The study of functional polymorphism within the deoxyribonuclease I gene associated with disease.

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Using both the PCR-RFLP and multiplex single base extension techniques, genotyping of all the non-synonymous SNPs was performed in healthy subjects (n=1,559) of three ethnic groups including 15 populations. Among them, only four SNPs, R-21S, Y95S, G105R, and Q222R, together with the synonymous SNP L186L, were polymorphic in all or some populations. The Asian group showed a relatively low genetic diversity of these SNPs, whereas the African group had the highest diversity. The distribution pattern of the common SNP Q222R was classified into three ethnic groups. Activity levels of the amino acid-substituted DNase I forms derived from SNPs R-21S, G105R, P132A, and P197S were significantly high compared with that of the wild type; the polymorphic SNPs R-21S (Africans and Mexicans) and G105R (Africans) gave rise to a high activity-harboring DNase I isoform. On the other hand, activity levels from Q35H, R85G, V89M, C209Y, Q222R, and A224P were significantly low, but these SNPs, except Q222R, were not distributed in any of the populations examined. However, since these SNPs may produce potentially low levels of in vivo DNase I activity, a minor allele in each SNP will be served as a genetic risk factor for autoimmune diseases. Therefore, information on the worldwide distribution of non-synonymous SNPs in DNASE1 and the effects of the corresponding amino acid substitution on the activity levels will provide a genetic basis for the clarification of a possible relationship between DNase I and diseases.