Blood pressure (BP) responses to dietary sodium intervention vary among individuals. The inwardly rectifying potassium channel (Kir) is a potassium-selective ion channel that allows potassium ions to move more easily into rather than out of the cell. We aimed to investigate the associations of Kir genes with BP responses to dietary sodium intervention. A 7-day low-sodium intervention followed by a 7-day high-sodium intervention was conducted among 1906 participants. BP measurements were obtained at baseline and during each dietary intervention. Both single-marker and gene-based analyses were performed to explore the associations between Kir gene variants and BP responses to dietary sodium interventions. The genetic risk score (GRS) was used to assess the cumulative effect of the variants on the BP response to the sodium interventions. During the low-sodium intervention, markers rs858009, rs2835904, and rs860795 in KCNJ6 were significantly associated with the systolic BP (SBP) response (P = 8.82 × 10−6, 3.32 × 10−6, and 2.39 × 10−4, respectively), whereas rs858009 and rs2835904 were significantly correlated with the mean arterial pressure (MAP) response (P = 1.64 × 10−4 and 2.72 × 10−4, respectively). Marker rs2836023 showed a significant association with the SBP response (P = 5.72 × 10−5) to the high-sodium intervention. The GRS stratified by quartile grouping or as a continuous variable was associated with the BP response to the sodium interventions. Gene-based analyses consistently revealed that KCNJ6 was significantly associated with the BP response to the sodium interventions. These findings suggest that KCNJ6 may contribute to variation of BP responses to dietary sodium interventions. Future studies are warranted to confirm these findings and to identify functional variants for salt sensitivity.
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Mills KT, Bundy JD, Kelly TN, Reed JE, Kearney PM, Reynolds K, Chen J, He J. Global disparities of hypertension prevalence and control: a systematic analysis of population-based studies from 90 countries. Circulation. 2016;134:441–50.
GBD 2015 Risk Factors Collaborators. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1659–724.
He FJ, MacGregor GA. A comprehensive review on salt and health and current experience of worldwide salt reduction programmes. J Hum Hypertens. 2009;23:363–84.
Weinberger MH. Salt sensitivity of blood pressure in humans. Hypertension. 1996;27:481–90.
Kario K, Chen CH, Park S, Park CG, Hoshide S, Cheng HM, Huang QF, Wang JG. Consensus teristics. Hypertension. 2018;71:375–82.
Gu D, Rice T, Wang S, Yang W, Gu C, Chen CS, Hixson JE, Jaquish CE, Yao ZJ, Liu DP, Rao DC, He J. Heritability of blood pressure responses to dietary sodium and potassium intake in a Chinese population. Hypertension. 2007;50:116–22.
Liu Z, Qi H, Liu B, Liu K, Wu J, Cao H, Zhang J, Yan Y, He Y, Zhang L. Genetic susceptibility to salt-sensitive hypertension in a Han Chinese population: a validation study of candidate genes. Hypertens Res. 2017;40:876–84.
Han X, Hu Z, Chen J, Huang J, Huang C, Liu F, Gu C, Yang X, Hixson JE, Lu X, Wang L, Liu DP, He J, Chen S, Gu D. Associations between genetic variants of NADPH oxidase-related genes and blood pressure responses to dietary sodium intervention: the GenSalt study. Am J Hypertens. 2017;30:427–34.
Fang Y, Mu JJ, He LC, Wang SC, Liu ZQ. Salt loading on plasma asymmetrical dimethylarginine and the protective role of potassium supplement in normotensive salt-sensitive asians. Hypertension. 2006;48:724–9.
Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y. Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol Rev. 2010;90:291–366.
Geraldes V, Gonçalves-Rosa N, Liu B, Paton JF, Rocha I. Chronic depression of hypothalamic paraventricular neuronal activity produces sustained hypotension in hypertensive rats. Exp Physiol. 2014;99:89–100.
Fujita T, Henry WL, Bartter FC, Lake CR, Delea CS. Factors influencing blood pressure in salt-sensitive patients with hypertension. Am J Med. 1980;69:334–44.
Fujita M, Ando K, Nagae A, Fujita T. Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in salt-sensitive hypertension. Hypertension. 2007;50:360–7.
GenSalt Collaborative Research Group. GenSalt: rationale, design, methods and baseline characteristics of study participants. J Hum Hypertens. 2007;21:639–46.
He J, Gu D, Chen J, Jaquish CE, Rao DC, Hixson JE, Chen JC, Duan X, Huang JF, Chen CS, Kelly TN, Bazzano LA, Whelton PK, GenSalt Collaborative Research Group. Gender difference in blood pressure responses to dietary sodium intervention in the GenSalt study. J Hypertens. 2009;27:48–54.
Perloff D, Grim C, Flack J, Frohlich ED, Hill M, McDonald M, Morgenstern BZ. Human blood pressure determination by sphygmomanometry. Circulation. 1993;88:2460–70.
Sheng X, Yang J. An adaptive truncated product method for combining dependent p-values. Econ Lett. 2013;119:180–2.
Mishra A, Macgregor S. VEGAS2: software for more flexible gene-based testing. Twin Res Hum Genet. 2015;18:86–91.
Weber CS, Thayer JF, Rudat M, Sharma AM, Perschel FH, Buchholz K, Deter HC. Salt-sensitive men show reduced heart rate variability, lower norepinephrine and enhanced cortisol during mental stress. J Hum Hypertens. 2008;22:423–31.
Whorton MR, MacKinnon R. Crystal structure of the mammalian GIRK2 K+ channel and gating regulation by G proteins, PIP2, and sodium. Cell. 2011;147:199–208.
Huang CL, Feng S, Hilgemann DW. Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbetagamma. Nature. 1998;391:803–6.
Guo L, Liu F, Chen S, Yang X, Huang J, He J, Jaquish CE, Zhao Q, Gu CC, Hixson JE, Gu D. Common variants in the Na-coupled bicarbonate transporter genes and salt sensitivity of blood pressure: the GenSalt study. J Hum Hypertens. 2015;30:1–6.
Kelly TN, Rebholz CM, Gu D, Hixson JE, Rice TK, Cao J, Chen J, Li J, Lu F, Ma J, Mu J, Whelton PK, He J. Analysis of sex hormone genes reveals gender differences in the genetic etiology of blood pressure salt sensitivity: the GenSalt study. Am J Hypertens. 2013;26:191–200.
Sakura H, Bond C, Warren-Perry M, Horsley S, Kearney L, Tucker S, Adelman J, Turner R, Ashcroft FM. Characterization and variation of a human inwardly-rectifying-K-channel gene (KCNJ6): a putative ATP-sensitive K-channel subunit. FEBS Lett. 1995;367:193–7.
Wang W, Whorton MR, MacKinnon R. Quantitative analysis of mammalian GIRK2 channel regulation by G proteins, the signaling lipid PIP2 and Na+ in a reconstituted system. eLife. 2014;3:e03671.
Ho IH, Murrell-Lagnado RD. Molecular determinants for sodium-dependent activation of G protein-gated K+ channels. J Biol Chem. 1999;274:8639–48.
ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74.
Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M, Karczewski KJ, Park J, Hitz BC, Weng S, Cherry JM, Snyder M. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 2012;22:1790–7.
Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40:D930–D934.
Nemoto K, Sekimoto M, Fukamachi K, Kageyama H, Degawa M, Hamadai M, Hendley ED, Macrae IM, Clark JS, Dominiczak AF, Ueyama T. No involvement of the nerve growth factor gene locus in hypertension in spontaneously hypertensive rats. Hypertens Res. 2005;28:155–63.
Lopatin AN, Nichols CG. Inward rectifiers in the heart: an update on I(K1). J Mol Cell Cardiol. 2001;33:625–38.
Vaidyanathan R, Van Ert H, Haq KT, Morotti S, Esch S, McCune EC, Grandi E, Eckhardt LL. Inward rectifier potassium channels (Kir2.x) and caveolin-3 domain-specific interaction: implications for Purkinje cell-dependent ventricular arrhythmias. Circ Arrhythm Electrophysiol. 2018;11:e005800.
This study is supported by the National Natural Science Foundation of China (91439202, 81570386, and 91643208) and the CAMS Innovation Fund for Medical Sciences (2017-I2M-1-004, 2016-I2M-2-001 and 2016- I2M-1-009). The GenSalt study is supported by a cooperative agreement project grant (U01HL072507, R01HL087263, and R01HL090682) from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Conflict of interest
The authors declare that they have no conflict of interest.