Nicotinic acetylcholine receptor subunit variants are associated with blood pressure; findings in the Old Order Amish and replication in the Framingham Heart Study

Patrick F McArdle¹ , Sue Rutherford² , Braxton D Mitchell¹ , Coleen M Damcott¹ , Ying Wang¹ , Vasan Ramachandran³ , Sandy Ott¹ , Yen-Pei C Chang¹ , Daniel Levy⁴ and Nanette Steinle¹

¹Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

²Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio TX, USA

³Division of Cardiology, Boston University School of Medicine, Boston MA, USA

⁴National Heart, Lung, and Blood Institute, Bethesda, MD, USA

author email corresponding author email

BMC Medical Genetics 2008, 9:67doi:10.1186/1471-2350-9-67


Published:	14 July 2008

Abstract

Background

Systemic blood pressure, influenced by both genetic and environmental factors, is regulated via sympathetic nerve activity. We assessed the role of genetic variation in three subunits of the neuromuscular nicotinic acetylcholine receptor positioned on chromosome 2q, a region showing replicated evidence of linkage to blood pressure.

Methods

We sequenced CHRNA1, CHRND and CHRNG in 24 Amish subjects from the Amish Family Diabetes Study (AFDS) and identified 20 variants. We then performed association analysis of non-redundant variants (n = 12) in the complete AFDS cohort of 1,189 individuals, and followed by genotyping blood pressure-associated variants (n = 5) in a replication sample of 1,759 individuals from the Framingham Heart Study (FHS).

Results

The minor allele of a synonymous coding SNP, rs2099489 in CHRNG, was associated with higher systolic blood pressure in both the Amish (p = 0.0009) and FHS populations (p = 0.009) (minor allele frequency = 0.20 in both populations).

Conclusion

CHRNG is currently thought to be expressed only during fetal development. These findings support the Barker hypothesis, that fetal genotype and intra-uterine environment influence susceptibility to chronic diseases later in life. Additional studies of this variant in other populations, as well as the effect of this variant on acetylcholine receptor expression and function, are needed to further elucidate its potential role in the regulation of blood pressure. This study suggests for the first time in humans, a possible role for genetic variation in the neuromuscular nicotinic acetylcholine receptor, particularly the gamma subunit, in systolic blood pressure regulation.