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. 2014 Apr 22;63(15):1542-55.
doi: 10.1016/j.jacc.2014.01.007. Epub 2014 Feb 5.

Genetic implication of a novel thiamine transporter in human hypertension

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

Genetic implication of a novel thiamine transporter in human hypertension

Kuixing Zhang et al. J Am Coll Cardiol. .

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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Conflict of interest statement

Conflicts of interest: None to disclose.

Figures

Figure 1
Figure 1. Population BP extremes: A powerful approach to genotypes underlying hypertension
Blood pressure distribution in a primary care population of ~53,000 adults. From a primary care database of over 53,000 people (27,478 females and 25,528 males), we ascertained age-, gender-and ethnicity-matched individuals with extremely high and low DBPs (from the upper and lower 5th percentiles of the DBP distribution). This approach has >90% power to detect loci contributing >2.5% of BP variance. Red rectangles: DBP range for upper and lower %ile (extreme) sample selection. Schork et al. AJHG 67:1208–1218, 2000. Kaiser health maintenance screening, San Diego, California.
Figure 2
Figure 2. SLC35F3 tagging variants
Effect on blood pressure in population BP extreme subjects, and replication. Each of the two tagging variants is located within the same LD block in SLC35F3 Intron-2. A: Effect of rs17514104 on BP status (diagnosis: hypertensive, normotensive) as a dichotomous trait. The statistical test was chi-square. B: Effect of rs17514104 on SBP and DBP as quantitative traits (mmHg). The statistical test was ANOVA, adjusted for age and sex. C. Effect of rs16842784 on SBP and DBP as quantitative traits (mmHg). ANOVA was adjusted for sex and age.
Figure 2
Figure 2. SLC35F3 tagging variants
Effect on blood pressure in population BP extreme subjects, and replication. Each of the two tagging variants is located within the same LD block in SLC35F3 Intron-2. A: Effect of rs17514104 on BP status (diagnosis: hypertensive, normotensive) as a dichotomous trait. The statistical test was chi-square. B: Effect of rs17514104 on SBP and DBP as quantitative traits (mmHg). The statistical test was ANOVA, adjusted for age and sex. C. Effect of rs16842784 on SBP and DBP as quantitative traits (mmHg). ANOVA was adjusted for sex and age.
Figure 2
Figure 2. SLC35F3 tagging variants
Effect on blood pressure in population BP extreme subjects, and replication. Each of the two tagging variants is located within the same LD block in SLC35F3 Intron-2. A: Effect of rs17514104 on BP status (diagnosis: hypertensive, normotensive) as a dichotomous trait. The statistical test was chi-square. B: Effect of rs17514104 on SBP and DBP as quantitative traits (mmHg). The statistical test was ANOVA, adjusted for age and sex. C. Effect of rs16842784 on SBP and DBP as quantitative traits (mmHg). ANOVA was adjusted for sex and age.
Figure 3
Figure 3. SLC35F3 and thiamine metabolism
A: Uptake of [3H]-thiamine by expression of human SLC35F3 cDNA in E. coli. Augmentation of [3H]-thiamine uptake was ~3.3-fold in n=7 points (p=3.4E-04). The results were normalized to E.coli growth in the sample (A550). B: SLC35F3 genotype (C/C versus T/T homozygosity at rs17514104): Effect on blood thiamine concentration in twins and siblings.
Figure 3
Figure 3. SLC35F3 and thiamine metabolism
A: Uptake of [3H]-thiamine by expression of human SLC35F3 cDNA in E. coli. Augmentation of [3H]-thiamine uptake was ~3.3-fold in n=7 points (p=3.4E-04). The results were normalized to E.coli growth in the sample (A550). B: SLC35F3 genotype (C/C versus T/T homozygosity at rs17514104): Effect on blood thiamine concentration in twins and siblings.
Figure 4
Figure 4. SLC35F3 and hypertension: Effects on early pathogenic (or “intermediate”) traits in twins and siblings
Twin and sibling analyses were adjusted for sex and age. A: SLC35F3 variant rs17514104 effects on systemic vascular resistance and stroke volume in twins and sibling pairs. B: SLC35F3 variant rs17514104 effects on change in DBP and final DBP during cold stress. C: SLC35F3 variant rs17514104 effects on sympathochromaffin exocytosis (secretion of SCG2 fragment secretoneurin) and systemic vascular resistance.
Figure 4
Figure 4. SLC35F3 and hypertension: Effects on early pathogenic (or “intermediate”) traits in twins and siblings
Twin and sibling analyses were adjusted for sex and age. A: SLC35F3 variant rs17514104 effects on systemic vascular resistance and stroke volume in twins and sibling pairs. B: SLC35F3 variant rs17514104 effects on change in DBP and final DBP during cold stress. C: SLC35F3 variant rs17514104 effects on sympathochromaffin exocytosis (secretion of SCG2 fragment secretoneurin) and systemic vascular resistance.
Figure 4
Figure 4. SLC35F3 and hypertension: Effects on early pathogenic (or “intermediate”) traits in twins and siblings
Twin and sibling analyses were adjusted for sex and age. A: SLC35F3 variant rs17514104 effects on systemic vascular resistance and stroke volume in twins and sibling pairs. B: SLC35F3 variant rs17514104 effects on change in DBP and final DBP during cold stress. C: SLC35F3 variant rs17514104 effects on sympathochromaffin exocytosis (secretion of SCG2 fragment secretoneurin) and systemic vascular resistance.
Figure 5
Figure 5. SLC35F3 genetic variation
Hypothetical schema for the consequences of SLC35F3 polymorphism for thiamine regulation and cardiovascular disease.
See this image and copyright information in PMC

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