I'd say its the underlying theme. If they got rid of it and mutants were accepted the book would be just like any other superhero book.
That said, Marvel have really given it a good kicking over the years. The whole decimation has underrun half the point of the X-Men now. Theyre not a minority anymore, theyre effectively just a small gang with superpowers who fight lots of other gangs with superpowers. Theres no "millions of other mutants just trying to live normal lives" that theyre trying to protect. Theres so few mutants, If you just killed the whole lot of them it would actually save a lot more lives in the long run. Screw building Sentinels, you'd save a lot more money just giving all the "evil" villains a few million each just to live on a tropical island somewhere, miles from anywhere.
Now all the "middle ground" mutants are gone, you only have two groups of mutants left.
Group 1 : Wants to kill all the humans and rule the world or just use their powers for crime.
Group 2 : Never have jobs, all only look out for eachother and rarely socialise with non-mutants, seem to have ridiculously advanced alien technology (which they wont share with the "normal" population) and all sponge off a few Wealthy Mutants that give anyone all the money they could dreamof and a place to stay... as long as theyre a mutant.
This isnt a generalisation. Nearly all Mutants in the MU fit into one of these groups.No wonder people dont like mutants.
I call it the X-Men the Last Stand Effect (god I hated that movie). At the end of the Movie, when it all came down to the last stand, Good mutants who want to save people vs bad mutants that want to kill all the humans.. there was what.. 5, 6 Good mutants? against a whole friggin army of mutants that just seemed to want to kill everyone.
You begin to start thinking that maybe people are right to fear them and maybe it would just be common sense for a government to try and do something about them.