Serum γ-glutamyltransferase: Independent Predictor of Risk of Diabetes, Hypertension, Metabolic Syndrome, and Coronary Disease

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1 nture publishing group Serum γ-glutmyltrnsferse: Independent Predictor of Risk of Dibetes, Hypertension, Metbolic Syndrome, nd Coronry Disese Altn Ont 1, Güny Cn 2, Ender Örnek 3, Gökhn Çiçek 4, Erkn Ayhn 4 nd Yüksel Doğn 5 Serum γ-glutmyltrnsferse (GGT) is ssocited with oxidtive stress nd heptic stetosis. The extent to which its vlue in determining incident crdiometbolic risk (coronry hert disese (CHD), metbolic syndrome (MetS), hypertension nd type 2 dibetes) is independent of obesity needs to be further explored in ethnicities. After pproprite exclusions, cohort of 1,667 dults of generl popultion (ge 52 ±11 yers) ws evluted prospectively t 4 yer s follow-up using prtly Cox proportionl hzrd regressions. GGT ctivity ws mesured kineticlly, nd vlues were log-trnsformed for nlyses. MetS ws identified by Adult Tretment Pnel-III criteri modified for mle bdominl obesity. Medin (interqurtile rnge) GGT ctivity ws 24.9 (17.0; 35.05) U/l in men, 17.0 (12.3; 24.0) U/l in women. In liner regression nlysis, while smoking sttus ws not ssocited, (mle) sex, sexdependent ge, lcohol usge, BMI, fsting triglycerides nd C-rective protein (CRP) were significnt independent determinnts of circulting GGT. Ech 1-s.d. increment in (= 0.53 ln GGT) GGT ctivity significntly predicted in ech sex incident hypertension (hzrd rtio (HR) 1.20 (95% confidence intervl (CI) 1.10; 1.31)), nd similrly MetS, fter djustment for ge, lcohol usge, smoking sttus, BMI nd menopuse. Strongest independent ssocition existed with dibetes (HR 1.3 (95% CI 1.1; 1.5)) wheres GGT ctivity tended to mrginlly predict CHD independent of totl bilirubin but not of BMI. Higher serum totl bilirubin levels were protective ginst CHD risk in women. We conclude tht elevted serum GGT confers, dditively to BMI, risk of hypertension, MetS, nd type 2 dibetes but only medites diposity ginst CHD risk. Obesity (2012) 20, doi: /oby Introduction Elevtion in serum γ-glutmyltrnsferse (GGT) ctivity, previously scribed to lcohol intke or liver disese, hs been shown to predict morbidity nd mortlity independent of these (1,2). Modest increses within norml rnge my be n erly mrker of cellulr oxidtive stress (3) nd explin the strong ssocitions of serum GGT with mny crdiovsculr risk fctors nd disese. Oxidtive stress, ssessed by circulting prostglndin F2α levels, is recognized to be relted to obesity (4). Indeed, BMI ws observed to be determinnt of GGT concentrtions in both genders in the Tromsö study (5). Increses in GGT ctivity hve been found to predict hypertension (6,7), s well s incident cses of type 2 dibetes (8 10). GGT ctivity lso predicted ll-cuse nd coronry hert disese (CHD) mortlity, independent of lcohol intke or liver disese (1,2). Metbolic syndrome (MetS) lso ws found to be ssocited with incresed GGT ctivity in prospective study of Jpnese men (10), in the Frminghm Study (2), nd cross-sectionlly mong Turkish dults (11). Despite the vilbility of considerble knowledge in the topic, further informtion is needed in regrd to the mgnitudes of risk ssocited between GGT ctivity nd the individul crdiometbolic disorders, the extent of ethnic vrition therein nd to wht extent the observed ssocitions re dependent on excess diposity. Serum bilirubin is recognized to ct s n ntioxidnt; nd prospective cohort studies hve shown tht higher serum bilirubin concentrtions re ssocited with decresed risk for CHD (12,13). In dyslipidemic ptients with MetS, men bilirubin levels decresed progressively with the number of MetS components s men GGT ctivity incresed (14). Whether n interction exists between the two stted oxidtion-relted vribles with respect to dibetes or CHD is not defined. Studies exmining the reltionship of serum GGT levels with ech of the risks of hypertension, MetS, dibetes nd CHD in the sme popultion-bsed cohort might provide clues to the preferentil oxidtive pthwys opertive in regrd to different 1 Deprtment of Crdiology, CerrhpȘ Medicl Fculty, Istnbul University, Istnbul, Turkey; 2 Deprtment of Public Helth, CerrhpȘ Medicl Fculty, Istnbul University, Istnbul, Turkey; 3 Deprtment of Crdiology, Etlik Eductionl nd Reserch Hospitl, Ankr, Turkey; 4 Deprtment of Crdiology, S. Ersek Crdiovsculr Surgery Center, Istnbul, Turkey; 5 Deprtment of Crdiology, Bkirköy Sdi Konuk Eductionl Hospitl, Istnbul, Turkey. Correspondence: Altn Ont (lt_ont@yhoo.com.tr) Received 8 November 2010; ccepted 11 April 2011; published online 2 June doi: /oby VOLUME 20 NUMBER 4 pril

2 crdiometbolic risks; such informtion might eventully be used in risk ssessment or prevention. Turks hve high prevlence of MetS (15) nd enhnced low-grde inflmmtion (16), hence, re suitble to explore such ssocitions. We, therefore, imed to exmine: (i) the determinnts of GGT ctivity, including sex, ge, nd inflmmtory meditors, (ii) to explore prospectively its ssocitions with the development of individul crdiometbolic disorders independent of diposity mesures, nd (iii) to determine whether serum totl bilirubin concentrtions ct s ntioxidnt ginst type 2 dibetes or CHD in popultion smple representtive of middle-ged nd elderly Turkish dults. Methods nd Procedures This study smple is formed by the cohort of the Turkish Adult Risk Fctor Study, prospective survey on the prevlence of crdic disese nd risk fctors in representtive smple of dults in Turkey crried out biennilly since 1990 in 59 communities throughout ll geogrphicl regions of the country (17). Prtil logistic support ws provided by the Turkish Ministry of Helth. Written informed consent ws obtined from ll prticipnts. Dt were obtined by history of the pst yers vi questionnire, physicl exmintion of the crdiovsculr system, nd recording of resting electrocrdiogrm. During the screening serum GGT concentrtions were determined in 1,875 prticipnts, ged yers. Exclusions (11%) were mde s follows: 56 individuls with GGT vlues over 100 U/l to minimize confounding by unrecognized heptic disese nd hevy usge of lcohol, hormone replcement therpy or use of lipid lowering drugs (64 subjects), type 2 dibetes with or without renl impirment (97 persons). No subjects existed with recent myocrdil infrction or known heptic disese. This left 1,667 nondibetic persons (821 men nd 846 women) for nlysis in this study. Control ws mde for menopuse in 409 women (48.4%), for 245 persons with lcohol intke up to one to four times weekly (moderte) in regression nlyses. Mesurement of risk fctors Blood pressure ws mesured with n neroid sphygmomnometer (Erk, Bd TÖlz, Germny) in the sitting position on the right rm, nd the men of two recordings 3-min prt ws recorded. Weight ws mesured in light indoor clothes using scles. Wist circumference ws mesured with the subject stnding nd wering only underwer, t the level midwy between the lower rib mrgin nd the ilic crest. BMI ws computed s weight divided by height squred (kg/m 2 ). In regrd to cigrette smoking, never smokers, pst smokers, nd current smokers formed the ctegories. Anyone who drnk lcoholic drinks between once month nd four times per week ws considered s moderte user. Blood smples were collected in 11-h or longer fsting stte in this study except for 15% of individuls. Smples were spun t 1,000 g for 10 min nd shipped on cooled gel pcks t 2 5 C to Istnbul to be stored in deep-freeze t 75 C, until nlyzed t the Yıldız Technicl University in the sme city. Serum GGT ctivity ws ssyed by the kinetic method using Glucn s substrte (Thermo Trce, Noble Prk, Austrli) with Hitchi 902 utonlyzer, norml rnge being reported s 50 U/l in men, 30 U/l in women. PreciNorm U nd PreciPth U universl control ser were used s controls. Inter- nd intr-ssy coefficient of vrition for GGT were 1.2/1.1% nd 1.5/1.6%, respectively. Serum concentrtions of totl cholesterol, fsting triglycerides, glucose, high-density lipoprotein cholesterol (HDL-C plus 2nd genertion, directly without precipittion) nd totl bilirubin were determined by using enzymtic kits from Roche Dignostics (Mnnheim, Germny) with Hitchi 902 utonlyzer. Low-density lipoprotein cholesterol vlues were computed ccording to the Friedewld formul. Uric cid ws determined enzymticlly by Infinity kit utilizing modified Trinder method. Serum concentrtions of complement C3, high-sensitivity C-rective protein (CRP), polipoprotein A-I, nd B were mesured by Behring kits nd nephelometry (Behring Dignostics, Westwood, MA). Concentrtions of insulin were determined by the chemiluminescent immunometric method using Roche kits nd Elecsys 1010 immunutonlyzer (Roche Dignostics). Dignosis of CHD ws bsed on the presence of ngin pectoris, of history of myocrdil infrction with or without ccompnying Minnesot codes of the electrocrdiogrm (18), or on history of myocrdil revsculriztion (in one-qurter of ptients). Among women, ge >45 yers ws prerequisite for definitive dignosis dded to isolted typicl ngin. Electrocrdiogrm chnges of ischemic type of greter thn minor degree (codes 1.1-2, 4.1-2, 5.1-2, 7.1) were considered s myocrdil infrct sequele or myocrdil ischemi, respectively. Hypertension ws defined s blood pressure ³140 mm Hg nd/or ³90 mm Hg, nd/or use of ntihypertensive mediction. Metbolic syndrome ws identified when three out of the five criteri of the Ntionl Cholesterol Eduction Progrm (Adult Tretment Pnel-III) (19) were met, modified for predibetes (fsting glucose ³100 mg/dl (>5.55 mmol/) (20) nd further for mle bdominl obesity using cutoff of ³95 cm, s ssessed in the Turkish Adult Risk Fctor study (21). Fsting triglyceride vlues of the previous prticiption in the survey were tken into ccount in few instnces of missing dt. Dibetes ws dignosed with the criteri of the Americn Dibetes Assocition (20), nmely by self-report or when plsm fsting glucose ws ³7.0 mmol/l or when 2-h postprndil glucose ws >11.1 mmol/l. Dt nlysis Descriptive prmeters were shown s men ± s.d. or in %. Due to skewed distribution, vlues derived from log-trnsformed (geometric) mens were used for GGT, CRP, nd insulin. Person correltion ws used for continuous vribles, nd Spermn correltion for log-trnsformed nd ctegoricl vribles. GGT ws dichotomized by the ner-medin 25 U/l in men, nd 17 U/l in women to evlute the distribution of bseline chrcteristics in prticipnts. Qurtiles were formed of sex-specific serum totl bilirubin, mrker of oxidtive stress, using cutoff points of 0.4, 0.585, 0.80 mg/dl in men nd 0.3, 0.465, 0.60 mg/dl in women. Multiple liner regression nlyses were performed. Since logrithmic vlues were used for the dependent vrible GGT in liner regression models, the β-coefficient of n independent vrible ws clculted by log-trnsforming the obtined vlues nd using the exponents corresponding to the stndrd devition. The reltive risk for GGT by logistic regression or Cox regression nlyses ws expressed in terms of 1-s.d. increment which corresponded to ln Sttisticl nlyses were performed using SPSS-10 for Windows (Nr ; SPSS, Chicgo, IL). A vlue of P < 0.05 on the two-til test ws considered sttisticlly significnt. Results In 1,667 nondibetic subjects t bseline, 101 (6.1%) developed dibetes, nd of 1,533 persons free of CHD t bseline, 118 (7.7%) developed CHD over period of 3.93 (±1.0, rnge 2 5) yers for either outcome. Medin (interqurtile rnge) GGT ctivity t bseline ws 24.9 (17.0; 35.05) U/l in 820 men, 17.0 (12.3; 24.0) U/l in 847 women. Correltes of GGT High compred with low GGT concentrtions significntly distinguished prcticlly ll risk fctors relted to MetS nd crdiovsculr disese including lcohol usge nd CRP, except smoking sttus, HDL-cholesterol nd po A-I (Tble 1). Gender ws similr in the two groups (P = 0.28). obesity VOLUME 20 NUMBER 4 pril

3 Tble 1 Mens (s.d.) of bseline chrcteristics in the study smple strtified by sex-specific low/high GGT vlues (n = 1,667) Low GGT (<25/17 U/l) High GGT ( 25/17 U/l) n Men s.d. n Men s.d. Age, yers P vlue GGT, miu/l <0.001 Totl bilirubin, mg/dl Wist circumference, cm <0.001 BMI, kg/m <0.001 Systolic BP, mm Hg <0.001 Distolic BP, mm Hg <0.001 Fsting glucose, mmol/l Totl cholesterol, mmol/l <0.001 Fsting triglycerides, mmol/l <0.001 HDL-cholesterol, mmol/l Apolipoprotein A-I, g/l Apolipoprotein B, g/l <0.001 Uric cid, μmol/l <0.001 CRP mg/l <0.001 Complement C3, g/l <0.001 Fsting insulin, miu/l <0.001 Fibrinogen, g/l Alcohol usge, n, % <0.001 Current smoking, n, % Some prmeters were not mesured t bseline in ech prticipnt. BP, blood pressure; CRP, C-rective protein; GGT, γ-glutmyltrnsferse; HDL, high-density lipoprotein. Geometric men nd s.d. vlues. Highest correltions of log GGT were observed with fsting triglycerides, wist circumference, lcohol usge, complement C3 nd fsting insulin (r rnging from 0.2 to 0.3, Tble 2). Tble 3 depicts multiple regression nlysis for log GGT in model comprising five independent vribles tht explined 20% of the vrition in GGT vlues; it showed mle sex (vlues 1.37-fold those in women), usge of moderte lcohol (1.4-fold thn in bstiners) nd wist circumference (1.16-fold per 1-s.d. increment) to be mjor determinnts of circulting GGT. While smoking ws not independently ssocited, seprte nlyses in sexes disclosed ge to be inversely ssocited in men but positively in women. Further liner regression nlyses for log GGT djusted for sex, ge, lcohol usge, smoking sttus, nd BMI were used with the following dditionl individul vribles tht proved to be significntly nd independently ssocited: elevted fsting triglycerides (β-coefficient 1.29 per 1 s.d.), CRP (β-coefficient 1.13) nd low-density lipoprotein cholesterol (β-coefficient 1.11). Prediction of incident crdiometbolic disorders In multivrible Cox models for incident CHD nd dibetes, djusted for sex, ge, nd menopuse, we first exmined whether log GGT nd serum totl bilirubin qurtiles were ech of independent predictive vlue. While GGT ws modestly Tble 2 Person/Spermn correltions of GGT concentrtions (n = 1,667) n r P vlue Wist circumference, cm 1, <0.001 BMI, kg/m 2 1, <0.001 Systolic BP, mm Hg 1, Distolic BP, mm Hg 1, <0.001 Totl cholesterol, mg/dl 1, <0.001 Fsting triglycerides, mmol/l 1, <0.001 HDL-cholesterol, mmol/l 1, <0.001 Fsting glucose, mmol/l 1, <0.001 Uric cid, μmol/l 1, Totl bilirubin, mg/dl 1, Complement C3, g/l 1, <0.001 C-rective protein, mg/l 1, <0.001 Fsting insulin miu/l 1, <0.001 Apolipoprotein A-I, g/l 1, Apolipoprotein B, g/l 1, <0.001 Smoking sttus 1, <0.001 Alcohol usge 1, <0.001 Some prmeters were not mesured t bseline in ech prticipnt. Significnt vlues re provided in boldfce nd borderline significnt vlues re itlicized. BP, blood pressure; GGT, γ-glutmyltrnsferse; HDL, high-density lipoprotein. Log-trnsformed vlues. 844 VOLUME 20 NUMBER 4 pril

4 Tble 3 Liner regression nlyses for GGT β-coefficient s.e. P vlue β-coefficient s.e. P vlue β-coefficient s.e. P vlue Totl (n = 1,641) Men (n = 807) Women (n = 834) Constnt < < <0.001 Sex, mle <0.001 Alcohol intke, yes/no < < Wist circumference, 11/13 cm < < <0.001 Age, 11 yers < <0.001 Smokers, current vs. never Vrince r ; P < ; P < ; P < Log-trnsformed vlues. Significnt vlues re provided in boldfce. GGT, γ-glutmyltrnsferse. Denotes 1-s.d. increment in men/women. Tble 4 Cox regression for prediction of incident CHD nd dibetes by serum GGT, djusted for sex, ge nd totl bilirubin qurtiles HR 95% CI HR 95% CI HR 95% CI For CHD Totl (n = 103/1,125) Men (n = 45/542) Women (n = 58/583) Sex, femle ; 2.12 Age, 11 yers b ; ; ; 3.18 GGT, 1.7-fold c ; ; ; 1.36 Bilirubin qurtile 2 ( / ) d ; ; ; 1.41 Bilirubin qurtile 3 ( / ) d ; ; ; 0.92 Bilirubin qurtile 4 (>0.8/0.6) d ; ; ; 1.23 Menopuse ; 2.32 For type 2 dibetes n = 85/1,211 n = 53/587 n = 32/624 GGT, 1.7-fold c ; ; ; 1.64 Bilirubin qurtile 2 ( / ) d ; ; ; 4.87 Bilirubin qurtile 3 ( / ) d ; ; ; 1.97 Bilirubin qurtile 4 (>0.8/0.6) d ; ; ; 4.87 Menopuse ; 3.12 Overll smples vry depending on exclusion of the prevlent cses for ech disorder t bseline. Age djusted in both models. Individuls tking hormone replcement therpy or f lipid lowering drugs (64 subjects) hd been excluded. Significnt vlues re provided in boldfce. CHD, coronry hert disese; CI, confidence intervl; GGT, γ-glutmyltrnsferse; HR, hzrd rtio. Number of cses/number t risk. b Denotes 1-s.d. increment. c Log-trnsformed vlues 25/17 vs. <25/17 U/l expressed in terms of 1 s.d. =70% higher geometric men vlues. d Referent <0.4/<0.3 mg/dl. predictive of CHD nd firly strongly of dibetes (Tble 4), high bilirubin qurtiles did not prove to be inversely nd significntly ssocited with these diseses. Though GGT ws not ssocited with CHD in femles, women with totl bilirubin 0.47 mg/dl (in the two highest qurtiles) were ssocited with protection ginst CHD lone: reltive risk (RR) 0.52 (95% confidence intervl (CI) 0.28; 0.95) compred with the lowest qurtile. While in men RR ws not significnt with 0.81, in the totl study smple, the two highest qurtiles disclosed n RR of 0.64 (95% CI 0.40; 1.006). When BMI ws substituted for bilirubin to evlute the degree of medition of the GGT ssocitions by diposity (Tble 5), the introduced BMI ttenuted the ssocitions of GGT for CHD in women, contrsted to modest ttenution in men. The converse ws true in regrd to dibetes, nmely, the ssocitions of GGT were modestly ttenuted in men but becme significnt nd somewht stronger in women. GGT nd incidence of hypertension nd metbolic syndrome Tble 6 demonstrtes prediction of incident hypertension by log GGT in logistic regression model djusted for sex, ge, menopuse nd BMI, ll powerful determinnts of elevted blood pressure. GGT contributed to the ssocitions with n RR of 1.20 (95% CI 1.10; 1.31) per 1-s.d. increment. After exclusion of 40% of prticipnts who hd MetS t bseline, 332 mong 975 persons developed MetS during the follow-up. Serum GGT significntly predicted incident MetS t modest RR in ech sex, fter djustment for ge (nd menopuse in women). Further djustment for lcohol usge nd obesity VOLUME 20 NUMBER 4 pril

5 Tble 5 Cox regression for prediction of incident CHD nd dibetes by serum GGT, djusted for sex, ge, BMI nd menopuse HR 95% CI HR 95% CI HR 95% CI For CHD Totl (n = 116/1,334) Men (n = 52/647) Women (n = 64/687) Sex, femle ; 1.70 Age, 11 yers b ; ; ; 2.74 GGT, 1.7-fold c ; ; ; 1.23 BMI, kg/m 2, 4.5/5.5 b ; ; ; 1.55 Menopuse ; 2.76 For type 2 dibetes n = 99/1,439 n = 59/700 n = 40/739 Sex, femle ; 1.02 Age, 11 yers b ; ; ; 1.86 GGT, 1.7-fold c ; ; ; 1.71 BMI, kg/m 2, 4.5/5.5 b ; ; ; 2.18 Menopuse ; 2.04 Overll smples vry depending on exclusion of the prevlent cses for ech disorder t bseline. Significnt vlues re provided in boldfce. CHD, coronry hert disese; CI, confidence intervl; GGT, γ-glutmyltrnsferse; HR, hzrd rtio. Number of cses/number t risk. b Denotes 1-s.d. increment in men/women. c Log-trnsformed vlues 25/17 vs. <25/17 U/l expressed in terms of 1 s.d. =70% higher geometric men vlues. Tble 6 Logistic regression for prediction of incident hypertension (HT) nd metbolic syndrome (MetS) by serum GGT, djusted for sex, ge, menopuse nd BMI RR 95% CI RR 95% CI RR 95% CI For HT Totl (n = 476/1,422) Men (n = 224/735) Women (n = 252/678) Sex, femle ; 1.84 Age, 11 yers b ; ; ; 2.48 GGT, 1.7-fold c ; ; ; 1.31 BMI, kg/m 2, 4.5/5.5 b ; ; ; 1.92 Menopuse ; 3.32 For MetS n = 338/987 n = 157/486 n = 181/501 Sex, femle ; 2.12 Age, 11 yers b ; ; ; 2.22 GGT, 1.7-fold c ; ; ; 1.39 Menopuse ; 1.66 Sex, femle ; 1.30 n = 332/975 n = 153/479 n = 179/496 Age, 11 yers b ; ; ; 2.38 GGT, 1.7-fold c ; ; ; 1.32 BMI, kg/m 2, 4.5/5.5 b ; ; ; 2.65 Alcohol usge, yes/no ; ; NS Menopuse ; 1.53 Overll smples vry depending on exclusion of the prevlent cses for ech disorder t bseline. Significnt vlues re provided in boldfce. CI, confidence intervl; GGT, γ-glutmyltrnsferse; NS, not significnt; RR, reltive risk. Number of cses/number t risk. b Denotes 1-s.d. increment in men/women. c Log-trnsformed vlues 25/17 vs. <25/17 U/l expressed in terms of 1 s.d. =70% higher geometric men vlues. BMI led to reduction of significnce to n RR 1.17 (95% CI 1.04; 1.30) per 1-s.d. increment. Discussion In middle-ged popultion-bsed smple prone to MetS, we found tht GGT ctivity ws ssocited with ge inversely in men but positively in women nd furthermore with fsting triglycerides, CRP nd low-density lipoprotein cholesterol, ll independent of BMI nd lifestyle hbits. High bilirubin qurtiles were not inversely ssocited with incident dibetes nd only in women with CHD, independent of circulting GGT. In logistic regression models djusted for sex, ge, menopuse 846 VOLUME 20 NUMBER 4 pril

6 nd BMI, GGT contributed to the ssocition with incident hypertension with n RR of 1.20, significntly predicted incident MetS t similr RR which ws in prt BMI-medited. In similrly djusted Cox regression models, GGT ctivity ws most strongly predictive of dibetes independently in ech sex (hzrd rtio (HR) 1.30 per 1-s.d. increment). Yet introduction of BMI in the models ttenuted the modest predictive bility of GGT for incident CHD in women, contrsted to minor ttenution in men. Thus GGT ctivity, likely modest independent CHD risk meditor in mles, is prt of the proinflmmtory stte/oxidtive stress in Turkish femles, for which other evidences hd been reported (16,22). Elevted generl levels nd independent covrites Generl levels of GGT ctivity in the study popultion ws substntilly higher thn those reported for other popultions. In four lrge community-bsed studies (2,8,23,24) medin vlues rnged between U/l in men nd 9 11 U/l in women, while current vlues were higher by 1.4-fold nd 1.7-fold, respectively. This reflects, in our opinion, the true difference in GGT levels (rther thn vrition in mesurement methodology) given the high prevlence of MetS nd dibetes mong Turks, prticulrly women. Aprt from the well-known GGT determinnts of mle sex nd lcohol intke, fsting triglycerides, CRP nd sex-dependent ge were the mjor covrites of GGT ctivity in the present study. A rise concomitnt with ge ws not unexpected in women, yet the significnt moderte independent decline of GGT (by 6%) per 1-s.d. increment in ge mong men might be scribed to the concomitnt decrese in Turkish men (but not women) of both SHBG nd totl testosterone with ge (25). Serum triglycerides nd CRP, recognized meditors of low-grde inflmmtion nd oxidtive stress, were documented to be significntly ssocited with GGT independent of BMI nd other covrites. The lck of significnt ssocition with high or low GGT ctivity of serum HDL-C, po A-I nd current smoking is not surprising in this popultion smple, in view of previously documented dysfunction of HDL nd po A-I nd lck of current smoking to confer crdiometbolic risk, especilly mong Turkish women (16). Serum bilirubin in prediction of CHD risk In Cox regression nlyses jointly with GGT ctivity, totl bilirubin qurtiles were not of independent predictive vlue for the risk of incident dibetes. Regrding incident CHD risk, qurtiles 3 nd 4 (vlues >0.46 mg/dl) proved to confer protection in women, but not in men, nd mrginlly in the whole smple. Turkish women rther thn men were demonstrted to be more influenced by low-grde inflmmtion (16) which might explin the observed inverse ssocition of higher bilirubin with decresed CHD risk being confined to femles. Ltter findings in women re in essentil greement with those reported (12,13). Independent influence of serum GGT on metbolic risk but BMI-medition in CHD risk The mgnitude of the ssocition between GGT ctivity nd outcome hs previously been expressed vribly, either in quntiles (8,24), per doubling of levels or per log unit increse in GGT (26). In greement with stndrd expression nd in line with the Frminghm study (2), we expressed HRs in terms of 1-s.d. increment in GGT. It is to be noted tht such expression mkes HRs pper lower thn previously reported. We confirmed findings by Lee nd ssocites (2) regrding incident MetS tht GGT predicted this development dditively to BMI nd other confounders. The mgnitude of the HR (1.17) ws slightly lower thn the 1.26 of the Frminghm study (2) in which longer follow-up ws vilble, but reltively high GGT levels in the lowest qurtile in this study smple my lso be implicted. The HR in the independent prediction of hypertension, component of MetS, ws of similr mgnitude s tht for MetS in the current study suggesting tht the contribution of GGT to the ltter risk ws minly vi the component of hypertension. In contrst, type 2 dibetes ws linked to GGT more strongly, nmely t n HR of 1.3, roughly prlleling the risk mgnitude in women of the KORA study (24). This supports our previously expressed view tht enhnced proinflmmtory stte/ oxidtive stress hs n especilly prominent role in dibetes mong Turks (16,27). Results on the prediction of CHD by GGT ctivity hve been divergent. Though most studies hve reported significnt ssocitions, these were of smll mgnitude, nd heterogeneity existed. A met-nlysis of eight studies with respect to incident CHD (26) yielded fully-djusted pooled HR for 1-s.d. of GGT tht corresponded to 1.10 (1.01; 1.20). Greter heterogeneity ws notble mong women. Our findings showing no independent predictive vlue of GGT ctivity for CHD in women nd mrginl vlue in men re closely in line with results of the pooled met-nlysis. Oxidtive processes in therogenesis presumbly merely medite nd re not dditive to the diposity-relted fctors in women; this seems to be distinct from CRP tht hs dditive fetures nd from GGT with respect to metbolic outcomes of dibetes nd hypertension in which it contributes dditively to diposity. In the KORA study, the enhnced development of type 2 dibetes mong obese subjects required the interction of high GGT ctivity in women but not in men (24) suggesting sex-dependent independent dibetogenic ction. Elevted serum GGT could be involved in crdiometbolic risk either s mrker of heptic stetosis (28), with or without heptic insulin resistnce (5), nd/or s meditor of oxidtive stress vi medition of extrcellulr glutthione trnsport into cells of orgn systems (9), or s meditor of low-grde systemic inflmmtion (29). The documented predictbility of ll three metbolic disorders of MetS, hypertension, nd dibetes by GGT ctivity suggests tht, s reflection of oxidtive stress, elevted GGT levels re ctively involved in the pthogenesis of these disorders. Strengths nd limittions Avilbility of cohort of both genders representtive of the generl popultion, exclusion of potentilly confounding conditions nd, especilly, the simultneous ssessment of obesity VOLUME 20 NUMBER 4 pril

7 the diverse crdiometbolic disorders form the strengths of the present study. A study smple prone to MetS nd hving high GGT levels, while constituting strength in view of lck of similr smples, my limit somewht the pplicbility of conclusions to popultions hving lower prevlence of MetS. Our use of multiple nlyses my be limittion in interpreting the findings, s my be the reltively limited number of events for dibetes nd CHD. Although the identifiction of CHD included soft endpoints beyond myocrdil infrction, this my reflect the nturl distribution of CHD, especilly in women. The reltively short men follow-up of 4 yers my hve precluded the obtining of higher HRs for GGT ctivity regrding crdiometbolic risk. Nonetheless, findings were in close greement with minstrem results in prior studies. Conclusions In middle-ged dults with high prevlence of MetS, serum GGT ctivity is ssocited not with smoking sttus but with mle sex, lcohol usge, sex-dependent ge, fsting triglycerides, CRP nd low-density lipoprotein cholesterol, independent of BMI. High bilirubin qurtiles did not contribute to the prediction of type 2 dibetes but higher levels were protective of CHD risk in women, independent of circulting GGT. GGT ctivity modestly predicted hypertension, MetS, nd dibetes in ech sex, independent of multiple confounders including BMI, whereby the strongest HR existed regrding dibetes risk. GGT is involved in CHD risk minly by mediting diposity. Mintennce of norml triglycerides nd CRP, regrdless of coexisting obesity, my be relevnt in reducing oxidtive stress nd risk of dibetes. Acknowledgments We thnk the phrmceuticl compnies AstrZenec, Novrtis, Pfizer, nd SnofiAventis, Istnbul, Turkey, which hve supported the Turkish Adult Risk Fctor survey over the yers. We cknowledge the work of G. 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