2. Academic Validation
  3. Genetic implication of a novel thiamine transporter in human hypertension

Genetic implication of a novel thiamine transporter in human hypertension

  • J Am Coll Cardiol. 2014 Apr 22;63(15):1542-55. doi: 10.1016/j.jacc.2014.01.007.
Kuixing Zhang 1,  Matthew J Huentelman 2,  Fangwen Rao 1,  Eric I Sun 3,  Jason J Corneveaux 2,  Andrew J Schork 1,  Zhiyun Wei 1,  Jill Waalen 4,  Jose Pablo Miramontes-Gonzalez 1,  C Makena Hightower 1,  Adam X Maihofer 5,  Manjula Mahata 1,  Tomi Pastinen 6,  Georg B Ehret 7,  International Consortium for Blood Pressure Genome-Wide Association Studies,  Nicholas J Schork 8,  Eleazar Eskin 6,  Caroline M Nievergelt 5,  Milton H Saier Jr 3,  Daniel T O'Connor 9
Affiliations

Affiliations

  • 1 Department of Medicine, University of California at San Diego (UCSD), La Jolla, California.
  • 2 Division of Neurogenomics, Translational Genomics Research Institute, Phoenix, Arizona.
  • 3 Department of Biology, UCSD, La Jolla, California.
  • 4 Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California.
  • 5 Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California; Departments of Human and Medical Genetics, McGill University and Génome Québec Innovation Centre, Montréal, Québec, Canada.
  • 6 Departments of Human and Medical Genetics, McGill University and Génome Québec Innovation Centre, Montréal, Québec, Canada.
  • 7 Center for Complex Disease Genomics, McKusick-Nathans, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • 8 Department of Psychiatry, UCSD, La Jolla, California; Departments of Computer Science and Human Genetics, University of California at Los Angeles, Los Angeles, California.
  • 9 Department of Medicine, University of California at San Diego (UCSD), La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California; Department of Pharmacology and the Institute for Genomic Medicine, UCSD, La Jolla, California. Electronic address: doconnor@ucsd.edu.
PMID: 24509276 DOI: 10.1016/j.jacc.2014.01.007
Abstract

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 [(3)H]-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.

Keywords

SLC35F3; hypertension; thiamine; transporter.

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