Identification of the functional alleles of the nonsynonymous single-nucleotide polymorphisms potentially implicated in systemic lupus erythematosus in the human deoxyribonuclease I gene.

In the present study, we have extensively continued our previous investigations of the nonsynonymous single-nucleotide polymorphisms (SNPs) in the human DNase I (DNASE1) gene potentially relevant to systemic lupus erythematosus (SLE); therefore, all of the 58 nonsynonymous SNPs registered in the NCBI dbSNP database could be evaluated and it could be checked as to whether these SNPs might serve as a functional SNP. From a compiled expression analysis of the amino-acid-substituted DNase I corresponding to each of the SNPs, it was possible to sort them into 23 SNPs while not affecting the activity: 12 abolishing it, 14 reducing it, and 9 increasing it. Among a total of 58 nonsynonymous SNPs, only 4 SNPs exhibited genetic polymorphisms in some of the populations examined; a minor allele producing a loss-of-function variant of each SNP was not distributed in 14 different populations derived from three ethnic groups. It could be assumed that a minor allele of these functional SNPs, despite their remarkably low genetic heterogeneity, could directly serve as a genetic risk factor for SLE. Furthermore, among the human DNase family genes, it seems that DNASE1 is able to tolerate the generation of nonsynonymous SNPs, and that the amino-acid substitutions resulting from the SNPs in DNASE1 easily alter the activity.