Actually its a prequel, with just enough room left over to expand a little on how the two fit in (obviously via DLC for this game, if they bother at all).
JC doesn't know his brother yet. That's because they are both adoptees to different couples supposedly. The old woman in DEx3 confirms this. He was actually known as JC Denton to her (from White Labs) prior to the fire that took his parents, (who weren't actually his parents but scientists). I could be wrong but I thought 'White Labs' was one of the many researchers into the genomic project initiative. Genomic projects (beginning as early as the 1960's) were everything from finding genetic to synthetic bonds all the way up to super soldiers and so on. It;s not a sinister thing, just science doing what's requested of it.
In DEx1, the two brothers discuss this and JC finds out more as he goes along in that game (if I remember correctly) so it's only loosely connected to anyone that didn't play the first game (or simply doesn't remember it).
Actually in playing this game, it dredged up alot of the things I remember about the Original in order for me to be writing this. So I'd definitely say that its done its job well, to do that.
I wasn't surprised by Megan; much throughout the game pretty much softens the blow about what eventually occurs. It's completely irritating that you can't tell JC that he's barking up the wrong tree regarding her. If one could I would've tasked him to assassinate her as a priority target and then probe deeper into what's behind her. Alas we're years away from that kinda interactive entertainment.