HAPLOTYPES IN THE WNK1 AND SLC12A3 GENES ARE ASSOCIATED TO HYPERTENSION IN A CHINESE POPULATION: 6B.02

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Objective: Deletions in with-no-lysine-kinase 1 gene (WNK1) cause Gordon's syndrome, a rare Mendelian form of hypertension. The mechanism might partially be WNK1 activates thiazide-sensitive Na-Cl cotransporter(NCC, encoded by SLC12A3), leading to increased salt reabsorption in distal nephron. Our study aimed to evaluate the role of genetic variants at WNK1 and a possible interaction with SLC12A3 on BP and hypertension in a Chinese population. Methods: 13 polymorphisms were selected at the WNK1 and SLC12A3 genes and 550 hypertensives (HT1), a more severely affected group HT2 (n = 227) and 538 normotensive controls (NT) were collected. All SNPs were genotyped using Taqman assay. Multi-dimensional reduction (MDR) and R package HaploStats were used for data analysis. Results: Genotype and allele frequencies distribution of rs2286028 were different between cases and controls (p = 0.05 and 0.03 for allele for HT1, HT2, p = 0.006 for genotype for HT2) even after multiple correction the latter association remained the significance (p = 0.04). We found one common WNK1 haplotype significantly associated with higher risk for hypertension (P = 0.03 and P = 0.007 for HT1 and HT2) and BP (P = 0.005 and P = 0.001 for SBP and DBP) after adjustment for confounding factors and multiple testing. Another common haplotype was associated with potassium excretion (P = 0.04). One rare WNK1 haplotype was strongly associated with hypertension (p = 0.003and 0.005 for HT1 and HT2), BP (p = 0.03 and 0.005 for SBP and DBP) and potassium excretion (P = 0.04). Using MDR we generated a five-locus model in the two genes for gene interaction analysis. One common allelic combination showed significant association with SBP (p = 0.0009) and hypertension in HT1 (P = 0.01). Combinations with lower frequencies showed more striking associations with hypertension and BP, one of which presented a high risk factor for hypertension with highest OR = 31.5 (P = 0.00005). Conclusion: Our results strongly support the findings that WNK1 gene contributes to hypertension and BP, also in the Chinese population. A synergistic genetic interaction between WNK1 and SLC12A3 could play a significant role in hypertension and BP variation.