Polymorphisms in the <b><i>SLC12A3</i></b> Gene Encoding Sodium-Chloride Cotransporter are Associated with Hypertension: A Family-Based Study in the Mongolian Population

Abstract

Background/Aims: Hypertension or persistent high blood pressure (BP) is a leading cause of death worldwide. Extensive evidence indicates that the thiazide-sensitive Na⁺-Cl^- cotrans-porter (NCC) affects BP via regulation of renal sodium reabsorption. However, the relationship between genetic variants of the NCC-encoding SLC12A3 gene and hypertension in the Mongolian population is still ambiguous. In this study, we aimed to genotype an extended cohort of hypertensive Mongolian families for polymorphisms in the SLC12A3 locus. Methods: Eighty-eight families with a history of hypertension, including parents, offspring, and relatives underwent clinical testing. Family-based association tests and haplotype analysis were used to evaluate the association between hypertension and polymorphisms in the SLC12A3 locus. Results: We identified three single nucleotide polymorphisms (SNPs), one in the SLC12A3 coding region (p = 0.05) and two in the intron (p = 0.02 and p = 0.07), which were significantly associated with the hypertension phenotype. Haplotype-specific association tests confirmed the correlation of these SNPs with hypertension (p < 0.05). Conclusion: These results suggest that SNPs in the SLC12A3 gene confer susceptibility to hypertension in the Mongolian population. Further research is needed to validate the functional role of SLC12A3 polymorphisms in hypertension.

SLC12A3 variants modulate LDL cholesterol levels in the Mongolian population

“…Our previous studies demonstrated the association of SLC12A3 gene variants with Mongolian hypertension [ 21 – 23 ] and meanwhile we also found that the levels of TC [ 21 ], TG [ 21 – 23 ] and LDL-c [ 21 , 23 ] are significantly increased, whereas that of HDL-c [ 21 ] is slightly decreased in Mongolian hypertension when compared with Mongolian normotensives. Thus, it is possible that the genetic polymorphisms of SLC12A3 might be associated with hypertension via modulating an individual’s serum lipid levels.…”

Genetic variants of SLC12A3 modulate serum lipid profiles in a group of Mongolian pedigree population

“…SLC12A3 gene had been identified and speculated that, its genetic variants and rare mutations will impact the development of hypertension, although more mutations are need to verify [ 27 ]. Within Mongolian population, two previous reports also demonstrated the close relationship between SLC12A3 and hypertension, both with random case-control sample and pedigree cohort [ 10 , 11 ]. In this study, within parental group which looked as a rough random population, the subjects with homozygous risk alleles also show a higher blood pressure (Additional file 1 : Table S3).…”

“…Asselbergs et al, [ 9 ] confirms the association between SLC12A3 variants and individuals’ HDL-C levels, which may lead to CVD, in a large-scale meta-analysis related to 66,240 individuals of European ancestry. Our previous work also demonstrated a close association between SLC12A3 polymorphism and human hypertension in Mongolians, both within random and pedigree populations [ 10 , 11 ]. Therefore, we hypothesized that SLC12A3 gene might influence individuals’ serum lipid levels, modify their blood pressure, and increase the risk of CVD or related diseases in Mongolians and the aim of this study is to certify the relationship between genetic variants of SLC12A3 and individual’s serum lipid levels in Mongolians.…”

“…One possible explanation is that SLC12A3 may indirectly affect blood lipid levels by affecting individual blood pressure. SLC12A3 gene, encoding the renal thiazide-sensitive Na-Cl cotransporter, is closely related to blood pressure by influencing renal sodium reabsorption, which has been well confirmed by a large number of association studies and functional validation tests [ 10 , 22 , 23 ]. Hypertensive patients are often accompanied by abnormal lipid metabolism; therefore, hypertension and dyslipidemia are closely associated with each other and can affect each other’s morbidity.…”

“…The tagger SNPs of SLC12A3 gene were designed, chosen and genotyped among this pedigree sample, as described previously [ 10 ]. Briefly, 15 SNPs of the SLC12A3 gene were selected in this study, including rs4784733, rs2304478, rs13306673, rs2289119, rs8043560, rs2304483, rs5803, rs7187932, rs6499858, rs11644728, rs8049280, rs7204044, rs2010501, rs2399594 and rs711746.…”