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CLINICAL RESEARCH: GENETICS/GENOMICS

Neuropeptide Y₁ Receptor NPY1R

Discovery of Naturally Occurring Human Genetic Variants Governing Gene Expression In Cella as Well as Pleiotropic Effects on Autonomic Activity and Blood Pressure In Vivo

Lei Wang, MD^_*, Fangwen Rao, MD^_*, Kuixing Zhang, MD, PhD^_*, Manjula Mahata, PhD^_*, Juan L. Rodriguez-Flores, PhD^_*, Maple M. Fung, MD^_*,, Jill Waalen, MD, Myles G. Cockburn, PhD^||, Bruce A. Hamilton, PhD^_*, Sushil K. Mahata, PhD^_*, and Daniel T. O'Connor, MD^_*,,,_*

^_* Department of Medicine, University of California at San Diego, California
Department of Pharmacology, University of California at San Diego, California
VA San Diego Healthcare System, San Diego, California
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California
^|| Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, California

Manuscript received February 17, 2009; revised manuscript received May 13, 2009, accepted May 14, 2009.

^_* Reprint requests and correspondence: Dr. Daniel T. O'Connor, Department of Medicine, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0838 (Email: doconnor{at}ucsd.edu).

Objectives: We asked whether naturally occurring genetic variation at the human NPY1R locus alters autonomic traits that might predispose individuals to cardiovascular disease.

Background: Neuropeptide Y (NPY) interacts with the Y₁ receptor, NPY1R, to control adrenergic activity and blood pressure (BP).

Methods: We searched for polymorphism at NPY1R by systematic resequencing in ethnically diverse people. There were 376 twins/siblings who were evaluated for heritable autonomic traits: baroreflex function and pressor response to environmental stress.

Results: The common NPY1R variant A+1050G in the 3'-untranslated region (3'-UTR) predicted baroreceptor slope (p = 0.014–0.047) and BP change to cold stress (p = 0.0091–0.016), with minor allele homozygotes displaying blunted slope and exaggerated pressor response. In 936 individuals with the most extreme BPs in the population, not only 3'-UTR A+1050G (p = 1.2 x 10^–4) but also promoter A-585T (p = 0.001) affected both systolic BP and diastolic BP, in interactive fashion (p = 0.007), with combined homozygotes showing the highest diastolic BP (>20 mm Hg). The 3'-UTR variant +1050G decreased expression of a transfected luciferase reporter/NPY1R 3'-UTR plasmid; promoter variant A-585 also decreased expression of an NPY1R promoter/luciferase reporter. Thus, alleles that increased BP in vivo (3'-UTR +1050G, promoter A-585) also decreased NPY1R expression in cella. Computational alignment showed that A+1050G disrupted a microRNA motif.

Conclusions: Our results indicate that naturally occurring genetic variation at the NPY1R locus has implications for heritable autonomic control of the circulation, and ultimately, for systemic hypertension. The findings suggest novel pathophysiological links between the NPY1R locus, autonomic activity, and blood pressure, and suggest new strategies to approach the mechanism, diagnosis, and treatment of systemic hypertension.

Key Words: hypertension • neuropeptide • genetics

Abbreviations and Acronyms   BP = blood pressure   DBP = diastolic blood pressure   Del = deletion   h2 = heritability   HR = heart rate   Ins = insertion   LD = linkage disequilibrium   NPY = neuropeptide Y   NPY1R = neuropeptide Y1 receptor   SBP = systolic blood pressure   SNP = single nucleotide polymorphism   UTR = untranslated region

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