In the current study, we found no association between two SNPs, rs3754777 and rs6749447, located within STK39 and hypertension in a cohort of 498 Koreans. Although there was no implication of these SNPs on adjusted BPs, they were associated with other cardiovascular risk factors. The carriers of AA genotype of rs3754777 had lower blood glucose and cholesterol levels. This relationship was more obvious in females. Although genotype of rs6749447 was not related to specific risk factors, it was associated with waist circumference, triglyceride, and HDL-C levels in gender stratified analysis. Association between haplotype combination of studied SNPs and risk factors were compatible with genotype-risk factor relationship of each SNP.
Polymorphisms of STK39
were reported to be associated with BP first in Caucasian samples.1)
In the meta-analysis combining four studies, Wang et al.1)
showed the effects of SNPs of rs6749447 and rs3754777 on BP. Another SNP of STK39
, rs35929607, was also related to the hypertension prevalence in women of two cohorts in Swedes.3)
In the Chinese population, two SNPs of STK39
, rs6433027 and 3754777, were found to be associated with hypertension.4)
In the results of this study, the associations between STK39
SNPs and hypertension or BP were not significant. Although the reason for the discrepancy is not clear, several possibilities may be suggested. First, all the samples were of Koreans residing in the Republic of Korea, and the STK39
-BP relationship may be weaker in this population. The influence of STK39
polymorphism on BP has not been consistently confirmed. In the two large GWAS, using more than 60000 people, the effects of STK39
SNPs on BP were not found.5),6)
In addition, in one British7)
and one Chinese8)
study, variants of STK39
were not associated with BP. Recently, Rhee et al.9)
reported four previously reported SNPs associated with salt-sensitivity in 101 Koreans. However, in that study, no polymorphism of STK39
showed significant effects after adjusting for confounding factors. Second, although STK39
gene encodes for a protein that plays a role in BP regulation, its final effects may be too small to be detected consistently in every study cohort. Third, as the population size of this study is not sufficiently large, it cannot be completely ruled out that some variants with impacts may not have obtained statistical significance.
We found significant associations between STK39
variants and cardiovascular risk factors other than BP. They include glucose, total cholesterol, and LDL-C in rs3754777; and waist circumference, triglyceride, and HDL-C in rs6749447. Four of the factors belong to the characteristics of metabolic syndrome. The minor allele carriers of rs3754777 had the tendencies to have lower levels of risk factors. Those of rs6749447 showed contradictory results on waist circumference and triglyceride and HDL-C. Thus, it is difficult to tell what clinical association the genotype of the latter STK39
SNP may finally have. However, to our knowledge, this study is the first to demonstrate the association between STK39
variants and the above factors. In a prior study by Wang et al.,1)
it was mentioned that STK39
SNPs were modestly associated with blood glucose level, insulin response to glucose, and triglyceride level in a subset of Amish population. In addition, two other STK39
SNPs were reported to be linked to multiple phenotypes of metabolic syndrome.10)
In the present study, we have shown the relationship between STK39
SNPs and cardiovascular risk factors more systemically. It has been known that STK39
was located in an area in which BP, obesity, and diabetes-related rodent quantitative trait loci have been mapped. Furthermore, STK39
/SPAK is able to activate the p38 MAP kinase pathway, providing evidence that it can act as a stress-mediated signals.11),12)
It has been recently demonstrated that p38 MAP kinase plays a role in glucose13)
and lipoprotein metabolism,14)
and this may support the biological mechanism of the current data. Although investigating the functional mechanism of STK39
is beyond the scope of this study, further projects focusing on this issue may unveil the role of this gene on multiple cardiovascular risk factors.
In this study, the influence of STK39
variants on the risk factors was clearer in women. This finding is in accordance with prior studies that have shown gender-dependency of STK39
effect. In the study by Fava et al.,3)
the association of STK39
rs35929607 variant and hypertension was evident only in women. However, in the study by Chen et al.,4)
rs6433027 and rs3754777 had more significant association with hypertension in male. Sex differences in hypertension may be attributed to multiple factors such as lifestyle, diet, and genetic polymorphism.15)
Interestingly, it has been documented that SPAK expression is affected by both androgen and estrogen in human prostate cancer cells.16)
Nevertheless, further studies are needed to clarify the underlying mechanism of gender dependency in STK39 effect on cardiovascular risk factors.
The present study has several limitations. Although rs3754777 and rs6749447 were the first variants known to be hypertension susceptible in STK39 gene, other SNPs have been reported to have effects thereafter. Inclusion of more STK39 variants in the study may have been helpful to understand the role of STK39 in this Asian population more completely. As mentioned above, the study population was not sufficiently large, and some important analyses did not obtain statistical significance. However, it was strength of the study to systemically analyze and present the association between STK39 variants and multiple cardiovascular risk factors.
In conclusion, the associations between two SNPs of STK39, rs3754777 and rs6749447, and hypertension were not significant in this Korean cohort. However, we identified that AA genotype of rs3754777 had lower glucose and cholesterol levels, especially in females. Genotype of rs6749447 was associated with waist circumference, triglyceride, and HDL-C levels in gender stratified analysis only. The genotype of rs6759447 was related to blood glucose levels. Further studies are needed to clarify the effect of STK39 variants in these cardiovascular risk factors.