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


CONCLUSIONS
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.
McArdle
Patrick F
PF
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA. pmcardle@medicine.umaryland.edu
Rutherford
Sue
S
Mitchell
Braxton D
BD
Damcott
Coleen M
CM
Wang
Ying
Y
Ramachandran
Vasan
V
Ott
Sandy
S
Chang
Yen-Pei C
YP
Levy
Daniel
D
Steinle
Nanette
N
D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000503:physiopathology; D002835:Christianity; D015331:Cohort Studies; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010414:Pennsylvania; D020641:Polymorphism, Single Nucleotide; D011950:Receptors, Cholinergic / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013599:Systole / Q000235:genetics
C523021:CHRNA1 protein, human; C514767:CHRND protein, human; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic