Haplotypes of the NR4A2/NURR1 gene and cardiovascular disease: the Rotterdam Study.

Nuclear receptor subfamily 4, group A, member 2 (NR4A2, also called Nurr1) has lately become of interest with regard to atherogenesis. We examined the association between common variation in the NR4A2 gene and cardiovascular disease in the Rotterdam Study, a prospective population-based study among persons aged > or = 55 years. Three SNPs that tag common haplotypes across a 36-kb region surrounding the NR4A2 gene were determined. Four haplotypes with frequencies >1% covered 96% of the genetic variation. In 5,650 participants without history of coronary heart disease, 729 coronary heart disease events occurred during a median follow-up time of 11.9 years. NR4A2 haplotypes were neither associated with coronary events nor with intima-media thickness (IMT), carotid plaques, or ankle-arm index (AAI). NR4A2 haplotypes showed a tendency toward associations with aortic and coronary calcification (haplo.score global simulation P values 0.076 and 0.075, respectively), which seemed to be based on haplotype 2 (individual P values were both P=0.015). Furthermore, NR4A2 haplotype 3 was associated with higher high-density lipoprotein (HDL) cholesterol and haplotype 4 with lower systolic blood pressure. In conclusion, NR4A2/NURR1 haplotypes were not associated with coronary events, carotid IMT, carotid plaques, or AAI. There was a tendency toward associations with aortic calcification and coronary calcification. Associations for NR4A2 were found with both HDL levels and blood pressure. It remains to be investigated which pathophysiological mechanisms pertain to NR4A2 function in cardiovascular disease.