Restricted accessResearch articleFirst published online 2020-07
IL-12B Polymorphisms Are Associated with the Presence of Premature Coronary Artery Disease and with Cardiovascular Risk Factors: The Genetics of Atherosclerotic Disease Mexican Study
The aim of this study was to evaluate the association of the IL-12B polymorphisms with the presence of premature coronary artery disease (pCAD) and with cardiovascular risk factors. The study included 2163 individuals (1133 patients with pCAD and 1030 healthy controls). Seven IL-12B polymorphisms (rs1363670, rs3212220, rs3212227, rs6887695, rs1433048, rs2853694, and rs1368439) were determined by TaqMan assays. The associations were evaluated by logistic regression using inheritance models adjusted for confounding variables. The rs1363670 was associated with a low risk of pCAD (odds ratio [OR] 0.718, pdominant = 0.034; OR 0.701, pheterozygote = 0.024; OR 0.702, pcodominant1 = 0.025). The association of the polymorphisms with cardiovascular risk factors was evaluated independently in each group. In controls, the rs3212227, rs3212220, and rs6887695 polymorphisms were associated with subcutaneous abdominal fat > p75, whereas the rs6887695 was associated with a high risk of central obesity. In pCAD patients, the rs2853694 was associated with a low risk of insulin resistance; and association of rs3212227 and rs3212220 with a low risk of metabolic syndrome was found, and the rs6887695 polymorphism was nominally associated with a high risk of hyperuricemia. In conclusion, the IL-12B rs1363670 polymorphism was associated with a low risk of pCAD, and in both pCAD patients and healthy controls, some IL-12B polymorphisms were associated with cardiovascular risk factors.
Get full access to this article
View all access options for this article.
References
1.
AbbasA., GregersenI., HolmS., DaissormontI., BjerkeliV., Krohg-SørensenK., et al. (2015). Interleukin 23 levels are increased in carotid atherosclerosis. Possible role for the interleukin 23/interleukin 17 axis. Stroke, 46, 793–799.
2.
AbhimanyuM., MangangchaI.R., JhaP., AroraK., MukerjiM., BanavalikerJ.N., et al. (2011). Differential serum cytokine levels are associated with cytokine gene polymorphisms in north Indians with active pulmonary tuberculosis. Infect Genet Evol, 11, 1015–1022.
3.
Adeva-AndanyM.M., Martínez-RodríguezJ., González-LucánM., Fernández-FernándezC., and Castro-QuintelaE. (2019). Insulin resistance is a cardiovascular risk factor in humans. Diabetes Metab Syndr, 13, 1449–1455.
4.
AggarwalS., GhilardiN., XieM.H., de SauvageF.J., and GurneyA.L. (2003). Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem, 278, 1910–1914.
5.
AliS., SrivastavaA.K., ChopraR., AggarwalS., GargV.K., BhattacharyaS.N., et al. (2013). IL12B SNPs and copy number variation in IL23R gene associated with susceptibility to leprosy. J Med Genet, 50, 34–42.
6.
AnX., YuD., ZhangR., ZhuJ., DuR., ShiY., et al. (2012). Insulin resistance predicts progression of de novo atherosclerotic plaques in patients with coronary heart disease: a one-year follow-up study. Cardiovasc Diabetol 11,71.
7.
BenjaminE.J., MuntnerP., AlonsoA., BittencourtM.S., CallawayC.W., CarsonA.P., et al. (2019). Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation, 139, e56–e528.
8.
BragaF., PasqualettiS., FerraroS., and PanteghiniM. (2016). Hyperuricemia as risk factor for coronary heart disease incidence and mortality in the general population: a systematic review and meta-analysis. Clin Chem Lab Med, 54, 7–15.
9.
CargillM., SchrodiS.J., ChangM., GarciaV.E., BrandonR., CallisK.P., et al. (2007). A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet, 80, 273–290.
10.
DavidA., SaittaS., De CaridiG., BenedettoF., MassaraM., RisitanoD.C., et al. (2012). Interleukin-23 serum levels in patients affected by peripheral arterial disease. Clin Biochem, 45, 275–278.
11.
DawsonJ., QuinnT., and WaltersM. (2007). Uric acid reduction: a new paradigm in the management of cardiovascular risk?. Curr Med Chem, 14, 1879–1886.
12.
DuvalletE., SemeranoL., AssierE., FalgaroneG., and BoissierM.C. (2011). Interleukin-23: a key cytokine in inflammatory diseases. Ann Med, 43, 503–511.
13.
EddyD., SchlessingerL., KahnR., PeskinB., and SchiebingerR. (2009). Relationship of insulin resistance and related metabolic variables to coronary artery disease: a mathematical analysis. Diabetes Care, 32, 361–366.
14.
ErbelC., DenglerT.J., WanglerS., LasitschkaF., BeaF., WambsganssN., et al. (2011). Expression of IL-17A in human atherosclerotic lesions is associated with increased inflammation and plaque vulnerability. Basic Res Cardiol, 106, 125–134.
15.
Eskandari-NasabE., MoghadampourM., Asadi-SaghandiA., Kharazi-NejadE., RezaeifarA, and PourmasoumiH. (2013). Levels of interleukin-(IL)-12p40 are markedly increased in brucellosis among patients with specific IL-12B genotypes. Scand J Immunol, 78, 85–91.
16.
FergusonL.R., HanD.Y., FraserA.G., HuebnerC., LamW.J., and MorganA.R. (2010). IL23R and IL12B SNPs and haplotypes strongly associate with Crohn's disease risk in a New Zealand population. Gastroenterol Res Pract 2010,539461.
17.
GunstenS., MikolsC.L., GraysonM.H., SchwendenerR.A., AgapovE., TidwellR.M., et al. (2009). IL-12 p80-dependent macrophage recruitment primes the host for increased survival following a lethal respiratory viral infection. Immunology, 126, 500–513.
18.
HanleyA.J.G., WilliamsK., SternM.P., and HaffnerS.M. (2002). Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care, 25, 1177–1184.
19.
HanssonG.K. (2005). Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med, 352, 1685–1695.
20.
HanssonG.K., RobertsonA.K.L., and Söderberg-NauclérC. (2006). Inflammation and atherosclerosis. Ann Rev Pathol Mech Dis, 1, 297–329.
21.
HenckaertsL., Van SteenK., VerstrekenI., CleynenI., FrankeA., and SchreiberV.S. (2009). Genetic risk profiling and prediction of disease course in Crohn's disease patients. Clin Gastroenterol Hepatol, 7, 972–980.e2.
22.
IguchiT., HasegawaT., OtsukaK., MatsumotoK., YamazakiT., NishimuraS., et al. (2014). Insulin resistance is associated with coronary plaque vulnerability: insight from optical coherence tomography analysis. Eur Heart J Cardiovasc Imaging, 15, 284–291.
23.
IvanovaM., ManolovaI., MitevaL., GanchevaR., StoilovR., and StanilovaS. (2019). Genetic variations in the IL-12B gene in association with IL-23 and IL-12p40 serum levels in ankylosing spondylitis. Rheumatol Int, 39, 111–119.
24.
JavanM.R., ShahrakiS., SafaA., ZamaniM.R., SalmaninejadA., and AslaniS. (2017). An interleukin 12 B single nucleotide polymorphism increases IL-12p40 production and is associated with increased disease susceptibility in patients with relapsing-remitting multiple sclerosis. Neurol Res, 39, 435–441.
25.
JohnstonA., XingX., SwindellW.R., KochkodanJ., RiblettM., NairR.P., et al. (2013). Susceptibility-associated genetic variation at IL12B enhances Th1 polarization in psoriasis. Hum Mol Genet, 22, 1807–1815.
26.
KaarvatnM.H., VrbanecJ., KulicA., KnezevicJ., PetricevicB., BalenS., et al. (2012). Single nucleotide polymorphism in the interleukin 12B gene is associated with risk for breast cancer development. Scand J Immunol, 76, 329–335.
27.
KimS.Y., GuevaraJ.P., KimK.M., ChoiH.K., HeitjanD.F., and AlbertD.A. (2010). Hyperuricemia and coronary heart disease: a systematic review and meta-analysis. Arthritis Care Res, 62, 170–180.
28.
KvistH., ChowdhuryB., GrangårdU., TylénU., and SjöströmL. (1988). Total and visceral adipose-tissue volumes derived from measurements with computed tomography in adult men and women: predictive equations. Am J Clin Nutr, 48, 1351–1361.
29.
LiM., HuX., FanY., LiK., ZhangX., HouW., et al. (2016). Hyperuricemia and the risk for coronary heart disease morbidity and mortality a systematic review and dose-response meta-analysis. Sci Rep 6,19520.
30.
LiX., BaiL., FangJ., HouS., ZhouQ., YuH., et al. (2014). Genetic variations of IL-12B, IL-12Rβ1, IL-12Rβ2 in Behcet's disease and VKH syndrome. PLoS One 9,e98373.
31.
LimH.X., HongH.J., JungM.Y., ChoD., and KimT.S. (2013). Principal role of IL-12p40 in the decreased Th1 and Th17 responses driven by dendritic cells of mice lacking IL-12 and IL-18. Cytokine, 63, 179–186.
32.
LongoR., RicciC., MasuttiF., VidimariR., CrocéL.S., BercichL., et al. (1993). Fatty infiltration of the liver. Quantification by 1H localized magnetic resonance spectroscopy and comparison with computed tomography. Invest Radiol, 28, 297–302.
33.
ManginoM., BraundP., SinghR., SteedsR., StevensS., ChannerK.S., et al. (2008). Association analysis of IL-12B and IL-23R polymorphisms in myocardial infarction. J Mol Med, 86, 99–103.
34.
ManolovaI., IvanovaM., VasilevG., StoilovR., MitevaL., and StanilovaS. (2020). Impact of IL12B polymorphisms on genetic susceptibility and IL-12p40 and IL-23 serum levels in rheumatoid arthritis. Immunol Invest, 49, 1–14.
35.
MautnerG.C., MautnerS.L., FroehlichJ., FeuersteinI.M., ProschanM.A., RobertsW.C., et al. (1994). Coronary artery calcification: assessment with electron beam CT and histomorphometric correlation. Radiology, 192, 619–623.
36.
McGovernD.P.B., RotterJ.I., MeiL., HarituniansT., LandersC., DerkowskiC., et al. (2009). Genetic epistasis of IL23/IL17 pathway genes in Crohn's disease. Inflamm Bowel Dis, 15, 883–889.
37.
Medina-UrrutiaA., Posadas-RomeroC., Posadas-SánchezR., Jorge-GalarzaE., Villarreal-MolinaT., González-SalazarM.C., et al. (2015). Role of adiponectin and free fatty acids on the association between abdominal visceral fat and insulin resistance. Cardiovasc Diabetol 14,20.
38.
MohammadiM., HayatbakhshM.M., ZahediM.J., JalalpourM.R., and PakgoharA. (2011). Serum interleukin-23 levels in patients with ulcerative colitis. Iran J Immunol, 8, 183–188.
39.
MomiyamaY., OhmoriR., NaganoM., KatoR., TaniguchiH., EgashiraT., et al. (2005). Polymorphism of the 3′-untranslated region of interleukin-12 p40 gene is not associated with the presence or severity of coronary artery disease. Circ J, 69, 793–797.
40.
MorahanG., McKinnonE., BerryJ., BrowningB., JulierC., and PociotF. (2009). Evaluation of IL12B as a candidate type I diabetes susceptibility gene using data from the Type I Diabetes Genetics Consortium. Genes Immun, 10Suppl 1, S64–S68.
41.
MorrisG.A.J., EdwardsD.R.V., HillP.C., WejseC., BisseyeC., OlesenR., et al. (2011). Interleukin 12B (IL12B) genetic variation and pulmonary tuberculosis: a study of cohorts from The Gambia, Guinea-Bissau, United States and Argentina. PLoS One 6,e16656.
42.
MudigondaP., MudigondaT., FeneranA.N., AlamdariH.S., SandovalL., and FeldmanS.R. (2012). Interleukin-23 and interleukin-17: importance in pathogenesis and therapy of psoriasis. Dermatol Online J 18,1.
43.
Posadas-SánchezR., Pérez-HernándezN., Angeles-MartínezJ., López-BautistaF., Villarreal-MolinaT., Rodríguez-PérezJ.M., et al. (2017a). Interleukin 35 polymorphisms are associated with decreased risk of premature coronary artery disease, metabolic parameters, and IL-35 levels: the Genetics of Atherosclerotic Disease (GEA) Study. Mediators Inflamm 2017,6012795.
44.
Posadas-SánchezR., Pérez-HernándezN., Rodríguez-PérezJ.M., Coral-VázquezR.M., Roque-RamírezB., LlorenteL., et al. (2017b). Interleukin-27 polymorphisms are associated with premature coronary artery disease and metabolic parameters in the Mexican population: the genetics of atherosclerotic disease (GEA) Mexican study. Oncotarget, 8, 64459–64470.
45.
Posadas-SánchezR., and Vargas-AlarcónG. (2018). Innate immunity in coronary disease. The role of interleukin-12 cytokine family in atherosclerosis. Rev Invest Clin, 70, 5–17.
46.
RongC., HuW., WuF., CaoX., and ChenF. (2012). Interleukin-23 as a potential therapeutic target for rheumatoid arthritis. Mol Cell Biochem, 361, 243–248.
47.
RuggieroC., CherubiniA., BleA., BosA.J.G., MaggioM., DixitV.D., et al. (2006). Uric acid and inflammatory markers. Eur Heart J, 27, 1174–1181.
48.
SavvatisK., PappritzK., BecherP.M., LindnerD., ZietschC., VolkH.D., et al. (2014). Interleukin-23 deficiency leads to impaired wound healing and adverse prognosis after myocardial infarction. Circ Heart Fail, 7, 161–171.
49.
StanilovaS., and MitevaL. (2005). Taq-I polymorphism in 3′UTR of the IL-12B and association with IL-12p40 production from human PBMC. Genes Immun, 6, 364–366.
50.
SteinR., FerrariF., and ScolariF. (2019). Genetics, dyslipidemia, and cardiovascular disease: new insights. Curr Cardiol Rep 21,68.
51.
TiongA.Y., and BriegerD. (2005). Inflammation and coronary artery disease. Am Heart J, 150, 11–18.
52.
TrinchieriG., PflanzS., and KasteleinR.A. (2003). The IL-12 family of heterodimeric cytokines. Immunity, 19, 641–644.
53.
TzagournisM., ChilesR., RyanJ.M., and SkillmanT.G. (1968). Interrelationships of hyperinsulinism and hypertriglyceridemia in young patients with coronary heart disease. Circulation, 38, 1156–1163.
54.
van VeenT., CrusiusJ.B., SchrijverH.M., BoumaG., KillesteinJ., van WinsenL., et al. (2001). Interleukin-12p40 genotype plays a role in the susceptibility to multiple sclerosis. Ann Neurol 50,275.
55.
Vázquez-VázquezC., Posadas-SánchezR., Pérez-HernándezN., Rodríguez-PérezJ.M., FragosoJ.M., Cardoso-SaldañaG., et al. (2019). The rs2066808 polymorphism located near the IL-23A gene is associated with premature coronary artery disease in Mexican population (GEA study). DNA Cell Biol, 38, 880–886.
56.
VermeireS., Van AsscheG., and RutgeertsP. (2010). Role of genetics in prediction of disease course and response to therapy. World J Gastroenterol 16,2609.
57.
WangE.Y.Y., YangQ., and LiaoZ.G.G. (2015). Association of polymorphisms in interleukin (IL)-12A and -B genes with rheumatoid arthritis in a Chinese population. Clin Exp Immunol, 180, 83–89.
58.
WaringW., MaxwellS.R.J., and WebbD.J. (2002). Uric acid concentrations and the mechanisms of cardiovascular disease. Eur Heart J, 23, 1888–1889.
59.
WeiP., KouW., ZhangC., KangH., YaoH., TangX., et al. (2016). Genetic variations in interleukin-12B in allergic rhinitis. Immunol Res, 64, 329–336.
60.
WheelerJ.G., JuzwishinK.D.M., EiriksdottirG., GudnasonV., and DaneshJ. (2005). Serum uric acid and coronary heart disease in 9,458 incident cases and 155,084 controls: prospective study and meta-analysis. PLoS Med 2,e76.
61.
WindsorL., MorahanG., HuangD., McCannV., JonesT., JamesI., et al. (2004). Alleles of the IL12B 3′UTR associate with late onset of type 1 diabetes. Hum Immunol, 65, 1432–1436.
62.
WongR.H., WeiJ.C.C., HuangC.H., LeeH.S., ChiouS.Y., LinS.H., et al. (2012). Association of IL-12B genetic polymorphism with the susceptibility and disease severity of ankylosing spondylitis. J Rheumatol, 39, 135–140.
63.
XiaL.P., LiB.F., ShenH., and LuJ. (2015). Interleukin-27 and interleukin-23 in patients with systemic lupus erythematosus: possible role in lupus nephritis. Scand J Rheumatol, 44, 200–205.
64.
YaghiniN., MahmoodiM., HassanshahiG., AsadikaramG., ArababadiM.K., RezaeianM., et al. (2012). Genetic variation of IL-12B (+1188 region) is associated with its decreased circulating levels and susceptibility to type 2 diabetes. Biomark Med, 6, 89–95.
65.
YenD., CheungJ., ScheerensH., PouletF., McClanahanT., McKenzieB., et al. (2006). IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest, 116, 1310–1316.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
