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A Variant Upstream of the CDH13 Adiponectin Receptor Gene and Metabolic Syndrome in Swedes

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A Variant Upstream of the CDH13 Adiponectin Receptor Gene and Metabolic Syndrome in Swedes
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  A Variant Upstream of the CDH13 Adiponectin Receptor Gene andMetabolic Syndrome in Swedes Cristiano Fava, MD, PhD a,c, *, Elisa Danese, PharmD a,d,† , Martina Montagnana, MD a,d,† ,Marketa Sjögren, PhD a , Peter Almgren, MSc a , Gian Cesare Guidi, MD d , Bo Hedblad, MD, PhD a,b ,Gunnar Engström, MD, PhD a , Alessandro Lechi, MD c , Pietro Minuz, MD c , andOlle Melander, MD, PhD a Metabolic syndrome (MetS) constitutes a worldwide epidemic burst accounting for billions of cardiovascular disease events and deaths. The genetic basis of MetS is largely unknown. Thers11646213 T ¡  A polymorphism maps at 16q23.3 upstream of the CDH13 gene codifying forcadherin-13 (also known as T-cadherin or H-cadherin), which is considered a vascular adi-ponectin receptor. This and other single-nucleotide polymorphisms have been associated withhypertension and adiponectin level in separate studies. The aim of the present study was toevaluate the effect of the CDH13 rs11646213 T ¡  A polymorphism on individual componentsof MetS and on MetS. The polymorphism was genotyped in the cardiovascular cohort of theMalmö Diet and Cancer Study (n  4,942) and successively in the Malmö Preventive Project(n  17,675) cohort at baseline and after an average of 23 years of follow-up (reinvestigation).Four different definitions of MetS were applied to these cohorts. In the cardiovascular arm, CDH13 rs11646213 AA homozygotic women showed a trend toward higher triglycerides andlower high-density lipoprotein cholesterol and presented a higher MetS score (composite sumof MetS phenotypes). MetS (Adult Treatment Panel III definition) was more prevalent in AAhomozygotic women compared to T-carriers, a result confirmed in the Malmö PreventiveProject cohort at baseline and at reinvestigation with an increased risk from 19% to 45% in AAhomozygotic women. In conclusion, the  CDH13  rs11646213 T > A polymorphism was con-sistentlyassociatedwithMetSinSwedishwomenrecruitedin2largecohorts.Inlightoftheroleof cadherin-13 as a vascular receptor for adiponectin, our study supports the genetic basis forthe role of adiponectin in MetS pathogenesis. © 2011 Elsevier Inc. All rights reserved. (Am JCardiol 2011;108:1432–1437) Metabolic syndrome (MetS) represents 1 of the most diffi-cult challenges of modern medicine, being responsible for asubstantial burden of cardiovascular mortality and morbidityworldwide. 1,2 The pathogenesis of the syndrome remainsmostly elusive and the genetic basis largely unknown. 3 In arecent genomewide scan for hypertension-related traits, a sin-gle-nucleotide polymorphism, the  CDH13  rs11646213 T   A, has been associated with blood pressure (BP) level andhypertension prevalence in 2 European populations. 4 In theGenetic Epidemiology of Metabolic Syndrome (GEMS)study polymorphisms in the same locus were found to beassociated with adiponectin level independently from dyslipi- demia, 5 a result confirmed in a cohort of Korean volunteers. 6 Using factorial analysis, 2 single-nucleotide polymorphisms inthe  CDH13  gene were found to show a significant associationwith obesity–insulin and lipid–insulin latent factors in the Hy-pertension Genetic Epidemiology Network (HyperGEN) whitesample. 3,7 The  CDH13  gene codifies for cadherin-13, which isconsidered a vascular adiponectin receptor and is expressed onendothelial and smooth muscle cells. 8 Adiponectin is the mostabundant and adipose-specific adipokine and is tightly in-volved in obesity development and other features of MetSthrough its insulin-sensitizing effect. 9 Thus, the aim of thepresent study was to test the association of the  CDH13 rs11646213 T  A polymorphisms with individual MetS com-ponents, the MetS score (sum of standardized residuals fromall single components), and MetS as defined by different sci-entific societies. 10,11 Methods All study participants provided written informed consent.The ethics committee of the medical faculty of Lund Uni- Departments of   a Clinical Sciences and  b Medicine, Lund University,University Hospital of Malmö, Malmö, Sweden; Departments of   c Medicineand  d Life and Reproduction Sciences, University Hospital of Verona,Verona, Italy. Manuscript received May 31, 2011; revised manuscriptreceived and accepted June 28, 2011.This study was supported by grants from the Swedish Medical Re-search Council, Stockholm, Sweden, the Swedish Heart and Lung Foun-dation, Stockholm, Sweden, the Medical Faculty of Lund University, Lund,Sweden, Malmö University Hospital, Malmö, Sweden, the Albert PåhlssonResearch Foundation, Malmö, Sweden, the Crafoord Foundation, Malmö,Sweden, the Ernhold Lundströms Research Foundation, Malmö, Sweden,the Region Skane, Malmö, Sweden, Hulda and Conrad Mossfelt Founda-tion, Malmö, Sweden, and the King Gustaf V and Queen Victoria Foun-dation, Stockholm, Sweden. The Knut and Alice Wallenberg Foundation,Stockholm, Sweden provided economic support of the SWEGENE DNAextraction facility.*Corresponding author: Tel: 39-45-812-4414; fax: 39-45-802-7465.  E-mail addresses:  cristiano.fava@med.lu.se (C. Fava). † Drs. Danese and Montagnana contributed equally to this article.0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. www.ajconline.orgdoi:10.1016/j.amjcard.2011.06.068  versity approved the studies. Procedures were in accordwith institutional guidelines.The study population was derived from the Malmö Dietand Cancer Study (MDC). BP and other cardiovascular risk factors were measured in a subsample of the MDC study,referred to as the MDC cardiovascular arm (MDC-CVA;n  6,103). 12,13 Successfully extracted genomic DNA wasavailable from 5,763 participants in the MDC-CVA. Com-plete data for components of MetS (defined later) and the CDH13  rs11646213 genotype were available for 4,942. Inanalyses of the European Group for the Study of InsulinResistance definition, 500 patients (with diabetes and/orwithout data on fasting insulin concentration in plasma)were excluded from the cohort, leaving 4,442 subjects foranalysis.In the Malmö Preventive Project (MPP) 33,346 Swedishparticipants (22,444 men and 10,902 women, mean age 49years) from the city of Malmö in southern Sweden partici-pated in health screening from 1974 through 1992 (atten-dance rate 71%). 14 All subjects underwent physical exam-ination and measurements of fasting blood glucose andtriglyceride concentrations were performed. Information onlifestyle factors and medical history was obtained from aquestionnaire. Of subjects participating in the initial screen-ing 4,931 died and 551 were lost during follow-up for otherreasons. Of eligible subjects 25,000 were invited to a re-screening visit from 2002 through 2006 including physicalexamination and fasting blood samples for measurements of glucose, triglyceride, and high-density lipoprotein (HDL)cholesterol concentrations. Of the invited subjects 18,240participated in the rescreening; 565 were excluded from thepresent study because of lack of DNA or crucial clinicalinformation. Thus 17,675 participants were included in thefollow-up study.Waist circumference was measured at the umbilicuslevel with the patient standing. Body mass index was cal-culated as the ratio of weight in kilograms to the square of height in meters. Obesity was defined as a body mass index  30 kg/m 2 . BP was measured by specially trained nurses inthe right brachial artery with some differences betweenstudies (see supplementary methods available online). In-creased BP was defined as systolic BP   130 mm Hg ordiastolic BP  85 mm Hg or treatment by antihypertensivedrugs according to MetS criteria definitions (provided later).Details of the measurement of serum lipids, serum insu-lin, and whole blood glucose have been published else-where. 13 Diabetes was defined as fasting blood glucose  6.1 mmol/L (MDC-CVA and MPP at baseline) or   7.0mmol/L (MPP at reinvestigation) or long-term therapy withantidiabetic drugs or self-reported history of diabetes.When continuous traits were analyzed, to adjust for useof specific medications that could interfere with recordedvalues, we added 1 SD to the standardized age- and gender-adjusted residuals when data were available. Thus we added1 SD to subjects with long-term antihypertensive treatments(n  814 in MDC-CVA, n  774 in MPP at baseline, n  Table 1Anthropometric and metabolic features of investigated subjects in the Malmö Diet and Cancer Study cardiovascular arm and Malmö Preventive Project(baseline and reinvestigation)Variables Number of SubjectsMDC-CVA Number of SubjectsMPP atBaselineNumber of SubjectsMPP atFollow-UpMen 4,942 41.0% 17,274 63.4% 17,544 63.4%Age (years) 4,942 57.59  5.94 17,274 45.16  7.36 17,544 68.24  5.77Systolic blood pressure (mm Hg) 4,942 141.25  18.91 17,274 126.77  14.10 17,544 144.86  20.00Diastolic blood pressure (mm Hg) 4,942 86.97  9.38 17,274 85.26  8.69 17,544 83.55  10.56Body mass index (kg/m 2 ) 4,942 25.81  3.94 17,274 24.30  3.38 17,544 27.16  4.14Waist circumference (cm) 4,942 83.87  12.94 891 79.23  10.01 17,544 94.79  12.27Glucose (mmol/L) 4,942 5.16  1.36 17,274 4.90  0.74 17,544 5.84  1.43Cholesterolmmol/L 4,937 6.16  1.09 17,274 5.61  1.04 17,544 5.59  1.09mg/dl 238.2  42.2 216.9  40.2 216.2  42.2Triglycerides (mmol/L) 4,942 1.36  0.74 17,274 1.28  0.78 17,544 1.27  0.80High-density lipoprotein cholesterolmmol/L 4,942 1.38  0.37 0 — 17,544 1.41  0.42mg/dl 53.4  14.3 54.5  16.2Body mass index  30 kg/m 2 4,942 13.1% 17,274 5.6% 17,544 21.6%Increased blood pressure (National Cholesterol EducationProgram/Adult Treatment Panel III)4,942 76.2% 17,274 59.0% 17,544 84.6%Diabetes mellitus 4,936 8.2% 17,274 3.2% 17,544 13.3%Menopause (in women) 2,837 80% 3,430 87.4% 0 —Hormone-replacement therapy (in women) 2,560 20.0% 3,430 18.5% 5,638 12.3%Metabolic syndrome definitionPresent study 0 — 17,274 4.6% 0 —National Cholesterol Education Program/AdultTreatment Panel III4,942 21.5% 0 — 17,544 29.2%International Diabetes Federation 4,942 29.3% 0 — 17,544 45.2%European Group for the Study of Insulin Resistance 4,612 20.1% 0 — 0 —American Heart Association/National Heart, Lung, andBlood Institute4,942 36.8% 0 — 17,544 47.9%1433 Preventive Cardiology/CDH13 Polymorphism and Metabolic Syndrome  6,666 in MPP at reinvestigation), glucose-lowering agents(n    68 in MDC-CVA, n    1,207 in MPP at reinvestiga-tion), and specific triglyceride-lowering drugs (n    109 inMDC-CVA, n  162 in MPP at reinvestigation).Data about menopause status and hormone-replacementtherapy were recorded from the standardized questionnaireand the “7-day book menu,” which subjects participating inthe 2 cohorts were asked to fill out. Women who confirmedthat their menstruation had ceased or who used hormone-replacement therapy because of  menopausal problems wereclassified as postmenopausal. 15 MetS was defined according to National Cholesterol Ed-ucation Program/Adult Treatment Panel III criteria, the In-ternational Diabetes Federation definition, the EuropeanGroup for the Study of Insulin Resistance definition (sub- jects without diabetes only), and the most recent AmericanHeart Association/National Heart, Lung, and Blood Institutedefinition (see supplementary methods for details).For the European Group for the Study of Insulin Resis-tance definition it is necessary to detect insulin resistance.We defined insulin resistance as homeostasis model assess-ment values   75th percentile (i.e.,   1.98 mmol/mU/L 2 inMDC-CVA) based on the distribution of all subjects with-out diabetes included in the present studies.In the MPP at baseline, because waist and HDL choles-terol measurements were not available for most participants,we were unable to construct the definitions of MetS accord-ing to any of the common definitions and therefore definedthe components of the MetS as (1) a body mass index  30kg/m 2 , (2) triglycerides  1.7 mmol/L and/or lipid-loweringtreatment, (3) BP  130/85 mm Hg and/or antihypertensivemedication, and (4) fasting plasma glucose   5.6 mmol/Land/or overt diabetes. Presence of   3 of these componentsdefined MetS. 16 In the MDC-CVA and MPP at reinvestigation we con-structed a MetS score to analyze MetS as a quantitative trait.First, we adjusted each variable included in the MetS defini-tions for gender and age. Second, residuals from these linearregression analyses were standardized by subtracting age- andgender-specific means and dividing by age- and gender-spe-cific standard deviation (SD). Because resultant residuals wereapproximately normally distributed, the standardization pro-cess yielded trait values that followed an n  (0,1) distribution.Because many subjects were using antihypertensive, antili-pemic, or antidiabetic medications, we added 1 SD if a patientwas treated. Outliers for each trait were handled as follows:subjects with values  3 SD were set as  3 SD. To generatethe MetS score for each subject’s available observations, wecombined standardized residuals for each component trait asfollows: MetS score    mean BP plus triglycerides plus glu-cose plus waist circumference minus HDL. HDL was sub-tracted from the score because it is protective against cardio-vascular diseases and tends to be inversely correlated with theother component traits; thus lower HDL values correspond toa higher MetS score.Genotypes of the  CDH13  rs11646213 T    A polymor-phism (db single-nucleotide polymorphism accession num-ber rs11646213) were determined by end-point fluorescentmeasurements. 17 Table 2Beta coefficient  SE for  CDH13  rs11646213 T ¡  A polymorphism tested by linear regression according to autosomal recessive genetic model andafter stratification for genderVariables (individual MetS components) Entire Population pValueWomen pValueMen pValueMalmö Diet and Cancer Study cardiovascular armSystolic blood pressure (mm Hg) 0.080  0.045 0.074 0.099  0.059 0.09 0.055  0.069 0.43Diastolic blood pressure (mm Hg) 0.064  0.045 0.16 0.087  0.058 0.13 0.033  0.072 0.65Waist circumference (cm) 0.043  0.40 0.28 0.087  0.053 0.10   0.014  0.060 0.81Body mass index (kg/m 2 ) 0.165  0.154 0.29 0.292  0.219 0.18   0.011  0.209 0.96Triglycerides (mmol/L) 0.043  0.040 0.29 0.098  0.050 0.052   0.030  0.064 0.64Glucose (mmol/L)   0.031  0.042 0.46   0.023  0.051 0.66   0.042  0.070 0.54High-density lipoprotein cholesterol (mmol/L)   0.048  0.039 0.22 0.101  0.052 0.054 0.020  0.060 0.74Metabolic syndrome score 0.207  0.128 0.10 0.382  0.168 0.023   0.022  0.197 0.91Malmö Preventive Project at baselineSystolic blood pressure (mm Hg) 0.008  0.022 0.71 0.006  0.041 0.88 0.010  0.025 0.70Diastolic blood pressure (mm Hg) 0.016  0.022 0.48 0.022  0.038 0.56 0.013  0.027 0.63Body mass index (kg/m 2 ) 0.067  0.067 0.32 0.064  0.036 0.07   0.008  0.023 0.74Triglycerides (mmol/L) 0.015  0.020 0.46 0.002  0.031 0.95 0.022  0.026 0.39Glucose (mmol/L) 0.019  0.019 0.32 0.029  0.032 0.38 0.013  0.022 0.56Malmö Preventive Project reinvestigationSystolic blood pressure (mm Hg) 0.011  0.024 0.64 0.010  0.041 0.81 0.012  0.029 0.69Diastolic blood pressure (mm Hg) 0.032  0.023 0.17 0.046  0.039 0.23 0.023  0.029 0.42Waist circumference (cm) 0.005  0.020 0.81 0.062  0.037 0.09   0.027  0.024 0.26Body mass index (kg/m 2 ) 0.009  0.020 0.65 0.075  0.038 0.051 0.09  0.020 0.65Triglycerides (mmol/L) 0.017  0.021 0.40 0.050  0.032 0.12   0.001  0.027 0.98Glucose (mmol/L) 0.016  0.024 0.51 0.030  0.036 0.41 0.007  0.031 0.81High-density lipoprotein cholesterol (mmol/L)   0.023  0.020 0.25   0.070  0.038 0.07 0.003  0.024 0.91Metabolic syndrome score 0.109  0.078 0.16 0.271  0.134 0.043 0.015  0.096 0.88All standardized residuals were adjusted for age and gender and 1 SD was added for each subject treated by specific drugs (see Methods for detaileddescription).1434  The American Journal of Cardiology (www.ajconline.org)  All data except for the power analysis were analyzedwith SPSS 18.0 (SPSS, Inc., Chicago, Illinois). Power cal-culation was performed using Power and Sample Size Cal-culator 2/1/31 (Vanderbilt University Medical Center,Nashville, Tennessee). Continuous variables are presentedas mean  SD. Pearson chi-square test was used to comparegroup frequencies and to test for deviations from the Hardy–Weinberg equilibrium. Multiple logistic and linear regres-sion analyses were used in multivariate models with MetSstatus, individual MetS components, and/or MetS score asdependent variables and genotype, age, and gender as inde-pendent variables. For variables with skewed distributionssuch as triglycerides, log-normalized values were used inthe analysis. All tests were 2-sided and p values  0.05 wereconsidered statistically significant. Results Genotyping success rates in subsamples with completedata for components of MetS were 97.3% in MDC-CVAand 96.9% in MPP. In MDC-CVA there were 1,818 CDH13  rs11646213 TT homozygotes (36.8%), 2,367 CDH13  rs11646213 TA heterozygotes (47.9%), and757  CDH13  rs11646213 AA homozygotes (15.3%); inMPP there were 6,381  CDH13  rs11646213 TT homozy-gotes (36.1%), 8,441  CDH13  rs11646213 TA heterozy-gotes (47.8%), and 2,853  CDH13  rs11646213 AA ho-mozygotes (16.1%).Genotype distributions did not deviate from Hardy–Weinberg equilibrium in all samples (predicted heterozy-gosity 0.476, observed heterozygosity 0.480, p    0.54 inMDC-CVA; predicted heterozygosity 0.480, observedheterozygosity 0.478, p    0.56 in MPP). Clinical charac-teristics of all participants are presented in Table 1. Detailed analyses about statistical power are reported in supplemen-tary Table S1 (available online). Based on preliminaryanalyses of the data we focused our attention especiallyon the autosomal recessive genetic model, which is pre-sented in the main report; data about autosomal dominantand additive genetic models are presented in the supple-mentary material. In the MDC-CVA as a whole, when Table 3Odds ratio (95% confidence interval) for metabolic syndrome conferred by the  CDH13  rs11646213 T ¡  A polymorphism tested by logistic regressionaccording to autosomal recessive genetic model in the Malmö Diet and Cancer Study cardiovascular arm and Malmö Preventive Project (baseline andfollow-up) in the entire population and after stratification for genderVariables Entire Population pValueWomen pValueMen pValueMalmö Diet and Cancer Study cardiovasculararmObesity 1.137 (0.910–1.421) 0.26 1.135 (0.848–1.517) 0.39 1.139 (0.805–1.613) 0.46Diabetes mellitus 1.001 (0.754–1.329) 0.99 0.914 (0.585–1.429) 0.69 1.061 (0.735–1.533) 0.75Increased blood pressure (American HeartAssociation/National Heart, Lung, andBlood Institute)1.168 (0.961–1.418) 0.12 1.365 (1.060–1.759) 0.016 0.914 (0.675–1.237) 0.56Metabolic syndrome definitionNational Cholesterol Education Program/ Adult Treatment Panel III1.088 (0.902–1.312) 0.38 1.337 (1.036–1.727) 0.026 0.871 (0.663–1.144) 0.87International Diabetes Federation 1.142 (0.964–1.352) 0.13 1.223 (0.968–1.546) 0.09 0.871 (0.663–1.144) 0.32European Group for the Study of InsulinResistance1.016 (0.828–1.248) 0.88 1.135 (0.852–1.511) 0.39 0.909 (0.678–1.217) 0.91American Heart Association/National Heart,Lung, and Blood Institute1.137 (0.966–1.337) 0.12 1.061 (0.772–1.457) 0.36 0.936 (0.738–1.188) 0.59Malmö Preventive Project baselineObesity 1.063 (0.894–1.263) 0.49 1.214 (0.958–1.538) 0.11 0.914 (0.709–1.179) 0.49Diabetes 1.185 (0.954–1.472) 0.13 1.334 (0.940–1.894) 0.11 1.094 (0.830–1.444) 0.52Increased blood pressure (American HeartAssociation/National Heart, Lung, andBlood Institute)1.033 (0.950–1.123) 0.45 1.033 (0.898–1.188) 0.65 1.030 (0.927–1.144) 0.58Metabolic syndrome defined in present study 1.243 (1.039–1.487) 0.017 1.451 (1.051–2.002) 0.024 1.158 (0.933–1.437) 0.18Malmö Preventive Project reinvestigationObesity 1.016 (0.921–1.119) 0.76 1.227 (1.051–1.432) 0.01 0.900 (0.793–1.021) 0.10Diabetes 1.089 (0.969–1.224) 0.15 1.236 (0.990–1.544) 0.061 1.038 (0.905–1.192) 0.77Increased blood pressure (American HeartAssociation/National Heart, Lung, andBlood Institute)0.969 (0.866–1.083) 0.97 0.972 (0.817–1.157) 0.75 1.026 (0.913–1.153) 0.67Metabolic syndrome definitionNational Cholesterol Education Program/ Adult Treatment Panel III1.070 (0.980–1.169) 0.13 1.1921 (1.03–1.380) 0.018 1.009 (0.904–1.126) 0.87International Diabetes Federation 1.011 (0.932–1.097) 0.78 1.090 (0.950–1.249) 0.22 0.971 (0.878–1.074) 0.57American Heart Association/National Heart,Lung, and Blood Institute1.005 (0.927–1.091) 0.89 1.089 (0.950–1.248) 0.22 0.967 (0.874–1.070) 0.51Adjusted for age and gender.1435 Preventive Cardiology/CDH13 Polymorphism and Metabolic Syndrome  adjusted for medication use, none of the individual MetScomponents resulted in statistical differences among CDH13  rs11646213 genotypes regardless of geneticmodel (Table 2 and complementary Table C1, availableonline). However, when stratifying the population by gen-der, MetS score showed significant increases in  CDH13 rs11646213 AA homozygotic women but not men com-pared to carriers of the G-allele, a result driven especially bya tendency toward higher triglycerides and systolic BP andlower HDL cholesterol, even if none of those attained for-mal statistical significance (Table 2). In the MPP at rein- vestigation  CDH13  rs11646213 AA homozygotes hadhigher MetS scores compared to carriers of the G-allele onlyin women. Similarly to the MDC-CVA, HDL cholesterolshowed a nonsignificant tendency toward a lower level inAA homozygotes compared to G-carriers.Analysis of the dichotomous trait MetS as defined by theNational Cholesterol Education Program/Adult TreatmentPanel III, International Diabetes Federation, EuropeanGroup for the Study of Insulin Resistance, American HeartAssociation/National Heart, Lung, and Blood Institute, andthe present study in the entire population showed no differ-ence between carriers of different  CDH13  rs11646213 T  A genotypes in the MDC-CVA and MPP regardless of thegenetic model employed (Table 3 and complementary TableC2, available online). However, the gender-specific analysisshowed a significant increase in the prevalence of the syn-drome (Adult Treatment Panel III definition and definitionin present study) in AA homozygotic women but not mencompared to G-carriers in the MDC-CVA and the MPP atbaseline and reinvestigation (Table 3) with the autosomal recessive genetic model.We also analyzed obesity and hypertension as in previousGenome Wide Association Studies and found that hyperten-sion in the MDC-CVA and obesity in the MPP at reinvestiga-tion were significantly associated with the  CDH13  rs11646213polymorphism (Table 3). Because the effect of the polymorphism was particularlyevident in women, we added some exploratory analyses (seesupplementary material). From these analyses, no clear as-sociation between menopause and/or hormone-replacementtherapy resulted between the polymorphism and MetS withthe exception of a weak but significant association when thepopulation was stratified according to menopause in theMDC-CVA: a significant association was found in womenin menopause between the  CDH13  rs11646213 variant andMetS score (beta  SE 0.43  0.19, p  0.022) and MetSprevalence (Adult Treatment Panel III definition, odds ratio1.36, 95% confidence interval 1.06 to 1.76, p  0.02). Thesame association was not detectable in women not in meno-pause and in the MPP. Discussion The main result of this study is that the common poly-morphism rs11646213 T ¡  A in the promoter region of the CDH13  gene could be associated with MetS, at leastin women.Also, analysis of the MetS score, an artificial measure-ment that has the advantage to create a comprehensiveand weighted measurement of MetS (by summing con-tinuous values of all individual MetS components), pro-duced the same results, thus corroborating our findings.Interestingly, none of the MetS-related traits when ana-lyzed alone provided statistically different results even if HDL cholesterol, triglycerides, and marginally systolicBP showed a trend toward significance, at least in theMDC-CVA, whereas HDL cholesterol and waist circum-ference had borderline significance in the MPP at rein-vestigation. This latter finding suggests that this genecould be related in part to most components of MetS butits contribution is more important when the syndromeitself is considered. Also, when we analyzed the dichot-omized traits related to the syndrome such as obesity andhypertension, which were previously associated with the CDH13  gene, we found a significant association withhypertension in the MDC-CVA but not in the MPP andwith obesity in the MPP but not in the MDC-CVA.Adiponectin, probably the most important of the adipo-kines, is decreased in obesity-related diseases and is con-sidered a central player in MetS development by ameliorat-ing insulin sensitivity and regulating biological processessuch as apoptosis, proliferation, migration, and inflamma-tion. Cadherin-13, the protein codified by the  CDH13  gene,which is present in endothelial and smooth muscle cells, isa vascular adiponectin receptor, thus rendering it highlyplausible that it is involved in MetS development. 8 Its dif-fuse expression in endothelial cells of organs such as theliver suggests it could be implicated in cholesterol efflux/ influx or glucose metabolism. Recently, an experiment inT-cadherin–deficient mice revealed its central role in pro-tecting the heart from stress-induced damage, mediating theaction of adiponectin in that setting. 18 There are no dataabout the putative functionality of the analyzed polymor-phisms and it is unclear whether it or others in linkagedisequilibrium are responsible for the detected effect. How-ever, because it is located in the promoter region of thegene, it can be speculated it influences transcription of T-cadherin. It is worth emphasizing that different polymor-phisms (including the present polymorphism) in the samegene has so f ar been associated with hypertension, 4 adi-ponectin level, 5 and obesity–insulin and lipid–insulin latentfactors 3 in separate studies.Our analysis on continuous traits deserves some consid-erations. Because antihypertensive, antilipemic, and antidi-abetic medications decrease BP, triglyceride, and glucoselevels, respectively, we decided to add 1 SD of each trait tothe standardized residuals after adjustment for age and gen-der. Thus, averages of nearly 19/9 mm Hg of systolic/ diastolic BP, 0.74 mmol/L of triglycerides, and 1.4 mmol/Lof glucose were added to subjects under long-term treatmentin the MDC-CVA and averages of nearly 20/11 mm Hg of systolic/diastolic BP, 0.8 mmol/L of triglycerides, and 1.4mmol/L of glucose were added to subjects under long-termtreatment in the MPP at reinvestigation. With this approachwe may have under- or overestimated the real effect of thedrugs but the bias from excluding these informative subjectsor maintaining their measured levels would have beengreater. 19 The effect of the polymorphism was evident only inwomen, supporting the idea that this gene could be influ-enced by sex hormones as pointed out during in vitro ex- 1436  The American Journal of Cardiology (www.ajconline.org)
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