with nephropathy. Similarly, those with retinopathy but no proteinuria (mean duration of diabetes 29.8 years) had remarkably different p22phox distribution from those with nephropathy. The study by Cahilly et al. (3) only included patients, and the frequency of the C242T alleles were not dissimilar from those found in our study. The study by Gardemann et al. (4) included blood donors and patients without coronary artery disease and myocardial infarction, participants who may be subject to selection bias. Our normal control population consisted of sequential cord blood samples taken after normal obstetric delivery and had no selection bias.

The calculation of haplotype frequencies was based on gene counting. Because it is impossible to absolutely determine the haplotypes of the double heterozygotes, these were excluded from the analysis. It is entirely appropriate to use the χ2 test and contingency tables to compare haplotype frequencies between these groups because the values relate to the actual numbers of chromosomes and are not estimates.

We must note that since the publication of our study, Matsunaga-Irie et al. (5) published a study of the association between p22phox C242T and diabetic nephropathy in Japanese patients with type 2 diabetes. Unfortunately, no normal control subjects were included in the study, although they report a lower frequency of the T242 allele than we found in our study.

Clearly, further studies are required to unravel the role of this polymorphism in susceptibility to diabetic nephropathy as well as macrovascular disease.

Doi K, Noiri E, Tokunaga K: The association of NAD(P)H oxidase p22phox with diabetic nephropathy is still uncertain (Letter).
Diabetes Care
Hodgkinson AD, Millward BA, Demaine AG: Association of the p22phox component of NAD(P)H oxidase with susceptibility to diabetic nephropathy in patients with type 1 diabetes.
Diabetes Care
Cahilly C, Ballantyne CM, Lim DS, Gotto A, Marian AJ: A variant of p22phox, involved in generation of reactive oxygen species in the vessel wall, is associated with progression of coronary atherosclerosis.
Circ Res
Gardemann A, Mages P, Katz N, Tillmanns H, Haberbosch W: The p22phox A640G gene polymorphism but not the C242T gene variation is associated with coronary heart disease in younger individuals.
Matsunaga-Irie S, Hirose H, Maruyama T, Shimada A, Yamamoto Y, Murata M, Motohashi Y, Saruta T: Relation between development of nephropathy and the p22phox C242T and receptor for advanced glycation end product G1704T gene polymorphisms in type 2 diabetic patients.
Diabetes Care