TY - JOUR
T1 - Genetic implication of a novel thiamine transporter in human hypertension
AU - Zhang, Kuixing
AU - Huentelman, Matthew J.
AU - Rao, Fangwen
AU - Sun, Eric I.
AU - Corneveaux, Jason J.
AU - Schork, Andrew J.
AU - Wei, Zhiyun
AU - Waalen, Jill
AU - Miramontes-Gonzalez, Jose Pablo
AU - Hightower, C. Makena
AU - Maihofer, Adam X.
AU - Mahata, Manjula
AU - Pastinen, Tomi
AU - Ehret, Georg B.
AU - Schork, Nicholas J.
AU - Eskin, Eleazar
AU - Nievergelt, Caroline M.
AU - Saier, Milton H.
AU - O'Connor, Daniel T.
N1 - Funding Information:
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.
PY - 2014/4/22
Y1 - 2014/4/22
N2 - Objectives: 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.
AB - Objectives: 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.
KW - SLC35F3
KW - hypertension
KW - thiamine
KW - transporter
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U2 - 10.1016/j.jacc.2014.01.007
DO - 10.1016/j.jacc.2014.01.007
M3 - Article
C2 - 24509276
AN - SCOPUS:84902115288
SN - 0735-1097
VL - 63
SP - 1542
EP - 1555
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 15
ER -