My experience with Inish (Belfast based Science fiction, totally immersed in the land, and written in an unashamed Norn Irish voice) went like this:
Subbed to many agents, had interest from quite a few. One US agent (not Mr Blimes, but quite a high profile one) rejected on the basis that a UK agent would do better with it.
Finally signed with an American-born agent, based in the London office of a NY agency.
The agent didn't sell it (the market for YA and crossover sf, which it was subbed as, was terrible at the time) but I saw the editors' comments (both Uk and US.) Not one rejected based on the setting. In fact almost all, including the American editors liked the setting. Since it's come out, it has been more popular in the UK, by quite a long margin (but my profile is higher in the UK) but it is selling in America and getting good reviews - although not just as good as the UK reviews.
So, it was no barrier for US agents or editors or, if it was, it was a very tiny barrier. Having said that, as
@Hex pointed out earlier, Ireland and Scotland tend to be popular. In our case, it's not the hairy-kneed haggis-eating hunks, but the lephrechauns. That's a fact, shure t'is.
)