title: Genetic implication of a novel thiamine transporter in human hypertension.
abstract: OBJECTIVE
  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.
authors: Department of Medicine, University of California at San Diego (UCSD), La Jolla, California.
authors: Kuixing
authors: K
authors: Zhang
authors: Division of Neurogenomics, Translational Genomics Research Institute, Phoenix, Arizona.
authors: Matthew J
authors: MJ
authors: Huentelman
authors: Department of Medicine, University of California at San Diego (UCSD), La Jolla, California.
authors: Fangwen
authors: F
authors: Rao
authors: Department of Biology, UCSD, La Jolla, California.
authors: Eric I
authors: EI
authors: Sun
authors: Division of Neurogenomics, Translational Genomics Research Institute, Phoenix, Arizona.
authors: Jason J
authors: JJ
authors: Corneveaux
authors: Department of Medicine, University of California at San Diego (UCSD), La Jolla, California.
authors: Andrew J
authors: AJ
authors: Schork
authors: Department of Medicine, University of California at San Diego (UCSD), La Jolla, California.
authors: Zhiyun
authors: Z
authors: Wei
authors: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California.
authors: Jill
authors: J
authors: Waalen
authors: Department of Medicine, University of California at San Diego (UCSD), La Jolla, California.
authors: Jose Pablo
authors: JP
authors: Miramontes-Gonzalez
authors: Department of Medicine, University of California at San Diego (UCSD), La Jolla, California.
authors: C Makena
authors: CM
authors: Hightower
authors: 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.
authors: Adam X
authors: AX
authors: Maihofer
authors: Department of Medicine, University of California at San Diego (UCSD), La Jolla, California.
authors: Manjula
authors: M
authors: Mahata
authors: Departments of Human and Medical Genetics, McGill University and Génome Québec Innovation Centre, Montréal, Québec, Canada.
authors: Tomi
authors: T
authors: Pastinen
authors: Center for Complex Disease Genomics, McKusick-Nathans, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Georg B
authors: GB
authors: Ehret
authors: Department of Psychiatry, UCSD, La Jolla, California; Departments of Computer Science and Human Genetics, University of California at Los Angeles, Los Angeles, California.
authors: Nicholas J
authors: NJ
authors: Schork
authors: Departments of Human and Medical Genetics, McGill University and Génome Québec Innovation Centre, Montréal, Québec, Canada.
authors: Eleazar
authors: E
authors: Eskin
authors: 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.
authors: Caroline M
authors: CM
authors: Nievergelt
authors: Department of Biology, UCSD, La Jolla, California.
authors: Milton H
authors: MH
authors: Saier
authors: 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.
authors: Daniel T
authors: DT
authors: O'Connor
mesh_terms: D000328:Adult; D000483:Alleles; D001794:Blood Pressure; D004247:DNA / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011110:Polymorphism, Genetic; D013831:Thiamine / Q000235:genetics / Q000378:metabolism
chemical_list: D026901:Membrane Transport Proteins; C120043:SLC19A2 protein, human; D004247:DNA; D013831:Thiamine
keywords: SLC35F3; hypertension; thiamine; transporter