Association of KCNB1 polymorphisms with lipid metabolisms and insulin resistance: a case-control design of population-based cross-sectional study in Chinese Han population

Lipids in Health and Disease, Sep 2015

Background In our previous study, we had assessed in the Chinese Han population the association of KCNB1 rs1051295 with metabolic traits indicating metabolic syndrome, and showed that KCNB1 rs1051295 genotype TT was associated with increase of waist to hip ratio (WHR), fasting insulin (FINS), triglycerides (TG) and decreased insulin sensitivity at basal condition. Here, we aimed at detecting whether there were associations between other tag SNPs of KCNB1 and favorable or unfavorable metabolic traits. Methods We conducted a case–control design of population-based cross-sectional study to investigate the association between each of the 22 candidates tag SNPs of KCNB1 and metabolic traits in a population of 733 Chinese Han individuals. The association was assessed by multiple linear regression analysis or unconditional logistic regression analysis. Results We found that among the 22 selected tag SNPs, four were associated with an increase (rs3331, rs16994565) or decrease (rs237460, rs802950) in serum cholesterol levels; two of these (rs237460, rs802590) further associated or were associated with reduced serum LDL-cholesterol. Two novel tag SNPs (rs926672, rs1051295) were associated with increased serum TG levels. We also showed that KCNB1 rs926672 associated with insulin resistance by a case–control study, and two tag SNPs (rs2057077and rs4810952) of KCNB1 were associated with the measure of insulin resistance (HOMA-IR) in a cross-section study. Conclusion These results indicate that KCNB1 is likely associated with metabolic traits that may either predispose or protect from progression to metabolic syndrome. This study provides initial evidence that the gene variants of KCNB1, encoding Kv2.1 channel, is associated with perturbation of lipid metabolism and insulin resistance in Chinese Han population.

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Association of KCNB1 polymorphisms with lipid metabolisms and insulin resistance: a case-control design of population-based cross-sectional study in Chinese Han population

Yu et al. Lipids in Health and Disease Association of KCNB1 polymorphisms with lipid metabolisms and insulin resistance: a case-control design of population-based cross-sectional study in Chinese Han population Yuncui Yu 0 Jing Wang 3 Ruiying Kang 0 Jing Dong 3 Yuxiang Zhang 0 Fen Liu 0 Yuxiang Yan 0 Rong Zhu 0 Lili Xia 0 Xiaoxia Peng 0 Ling Zhang 0 Dian He 0 Gaisano Herbert 2 Zhenwen Chen 1 Yan He 0 0 School of Public Health, Capital Medical University , No.10 Xitoutiao, Youanmen, Fengtai District, Beijing 100069 , PR China 1 School of Basic Medicine, Capital Medical University , No.10 Xitoutiao, Youanmen, Fengtai District, Beijing 100069 , PR China 2 Departments of Medicine and Physiology, University of Toronto , 315 Bloor Street West, Toronto, Ontario , Canada 3 Departments of Emergency, Beijing Xuanwu Hospital, Capital Medical University , No.45Changchun Street, Xuanwu District, Beijing, 100053 Beijing , PR China Background: In our previous study, we had assessed in the Chinese Han population the association of KCNB1 rs1051295 with metabolic traits indicating metabolic syndrome, and showed that KCNB1 rs1051295 genotype TT was associated with increase of waist to hip ratio (WHR), fasting insulin (FINS), triglycerides (TG) and decreased insulin sensitivity at basal condition. Here, we aimed at detecting whether there were associations between other tag SNPs of KCNB1 and favorable or unfavorable metabolic traits. Methods: We conducted a case-control design of population-based cross-sectional study to investigate the association between each of the 22 candidates tag SNPs of KCNB1 and metabolic traits in a population of 733 Chinese Han individuals. The association was assessed by multiple linear regression analysis or unconditional logistic regression analysis. Results: We found that among the 22 selected tag SNPs, four were associated with an increase (rs3331, rs16994565) or decrease (rs237460, rs802950) in serum cholesterol levels; two of these (rs237460, rs802590) further associated or were associated with reduced serum LDL-cholesterol. Two novel tag SNPs (rs926672, rs1051295) were associated with increased serum TG levels. We also showed that KCNB1 rs926672 associated with insulin resistance by a case-control study, and two tag SNPs (rs2057077and rs4810952) of KCNB1 were associated with the measure of insulin resistance (HOMA-IR) in a cross-section study. Conclusion: These results indicate that KCNB1 is likely associated with metabolic traits that may either predispose or protect from progression to metabolic syndrome. This study provides initial evidence that the gene variants of KCNB1, encoding Kv2.1 channel, is associated with perturbation of lipid metabolism and insulin resistance in Chinese Han population. KCNB1 polymorphisms; Kv2; 1 channel; Lipid metabolism; Insulin resistance - Background KCNB1, also known as Kv2.1, is located on chromosome 20q13.2, and is mainly expressed in the brain cortex and hippocampus, islet β-cells, cardiac atrium and ventricle, skeletal muscles and some other tissues [1]. Our recently reported case–control study in Chinese Han population showed a strong association of KCNB1 rs1051295 genotype TT with an increased risk of becoming afflicted with metabolic syndrome leading to T2D. Specifically, we showed the genotype TT of this SNP was associated with several metabolic traits of metabolic syndrome, including increased waist to hip ratio (WHR), fasting insulin (FINS) levels, increased serum triglyceride (TG) levels, and decreased insulin sensitivity at basal condition [2]. Kv2.1 channel’s role in secretion is attributed not only to the regulation of membrane excitability but also to a more direct role in the exoctyotic machinery. Up-regulation of Kv2.1 channel in PC12 [3], bovine chromaffin cells [4], rat dorsal root ganglion cells [5] and rodent and human islet β-cells, [6] facilitated exocytotic SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex assembly initiated by direct interaction of its C-terminus with SNARE protein syntaxin-1A and subsequent further assembly with VAMP2 and SNAP25. In β-cells, these Kv2.1-SNARE complex interactions can enhance insulin secretion [6]. To our knowledge, there have been no in vivo or in vitro studies to demonstrate a possible role of Kv2.1 channel in metabolism to account for the perturbed metabolic traits we had reported [2]. However, in support of this possibility that Kv channels could be involved in body metabolic functions, Chandy and colleagues recently demonstrated that ShK-186, a selective and potent blocker of voltage-gated Kv1.3 channel, reduced weight gain, adiposity, and fatty liver with resultant enhancement of peripheral insulin sensitivity; and also decreased serum levels of cholesterol, glucose, HbA1c, insulin, and leptin [7]. To delve deeper into the role of KCNB1-encoded Kv2.1 in metabolic syndrome, we examined the associations between the tag SNPs of KCNB1 and different metab (...truncated)


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Yuncui Yu, Jing Wang, Ruiying Kang, Jing Dong, Yuxiang Zhang, Fen Liu, Yuxiang Yan, Rong Zhu, Lili Xia, Xiaoxia Peng, Ling Zhang, Dian He, Herbert Y Gaisano, Zhenwen Chen, Yan He. Association of KCNB1 polymorphisms with lipid metabolisms and insulin resistance: a case-control design of population-based cross-sectional study in Chinese Han population, Lipids in Health and Disease, 2015, pp. 112, 14, DOI: 10.1186/s12944-015-0115-1