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utilizing One-way analysis of variance(ONE WAY ANOVA). The STATCALC (Epi Info, Atlanta, USA) was used to compare the clinical and metabolism characteristics and genotypes or haplotypes. The significant level was set as p value < 0.05. Results

Clinical characteristics

In the present study, 94 of individuals defined as T2DM complicated with hypertension totally, and 103 of local healthy subjects were also recruited. The clinical parameters, including age, gender, BMI, SBP, DBP, FPG, TC, TG, LDL-C, HDL-C and HbA1C, have been presented in Table. 1. It is obviously that there is no significant difference of these clinical characteristics between each genotype.

Genotype distribution and allele frequency

The Table. 2 displayed the allele frequencies and genotype distribution of both rs2237892 and rs2237895 loci. The genotype of the rs2237892 loci were confirmed based on the high-resolution melting result. The genotype of the rs2237895 loci was determined according to the EFLP result. The genotype distribution of rs2237892 and rs2237895 was in accordance with the Hardy-Weinberg equilibrium in all participants (p>0.05). However, we do not observed any

significant difference of the genotype distribution between control and case group in rs2237892 and rs2237895 (P=0.359; OR=1.9551; 95%CI: 0.753-5.077; P=0.167; OR: 1.699; 95%CI: 0.977-2.952). Furthermore, the allele frequencies of alleles of these two loci did not show any difference between the case and control group either(P=0.215; OR 1.311; 95%CI:0.854-2.013;；P=0.098; OR=1.43; 95%CI:0.956-2.185).

Haplotype analysis

As shown in Table. 3, through the haplotype analysis for the rs2237895 and rs2237892 in KCNQ1 associated with hypertension with T2DM by case control comparison , we found that a haplotype with allele A(rs2237895) and allele

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C(rs2237892) significantly conferred the risk of hypertension with T2DM (p=1.6×10-6, OR= 2.62, ? CI=1.742-3.954). More importantly, according to the genotype-haplotype strata, we showed there existed the genetic dose-effect relationship, which compared with the wild-type-haplotype carriers, the homozygous genotype-haplotype carriers(p=6×10-6, OR=6.93, 95% CI: 2.828-16.997) had about two folds risk of T2DM with hypertension and the heterozygous genotype-haplotype carriers(p=4×10-5, OR=3.94, 95% CI:1.948-7.988) was about one time risk.

Association of two SNPs genotypes with clinical parameters in categories

As shown in Table. 4, we apply to the case only designed through the genotype-phenotype analysis, we genotyped these two SNPs by metabolic parameters strata in T2DM cases complicated with hypertension.

The heterozygous carriers of AC and homozygous carriers of AA genotype of rs2237895 were strongly associated with reduced total cholesterol level in the case group (p=0.01, OR=0.03, 95%CI: 0.0026-0.4293). Furthermore, when the group was set as gender, the homozygous carriers of CC genotype of rs2237892 from KCNQ1 conferred a soared risk of TG level in the female group (p=0.03, OR=14.40; 95% CI: 1.375-150.814); while in the male group, we noticed that heterozygous carriers of CT and homozygous carriers of TT genotype is capable for minimizing the diastolic blood pressure (p=0.021; OR= 0.30; 95% CI: 0.305-0.098).

Discussion

In this research, we identified the association of the new haplotype in KCNQ1 gene and hypertension with T2DM. More importantly, the haplotype has the relationship between genetic dose and risk effect of hypertension complicated with T2DM, which compared with the wild-type-haplotype carriers, the homozygous genotype-haplotype carriers(p=6×10-6, OR=6.93, 95% CI: 2.828-16.997) had about two folds risk of T2DM with hypertension and the heterozygous genotype-haplotype carriers(p=4×10-5, OR=3.94, 95% CI:1.948-7.988) was about one time risk.

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These two risk loci of T2DM on the KCNQ1 gene have been previously identified in European, Japanese and Chinese population by GWAS. For example, the rs2237892 extremely raise the possibility of developing Type 2 diabetes in Japanese and Chinese population (Yasuda, Miyake et al. 2008, Tsai et al. 2010, Ohshige et al. 2011). Besides, several studies also reported that the KCNQ1 can result in the increased blood pressure in several ethnics (Otway et al. 2007, Takagi et al. 2007), and the high SBP was much more prevalent in T2DM patients carrying CC genotype (Zhang, Wang et al. 2015). However, there is no researches concentrate on the association between KCNQ1 and hypertension with T2DM in the northern Chinese Han population. The location of both rs2237892 and rs2237895 are at the 40-kb LD region of the 15th intro in KCNQ1 gene, and the 95% CI: 1.375-150.814) and DBP (p=0.021; OR= 0.30; 95% CI: 0.305-0.098). Our results comparatively support our speculation, while given this study is a preliminary experiment; we still need to verify our conclusion in a larger sample size. Furthermore, this study also affords us a chance to confirm whether there is the existence of new casual SNPs in the region between these two loci.

This study has some merits and limitations. In terms of the advantages, we confirmed that there are likely some casual SNPs, which have not been reported, existed in the region between the rs2237892 and rs2237895 by means of haplotype analysis. These SNPs need to be further verified

in the following study. Furthermore, we identified a haplotype, which confer an increased risk of developing hypertension with T2DM. Besides, the study also contains limitation. The sample size of our study is too small to represent the whole population; it needs to be constantly expended.

In general, we identified that the haplotype of KCNQ1 sharply confers the risk of inducing In general, we identified that the haplotype of KCNQ1 sharply confers the risk of inducing hypertension with T2DM; besides, we also found that there exist robust association between the genotype of rs2237892 and rs2237895 and several metabolic phenotype in the diabetic

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patients with hypertension. These support our hypothesis of common etiology for the diabetic hypertension and suggest us that the T2DM with hypertension may share the same genetic risk factors, and it also provide some clues in terms of explaining the mechanism of developing the hypertension with T2DM.

In conclusion, we identified a novel risk haplotype with dose-effect, which are associated with hypertension complicated with T2DM in Chinese population. Furthermore, we also obtained the supporting evidences from the clinical parameters that showed the KCNQ1 genetic variants associated with the metabolic phenotypes (TC, TG and DBP) of hypertension with T2DM.

Acknowledgment

This work was funded by the Natural Science Foundation of China (81400790, 81061120527, 81370445, 81472408, 81571385), funding from National Department Public Benefit Research Foundation by Ministry of Health P. R. China (201302008), and 12th 5 Year National Program from the Ministry of Scientific Technology (2012BAI10B01, 2015BAI06B03).

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