Haplotypes of theNR4A2/NURR1gene and cardiovascular disease: The Rotterdam Study

Abstract

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.

Nuclear Receptor Nurr1 Is Expressed In and Is Associated With Human Restenosis and Inhibits Vascular Lesion Formation In Mice Involving Inhibition of Smooth Muscle Cell Proliferation and Inflammation

“…18 Genotypes were determined with the Taqman assay (Applied Biosystems, Foster City, Calif). Reactions were performed with the TaqmanPrism7900HT in 384-well format.…”

NR4All in the vessel wall

“…The association between Nurr1 haplotypes and cardiovascular disease was investigated in the 'Rotterdam Study', which is a prospective population-based study among persons aged ≥55 years. In this study, in which 5650 participants without a history of coronary heart disease were included, associations for Nurr1 were found with high density lipoprotein levels and blood pressure and Nurr1 haplotypes showed a tendency toward association with aortic and coronary calcification, however, Nurr1 variation was not associated with coronary events [28]. In a second study, the association between Nurr1 haplotypes and in-stent restenosis risk was investigated in a prospective cohort of patients undergoing percutaneous coronary intervention in combination with stent placement.…”

Bioinformatics analysis of potential key genes and mechanisms in type 2 diabetes mellitus

“…HLA-DRA [148], SERPINA1 [149], ABHD12 [150], IMPA2 [151], ARSA (arylsulfatase A) [152], LRFN5 [153], PLXNA4 [154], CHL1 [155], ITPKB (inositol-trisphosphate 3-kinase B) [156], PTN (pleiotrophin) [157], LAMA2 [158], CDH6 [159] and A2M [160] have been shown to have an important role in neurological disorders, but these genes might be associated with progression of T2DM. HLA-F [161], HLA-H [162], FGA (fibrinogen alpha chain) [163], HSPA1B [164], MRC1 [165], DAB2IP [166], KCNJ8 [167], KLKB1 [168], CXCL2 [169], SERPINE2 [170], ADH1C [171], AMBP (alpha-1-microglobulin/bikunin precursor) [172], NR4A2 [173], TYMP (thymidine phosphorylase) [174], TFRC (transferrin receptor) [175], PLAU (plasminogen activator, urokinase) [176], COL6A2 [177], COL15A1 [178], ABI3BP [179], NEXN (nexilin F-actin binding protein) [180], S1PR1 [181], THY1 [182], COL4A1 [183], COL5A2 [184], ADAMTS2 [185], ECM1 [186] and LTBP2 [187] have been found to be differentially expressed in cardiovascular diseases, but these genes might be linked with progression of T2DM. CCL20 [188], CRH (corticotropin releasing hormone) [189], SPP1 [190], LDLR (low density lipoprotein receptor) [191], RORA (RAR related orphan receptor A) [192], LYZ (lysozyme) [193], PTPRN2 [194], DAPK2 [195], OIP5 [196], PON3 [197], NR4A3 [198], VCAN (versican) [199], CNTNAP2 [200], IL1RAP [201], GLI2 [202], CDH13 [203], AEBP1 [204], BGN (biglycan) [205], LOX (lysyl oxidase) [206], IL1RL1 [207] and LUM (lumican) [208] were found to be involved in advancement of obesity, but these genes might be key for development of T2DM.…”