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
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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)