Evidence for a relationship between genetic polymorphisms of the L-DOPA transporter LAT2/4F2hc and risk of hypertension in the context of chronic kidney disease.

Publisher: BioMed Central Country of Publication: England NLM ID: 101319628 Publication Model: Electronic Cited Medium: Internet ISSN: 1755-8794 (Electronic) Linking ISSN: 17558794 NLM ISO Abbreviation: BMC Med Genomics Subsets: MEDLINE

Original Publication: London : BioMed Central

Hypertension*/genetics ; Hypertension*/complications ; Renal Insufficiency, Chronic*/genetics ; Renal Insufficiency, Chronic*/metabolism ; Amino Acid Transport System y+*/genetics; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Fusion Regulatory Protein 1, Heavy Chain/genetics ; Fusion Regulatory Protein 1, Heavy Chain/metabolism ; Genetic Predisposition to Disease ; Levodopa/therapeutic use ; Polymorphism, Single Nucleotide ; Risk Factors ; Fusion Regulatory Protein 1, Light Chains/genetics

Background: Chronic kidney disease (CKD) and hypertension are chronic diseases affecting a large portion of the population frequently coexistent and interdependent. The inability to produce/use adequate renal dopamine may contribute to the development of hypertension and renal dysfunction. The heterodimeric amino acid transporter LAT2/4F2hc (SLC7A8/SLC3A2 genes) promotes the uptake of L-DOPA, the natural precursor of dopamine. We examined the plausibility that SLC7A8/SLC3A2 gene polymorphisms may contribute to hypertensive CKD by affecting the L-DOPA uptake.
Methods: 421 subjects (203 men and 218 women, mean age of 78.9 ± 9.6 years) were recruited and divided in four groups according to presence/absence of CKD, defined as reduced estimated glomerular filtration rate (eGFR < 60 ml/min/m ² ) calculated using the creatinine-based Berlin Initiative Study-1 (BIS1) equation, and to presence/absence of hypertension (systolic blood pressure ≥ 140 and/or diastolic blood pressure ≥ 90 mmHg). Subjects were analysed for selected SNPs spanning the SLC7A8 and SLC3A2 loci by Sequenom MassARRAY iPLEX platform.
Results: The most significant SNP at the SLC3A2 (4F2hc) locus was rs2282477-T/C, with carriers of the C-allele having a lower chance to develop hypertension among CKD affected individuals [OR = 0.33 (CI 0.14-0.82); p = 0.016]. A similar association with hypertensive CKD was found for the SLC7A8 (LAT2) rs3783436-T/C, whose C-allele resulted associated with decreased risk of hypertension among subjects affected by CKD [OR = 0.56 (95% CI 0.35-0.90; p = 0.017]. The two variants were predicted to be potentially functional.
Conclusions: The association between SLC3A2 and SLC7A8 variants to hypertension development in patients with renal failure could be linked to changes in L-DOPA uptake and consequently dopamine synthesis. Although the associations do not survive correction for Bonferroni multiple testing, and additional research is needed, our study opens new avenues for future basic and translational research in the field of hypertensive CKD.
(© 2024. The Author(s).)

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PON ARS01_00568 MIUR (Ministry of Education, University and Research)

Keywords: 4F2hc/SLC3A2; Chronic kidney disease; Hypertension; L-DOPA; LAT2/SLC7A8; SNP

0 (Fusion Regulatory Protein 1, Heavy Chain)
46627O600J (Levodopa)
0 (SLC7A8 protein, human)
0 (Amino Acid Transport System y+)
0 (Fusion Regulatory Protein 1, Light Chains)

Date Created: 20240618 Date Completed: 20240619 Latest Revision: 20240703

20240704

PMC11186288

10.1186/s12920-024-01935-2

38890684