This study coupled 2 strategies—trait extremes and genome-wide pooling—to discover a novel blood pressure (BP) locus that encodes a previously uncharacterized thiamine transporter.
Background
Hypertension is a heritable trait that remains the most potent and widespread cardiovascular risk factor, although details of its genetic determination are poorly understood.
Methods
Representative genomic deoxyribonucleic acid (DNA) pools were created from male and female subjects in the highest- and lowest-fifth percentiles of BP in a primary care population of >50,000 patients. The peak associated single-nucleotide polymorphisms were typed in individual DNA samples, as well as in twins/siblings phenotyped for cardiovascular and autonomic traits. Biochemical properties of the associated transporter were evaluated in cellular assays.
Results
After chip hybridization and calculation of relative allele scores, the peak associations were typed in individual samples, revealing an association between hypertension, systolic BP, and diastolic BP and the previously uncharacterized solute carrier SLC35F3. The BP genetic association at SLC35F3 was validated by meta-analysis in an independent sample from the original source population, as well as the International Consortium for Blood Pressure Genome-Wide Association Studies (across North America and western Europe). Sequence homology to a putative yeast thiamine (vitamin B1) transporter prompted us to express human SLC35F3 in Escherichia coli, which catalyzed [3H]-thiamine uptake. SLC35F3 risk-allele homozygotes (T/T) displayed decreased erythrocyte thiamine content on microbiological assay. In twin pairs, the SLC35F3 risk allele predicted heritable cardiovascular traits previously associated with thiamine deficiency, including elevated cardiac stroke volume with decreased vascular resistance, and elevated pressor responses to environmental (cold) stress. Allelic expression imbalance confirmed that cis variation at the human SLC35F3 locus influenced expression of that gene, and the allelic expression imbalance peak coincided with the hypertension peak.
Conclusions
Novel strategies were coupled to position a new hypertension-susceptibility locus, uncovering a previously unsuspected thiamine transporter whose genetic variants predicted several disturbances in cardiac and autonomic function. The results have implications for the pathogenesis and treatment of systemic hypertension.
Key Words
hypertension
SLC35F3
thiamine
transporter
Abbreviations and Acronyms
AEI
allelic expression imbalance
ANOVA
analysis of variance
bp
base pairs
BP
blood pressure
cDNA
complementary deoxyribonucleic acid
CEU
Caucasian of European descent
CI
cardiac index
CO
cardiac output
DBP
diastolic blood pressure
DNA
deoxyribonucleic acid
HR
heart rate
ICBP
International Consortium for Blood Pressure Genome-Wide Association Studies
LD
linkage disequilibrium
MAF
minor allele frequency
mRNA
messenger ribonucleic acid
NCBI
National Center for Biotechnology Information
QTL
quantitative trait locus
RNA
ribonucleic acid
SBP
systolic blood pressure
SHR
spontaneously hypertensive rat
SNP
single-nucleotide polymorphism
SVR
systemic vascular resistance
SVRI
systemic vascular resistance index
TCDB
Transporter Classification Database
Cited by (0)
This research was funded by the National Institutes of Health (DK094894, HL58120, and UL1RR031980 [to UCSD Clinical and Translational Research Institute]; MD000220 [to UCSD Comprehensive Research Center in Health Disparities]) and the U.S. Department of Veterans Affairs. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Ronald G. Victor, MD, served as Guest Editor for this article.