Gender and the active smoking and high-sensitivity C-reactive protein relation in late adolescence

C-reactive protein (CRP), smoking, and oral contraceptive (OC) use are associated with CVD risk in adults. This study examines the effect of smoking on high-sensitivity CRP (hs-CRP) levels, and the interactive effects of sex and OC use on this relationship in an adolescent cohort. A total of 1,050 adolescents (mean age 17 ± 0.25 years) from the Western Australian Pregnancy Cohort (Raine) Study had anthropometric, lifestyle, and metabolic measures recorded. The association between smoking status and log-transformed hs-CRP was analyzed using multivariable Tobit linear regression models, with adjustment for adiposity, lifestyle, and early-life confounders. A three-level variable (girls not using OCs, girls using OCs, and boys) was employed to assess the interactive effects of sex, OC use, and smoking. Smoking associated with higher hs-CRP levels in girls not using OCs (b = 0.571; P = 0.001), but not in girls using OCs (b = −0.117; P = 0.598) or in boys (b = 0.183; P = 0.2). OC use in nonsmoking girls was the strongest factor associated with higher hs-CRP levels (b = 1.189; P < 0.001). This study has demonstrated a more robust effect of smoking on hs-CRP levels in girls not using OCs compared with boys. The findings may explain why CVD risk conferred by smoking is higher in women than in men. C-reactive protein (CRP), smoking, and oral contraceptive (OC) use are associated with CVD risk in adults. This study examines the effect of smoking on high-sensitivity CRP (hs-CRP) levels, and the interactive effects of sex and OC use on this relationship in an adolescent cohort. A total of 1,050 adolescents (mean age 17 ± 0.25 years) from the Western Australian Pregnancy Cohort (Raine) Study had anthropometric, lifestyle, and metabolic measures recorded. The association between smoking status and log-transformed hs-CRP was analyzed using multivariable Tobit linear regression models, with adjustment for adiposity, lifestyle, and early-life confounders. A three-level variable (girls not using OCs, girls using OCs, and boys) was employed to assess the interactive effects of sex, OC use, and smoking. Smoking associated with higher hs-CRP levels in girls not using OCs (b = 0.571; P = 0.001), but not in girls using OCs (b = −0.117; P = 0.598) or in boys (b = 0.183; P = 0.2). OC use in nonsmoking girls was the strongest factor associated with higher hs-CRP levels (b = 1.189; P < 0.001). This study has demonstrated a more robust effect of smoking on hs-CRP levels in girls not using OCs compared with boys. The findings may explain why CVD risk conferred by smoking is higher in women than in men. Atherosclerosis, the primary underlying pathological process that eventually leads to ischemic heart disease, begins early in life, and is influenced by potentially modifiable behavioral and lifestyle factors over the life course. Inflammation is a major component of atherosclerosis and an important factor in the early phase of arteriosclerosis (1Balagopal P.B. de Ferranti S.D. Cook S. Daniels S.R. Gidding S.S. Hayman L.L. McCrindle B.W. Mietus-Snyder M.L. Steinberger J. American Heart Association Committee on Atherosclerosis, Hypertension, and Obesity in Youth of the Council on Cardiovascular Disease in the Young Nontraditional risk factors and biomarkers for cardiovascular disease: mechanistic, research, and clinical considerations for youth: a scientific statement from the American Heart Association.Circulation. 2011; 123: 2749-2769Crossref PubMed Scopus (242) Google Scholar). C-reactive protein (CRP), an acute phase reactant and a biomarker of systemic inflammation, is associated with adverse cardiovascular outcomes (2Ridker P.M. Rifai N. Rose L. Buring J.E. Cook N.R. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events.N. Engl. J. Med. 2002; 347: 1557-1565Crossref PubMed Scopus (3039) Google Scholar). There is also strong evidence that CRP is an independent predictor of increased cardiovascular risk (3Pearson T.A. Mensah G.A. Alexander R.W. Anderson J.L. Cannon III, R.O. Criqui M. Fadl Y.Y. Fortmann S.P. Hong Y. Myers G.L. et al.Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association.Circulation. 2003; 107: 499-511Crossref PubMed Scopus (5172) Google Scholar), supporting a role for CRP in CVD risk prediction (4Kaptoge S. Di Angelantonio E. Pennells L. Wood A.M. White I.R. Gao P. Walker M. Thompson A. Sarwar N. Caslake M. et al.C-reactive protein, fibrinogen, and cardiovascular disease prediction.N. Engl. J. Med. 2012; 367: 1310-1320Crossref PubMed Scopus (808) Google Scholar, 5Sondermeijer B.M. Boekholdt S.M. Rana J.S. Kastelein J.J.P. Wareham N.J. Khaw K-T. Clinical implications of JUPITER in a contemporary European population: the EPIC-Norfolk prospective population study.Eur. Heart J. 2013; 34: 1350-1357Crossref PubMed Scopus (3) Google Scholar). Smoking exposure, adiposity, and the use of oral contraceptives (OCs) have been shown to be related to higher CRP levels in studies in adults (6Cauci S. Di Santolo M. Culhane J.F. Stel G. Gonano F. Guaschino S. Effects of third-generation oral contraceptives on high-sensitivity C-reactive protein and homocysteine in young women.Obstet. Gynecol. 2008; 111: 857-864Crossref PubMed Scopus (53) Google Scholar, 7Wannamethee S.G. Lowe G.D.O. Shaper A.G. Rumley A. Lennon L. Whincup P.H. Associations between cigarette smoking, pipe/cigar smoking, and smoking cessation, and haemostatic and inflammatory markers for cardiovascular disease.Eur. Heart J. 2005; 26: 1765-1773Crossref PubMed Scopus (331) Google Scholar, 8Bazzano L.A. He J. Muntner P. Vupputuri S. Whelton P.K. Relationship between cigarette smoking and novel risk factors for cardiovascular disease in the United States.Ann. Intern. Med. 2003; 138: 891-897Crossref PubMed Scopus (307) Google Scholar, 9Khera A. Vega G.L. Das S.R. Ayers C. McGuire D.K. Grundy S.M. de Lemos J.A. Sex differences in the relationship between C-reactive protein and body fat.J. Clin. Endocrinol. Metab. 2009; 94: 3251-3258Crossref PubMed Scopus (108) Google Scholar). Raised CRP levels later in life reflect lifetime exposure to smoking as well as adiposity levels (10Tracy R.P. Psaty B.M. Macy E. Bovill E.G. Cushman M. Cornell E.S. Kuller L.H. Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 2167-2176Crossref PubMed Scopus (463) Google Scholar). Further, sex differences in the association between CRP levels and other risk factors have been described. For example, leptin was shown to be associated with higher CRP levels in women but not in men (11Abdullah S.M. Khera A. Leonard D. Das S.R. Canham R.M. Kamath S.A. Bega G.L. Grundy S.M. McGuire D.K. de Lemos J.A. Sex differences in the association between leptin and CRP: results from the Dallas Heart Study.Atherosclerosis. 2007; 195: 404-410Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar), while adiponectin was shown to be inversely associated with CRP in females (12Kaisar M.O. Armstrong K. Hawley C. Campbell S. Mudge D. Johnson D.W. Prins J.B. Isbel N.M. Adiponectin is associated with cardiovascular disease in male renal transplant recipients: baseline results from the LANDMARK 2 study.BMC Nephrol. 2009; 10: 29Crossref PubMed Scopus (17) Google Scholar). Elevated CRP levels in smokers may contribute to the adverse effect of smoking on CVD risk; hence, both smoking and CRP have been incorporated in the Reynolds Risk Score for women in CVD risk assessment (13Ridker P.M. Buring J.E. Rifai N. Cook N.R. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score.JAMA. 2007; 297: 611-619Crossref PubMed Scopus (1435) Google Scholar), as recommended by the American Heart Association (14Greenland P. Alpert J.S. Beller G.A. Benjamin E.J. Budoff M.J. Fayad Z.A. Foster E. Hlatky M.A. Hodgson J.M. Kushner F.G. et al.2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.Circulation. 2010; 122: e584-e636Crossref PubMed Scopus (542) Google Scholar). Moreover, sex differences have been reported in the relationship between smoking and subclinical inflammation in adults (15Ahonen T.M. Kautiainen H.J. Keinänen-Kiukaanniemi S.M. Kumpusalo E.A. Vanhala M.J. Gender difference among smoking, adiponectin, and high-sensitivity C-reactive protein.Am. J. Prev. Med. 2008; 35: 598-601Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). Studies in adults have documented that smoking may reduce the efficacy of OCs (16Sparrow M.J. Pregnancies in reliable pill takers.N. Z. Med. J. 1989; 102: 575-577PubMed Google Scholar), and may adversely affect menstrual cycle control in OC users (17Rosenberg M.J. Waugh M.S. Stevens C.M. Smoking and cycle control among oral contraceptive users.Am. J. Obstet. Gynecol. 1996; 174: 628-632Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar). Estrogen levels were shown to be lower in smokers, compared with nonsmokers (18Jensen J. Christiansen C. Rødbro P. Cigarette smoking, serum estrogens, and bone loss during hormone-replacement therapy early after menopause.N. Engl. J. Med. 1985; 313: 973-975Crossref PubMed Scopus (320) Google Scholar). The cause of the anti-estrogenic effects of smoking may be an increase in the catabolism of estrogen (19Michnovicz J.J. Hershcopf R.J. Naganuma H. Bradlow H.L. Fishman J. Increased 2-hydroxylation of estradiol as a possible mechanism for the anti-estrogenic effect of cigarette smoking.N. Engl. J. Med. 1986; 315: 1305-1309Crossref PubMed Scopus (618) Google Scholar). To our knowledge, the potential interaction between smoking and OC use in relating to CRP levels in adolescence has not been studied. To date, there is scant and inconsistent literature on the relationship between smoking exposure and CRP in adolescence (20O'Loughlin J. Lambert M. Karp I. McGrath J. Gray-Donald K. Barnett T.A. Delvin E.E. Levy E. Paradis G. Association between cigarette smoking and C-reactive protein in a representative, population-based sample of adolescents.Nicotine Tob. Res. 2008; 10: 525-532Crossref PubMed Scopus (65) Google Scholar, 21Pirkola J. Vääräsmäki M. Ala-Korpela M. Bloigu A. Canoy D. Hartikainen A.L. Leinonen M. Miettola S. Paldanius M. Tammelin T.H. et al.Low-grade, systemic inflammation in adolescents: association with early-life factors, gender, and lifestyle.Am. J. Epidemiol. 2010; PubMed Scopus Google Scholar). of the of cigarette smoking the risk of this population-based study to the effect of smoking on high-sensitivity CRP (hs-CRP) levels, and the potential interactive effects of sex and OC use on this relationship in adolescents from the Western Australian Pregnancy Cohort (Raine) primary was that in this adolescent smoking CRP levels, and other factors as sex and OC use this This study is on the of the Western Australian Pregnancy Cohort (Raine) a population-based of the have been Effects of during a PubMed Scopus Google Scholar). from women from and in Western were of between and was in with the for in of the Australian and and was by the of and for in was from the and the the 17 there were adolescents from the cohort. adolescents to and for and lifestyle smoking, use, and were The adolescents for and and and had for in the 17 were more of the Western Australian population than the had a higher of to the public The smoking status and other of the adolescents were a The adolescent was in the and in the and the of in the were recorded. of the use of OCs was from the the have the and are were also the or and of or in the was as in a during the The that a heart of and has been in our study population D. H. L. M. The relationship among and in J. Med. 2009; PubMed Scopus Google Scholar), was employed to a and were using factor with and for were G.L. M. T.A. de S.R. S.R. et are associated with lifestyle and 2009; PubMed Scopus Google Scholar). was as Australian to and an were for the of total adiponectin, and as reported C. S. T.A. contraceptive use in girls and in boys are associated with increased in J. Prev. 2013; PubMed Scopus Google Scholar). was using a and body using a was using an with an The of the of of and was recorded. was from the of the age was from the of the menstrual there was of more than with as of than in the was on A smoking variable was to cigarette smoking, effects on hs-CRP levels smoking more than cigarette effects on hs-CRP of the effect of was analyzed using a that OC use is an important factor in CRP levels in in a three-level sex variable (girls using OCs, girls not using OCs, and boys) to the effects of sex and OC use, as well as on the relationship between smoking and Tobit regression models, the of M. outcomes with or an to the Tobit 2010; Scopus Google Scholar), were employed in to as a of the lower of the CRP hs-CRP were log-transformed and hs-CRP are to be the of acute inflammation, were in on by the American Heart Association (3Pearson T.A. Mensah G.A. Alexander R.W. Anderson J.L. Cannon III, R.O. Criqui M. Fadl Y.Y. Fortmann S.P. Hong Y. Myers G.L. et al.Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association.Circulation. 2003; 107: 499-511Crossref PubMed Scopus (5172) Google Scholar). Tobit regression the relationship between cardiovascular risk factors and hs-CRP were for sex, and for the adolescent multivariable Tobit regression for the association between adolescent smoking and hs-CRP were the potential effects of and a factors were the effects on and P were after the of variable to that had on the potential between the and the three-level sex the potential sex and OC use effect A P of was to in the is to adiposity effects on CRP in regression models, but the relationship between and in multivariable models, leptin and adiponectin, were to the to assess the independent effects of on hs-CRP College was for are P < the adolescents that in the 17 1,050 had anthropometric, and and 2 the and and of the adolescents studied. of the girls OCs, of adolescents were were smokers, and had hs-CRP levels in the of with the girls not using OCs, a of smokers as well as a of in the were in the girls hs-CRP levels were higher in girls than and in girls using OCs P < 0.001). There was difference in the of the relationship between smoking and the adolescent P = OC using girls P = boys and behavioral of the study = = = OCs = OCs = = OCs = OCs = = OCs = OCs = = of the for of over the cigarette in a of the to are as or or Australian Score of the for of over the Smoking cigarette in a the in a of the study adolescents = adolescents = adolescents = OCs = OCs = = OCs = OCs = = OCs = OCs = = are as or of assessment for in a are as or or Australian are as or of assessment for of the between factors and hs-CRP male was associated with lower hs-CRP levels < compared with the use of OCs in girls and smoking in adolescents were associated with higher levels of hs-CRP P < between cardiovascular risk factors and cigarette in a over the for in Australian to Smoking cigarette in a over the for in a a interaction between the three-level sex variable and smoking, there was a difference between using or not using OCs in the association of smoking with hs-CRP P = girls using OCs and smoking girls using OCs and not P = smoking boys nonsmoking the effects of smoking on hs-CRP in the multivariable girls not using OCs, smoking associated with a increase in hs-CRP levels (b = 0.571; P = 0.001). in girls using OCs, there was effect of smoking on hs-CRP (b = −0.117; P = there was a effect of smoking that was not as as that in girls not using models, was associated with higher hs-CRP levels, with of association in the by the interaction P = OC using girls and P = boys Further, OC use in nonsmoking girls was the strongest factor associated with higher hs-CRP levels (b = 1.189; P < 0.001). that there was a difference in the linear prediction of hs-CRP levels between smokers and nonsmokers in girls not using this was not demonstrated in girls using OCs or in for the effects of smoking on hs-CRP in the adolescent sample = not using OCs and using OCs and using OCs and not not multivariable in that P < in the are of the interaction between smoking and use, are in a multivariable in that P < in the are of the interaction between smoking and use, are adjustment for leptin in multivariable that leptin was associated with higher hs-CRP levels (b = P = 0.001), independent of as a of adiposity for leptin not the of the smoking in the there was independent association between adiponectin and with adjustment for models, there was sex difference in the of leptin or adiponectin in the relationship between smoking and a population of 17 have shown that smoking was associated with higher hs-CRP levels in girls not using OCs, but not in girls using OCs or in boys. was associated with higher hs-CRP levels in and OC use in nonsmoking girls was the strongest factor associated with higher hs-CRP To our knowledge, this is the study to in this age and the first to that the effects of smoking on hs-CRP is more robust in girls than in boys. OC use hs-CRP levels in women (6Cauci S. Di Santolo M. Culhane J.F. Stel G. Gonano F. Guaschino S. Effects of third-generation oral contraceptives on high-sensitivity C-reactive protein and homocysteine in young women.Obstet. Gynecol. 2008; 111: 857-864Crossref PubMed Scopus (53) Google Scholar). Studies in adolescents have shown a association between smoking and hs-CRP (20O'Loughlin J. Lambert M. Karp I. McGrath J. Gray-Donald K. Barnett T.A. Delvin E.E. Levy E. Paradis G. Association between cigarette smoking and C-reactive protein in a representative, population-based sample of adolescents.Nicotine Tob. Res. 2008; 10: 525-532Crossref PubMed Scopus (65) Google Scholar, 21Pirkola J. Vääräsmäki M. Ala-Korpela M. Bloigu A. Canoy D. Hartikainen A.L. Leinonen M. Miettola S. Paldanius M. Tammelin T.H. et al.Low-grade, systemic inflammation in adolescents: association with early-life factors, gender, and lifestyle.Am. J. Epidemiol. 2010; PubMed Scopus Google Scholar), not the potential between sex and OC use on the smoking the with over of the girls using OCs, that OC use in nonsmoking girls was a strong of higher hs-CRP Further, a effect of smoking on hs-CRP in the girls not using there was effect of smoking on hs-CRP in the girls and OCs, the a of and the smoking in this were in with smoking and the potential anti-estrogenic effect of smoking P. Anderson M. Cigarette smoking and effects on in 2005; PubMed Scopus Google may explain our findings of a role of OCs on hs-CRP levels in the Smoking has been reported to estradiol in the (19Michnovicz J.J. Hershcopf R.J. Naganuma H. Bradlow H.L. Fishman J. Increased 2-hydroxylation of estradiol as a possible mechanism for the anti-estrogenic effect of cigarette smoking.N. Engl. J. Med. 1986; 315: 1305-1309Crossref PubMed Scopus (618) Google Scholar), and in by smoking Christiansen C. on the effect of A literature with implications for and PubMed Scopus Google that to may contribute to an anti-estrogenic effect of smoking on to risk and effect CRP and have the to is risk for cardiovascular (4Kaptoge S. Di Angelantonio E. Pennells L. Wood A.M. White I.R. Gao P. Walker M. Thompson A. Sarwar N. Caslake M. et al.C-reactive protein, fibrinogen, and cardiovascular disease prediction.N. Engl. J. Med. 2012; 367: 1310-1320Crossref PubMed Scopus (808) Google Scholar, P.M. Kastelein J.J.P. J. C-reactive protein and cholesterol are strong of cardiovascular risk and both are important for clinical Heart J. 2013; 34: PubMed Scopus Google Scholar). from the JUPITER clinical evidence that CRP levels CVD from other cardiovascular risk factors B.M. Boekholdt S.M. Rana J.S. Kastelein J.J.P. Wareham N.J. Khaw K-T. Clinical implications of JUPITER in a contemporary European population: the EPIC-Norfolk prospective population study.Eur. Heart J. 2013; 34: 1350-1357Crossref PubMed Scopus (3) Google Scholar), a that a role for CRP in CVD risk Moreover, a demonstrated that the of CRP in of CVD risk major cardiovascular over for in that CRP had in CVD risk assessment in smokers than in nonsmokers (4Kaptoge S. Di Angelantonio E. Pennells L. Wood A.M. White I.R. Gao P. Walker M. Thompson A. Sarwar N. Caslake M. et al.C-reactive protein, fibrinogen, and cardiovascular disease prediction.N. Engl. J. Med. 2012; 367: 1310-1320Crossref PubMed Scopus (808) Google Scholar). The Reynolds Risk of both smoking and CRP are major has been and shown to CVD risk in women N.R. J.E. J.E. S. P.M. Comparison of the and Reynolds Risk for global cardiovascular risk prediction in the 2012; PubMed Scopus Google Scholar), compared with the CVD models, not that with smoking CRP levels increased over M.A. G. effects of 2007; Full Text Full Text PDF PubMed Scopus Google Scholar), and that CRP levels in CRP in M. L. J. C-reactive protein in CRP and in the Cardiovascular Risk in Young Thromb. Vasc. Biol. 26: PubMed Scopus Google Scholar), our novel of a effect of smoking on hs-CRP levels in girls not using OCs is important in this has been reported that smoking exposure is more to health in women than in smokers were more to than male smokers E. A. L. E. The increased risk of to cigarette smoking may be in women than Epidemiol. Prev. 2013; PubMed Scopus Google Scholar), and smoking in women was associated with heart disease risk compared with smoking in men M. Cigarette smoking as a risk factor for heart disease in women compared with a and of prospective 2011; Full Text Full Text PDF PubMed Scopus Google Scholar). with and the have shown in this adolescent population that smoking exposure was associated with lower levels of in girls but not boys C. S. T.A. Gender difference in the relationship between smoking exposure and levels in Clin. Endocrinol. Metab. 2013; PubMed Scopus Google Scholar). higher levels of hs-CRP in girls using OCs and also in girls not using OCs compared with a is with studies in adults (11Abdullah S.M. Khera A. Leonard D. Das S.R. Canham R.M. Kamath S.A. Bega G.L. Grundy S.M. McGuire D.K. de Lemos J.A. Sex differences in the association between leptin and CRP: results from the Dallas Heart Study.Atherosclerosis. 2007; 195: 404-410Abstract Full Text Full Text PDF PubMed Scopus (56) Google and adolescents J. Vääräsmäki M. Ala-Korpela M. Bloigu A. Canoy D. Hartikainen A.L. Leinonen M. Miettola S. Paldanius M. Tammelin T.H. et al.Low-grade, systemic inflammation in adolescents: association with early-life factors, gender, and lifestyle.Am. J. Epidemiol. 2010; PubMed Scopus Google higher levels of CRP in females compared with studies that leptin levels may explain the sex difference in CRP levels (11Abdullah S.M. Khera A. Leonard D. Das S.R. Canham R.M. Kamath S.A. Bega G.L. Grundy S.M. McGuire D.K. de Lemos J.A. Sex differences in the association between leptin and CRP: results from the Dallas Heart Study.Atherosclerosis. 2007; 195: 404-410Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar). our sex differences in hs-CRP levels were for by after for of leptin on the interaction effects on Further, may affect CRP levels between boys and be to the sex differences in adiponectin levels during A. J. G. T.M. S. E. M. Gender differences of adiponectin levels during the of and are related to serum Clin. Endocrinol. Metab. PubMed Scopus Google Scholar). in our study of of the girls and of the boys were or association between adiponectin and hs-CRP levels of A of our study is that employed from a population-based with anthropometric, and from to and over 17 the relationship between smoking and hs-CRP with adjustment for a of potential sex and OC of the study the of in may have the of interaction Smoking exposure was from and the smoking to potential the adolescents smoking and other behavioral a Moreover, a has shown and in for smoking exposure A. Thompson P. S. The of A and J. PubMed Scopus Google Scholar). OC use was but not the of OCs be that the findings to of a of adolescents 17 of have shown a more robust effect of smoking in girls that were not using OCs on hs-CRP levels, compared with girls OCs or boys. findings the important role of CRP in CVD risk in CVD risk assessment in that both smoking and CRP levels from to the findings explain why CVD risk conferred by smoking is higher in women than in men.