You can create your own UserControl (implementing ISettingControl) which validates the field based on other values in the DB. An example implementation is /Controls/GMapTypeSetting.ascx, which is used for choosing the map type in features that have Google maps. You can look at /Setup/applications/googlemap/FeatureDefinitions/50020_GoogleMapModule.config for an example configuration.
Using ISettingControl in Module Settings or in User Profiles is very similar. You store a single value in the DB and retreive that same value. You can do whatever you need to with the user-entered value before storing it.