Family History of Diabetes, Acculturation, and the Metabolic Syndrome among Mexican Americans: Proyecto SALSA

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Family History of Diabetes, Acculturation, and the Metabolic Syndrome among Mexican Americans: Proyecto SALSA
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  METABOLIC SYNDROME AND RELATED DISORDERSVolume 5, Number 3, 2007©Mary Ann Liebert, Inc.Pp. 262–269DOI: 10.1089/met.2006.0035 Family History of Diabetes, Acculturation, and theMetabolic Syndrome among Mexican Americans:Proyecto SALSA TAMARA NELSON, M.P.H. , 1 ANGELICA PEREZ, M.P.H. , 1  JOHN ALCARAZ, Ph.D. , 1 GREGORY TALAVERA, M.D., M.P.H., 1 and JEANETTE J MCCARTHY, Ph.D. 1 ABSTRACT Background : The purpose of this study was to examine effect modifiers of the relationshipbetween family history of diabetes, a proxy for genetic predisposition, and the metabolic syn-drome.  Methods : Subjects were a cross-sectional sample of 205 Mexican-Americans patients of theSan Ysidro Health Center in San Diego County. Self-reported parental history of diabetes wasexamined as a risk factor for individual metabolic syndrome traits (hyperglycemia, hyper-tension, abdominal obesity, hypertriglyceridemia and low HDL-cholesterol) and a compositephenotype, defined both by standard modified National Cholesterol Education Program—Adult Treatment Panel III (NCEP-ATPIII) criteria and using principal components analysis,in age and sex-adjusted multiple logistic and linear regression models. Results : Family history of diabetes was most strongly associated with individual traits ofhyperglycemia ( P  .0002) and low HDL-C ( P  .001) and conferred a significant increasedodds of metabolic syndrome defined by both NCEP-ATPIII criteria (odds ratio 3.57, 95% con-fidence interval 1.82, 7.01; P   .0002) and by principal components analysis ( P  0.003). More-over, the family history association with metabolic syndrome was modified by number ofyears living in the United States (interaction P  .04). This same effect was not seen for dia-betes ( P  .19). Conclusions : The results of our study support a common etiology for at least some compo-nents of the metabolic syndrome, especially hyperglycemia and low HDL-cholesterol, the ba-sis of which may be genetic. Moreover, the effect of genes on these traits may be modifiedby longer duration in the United States, supporting the concept of gene-environment inter-action in the development of the metabolic syndrome. INTRODUCTION T YPE 2 (N ON -I NSULIN -D EPENDENT ) D IABETES M ELLITUS (T2DM)has recently emerged asone of the most prevalent chronic diseases indeveloped countries. The pathological processpreceding T2DM is characterized by a constel-lation of metabolic abnormalities, collectivelyreferred to as the metabolic syndrome (MetS;Insulin Resistance Syndrome, Syndrome X)and includes a clustering of insulin resistance,abdominal obesity, dyslipidemia, and hyper- 1 School of Public Health, San Diego State University, San Diego, CA 262  FAMILY HISTORY AND METABOLIC SYNDROME263 tension. 1,2 An estimated 47 million U.S. resi-dents have been classified as having MetS, withthe highest burden among Mexican Americans,where the prevalence is estimated to be 32%. 3 Increases in the rates of T2DM and its riskfactors observed among Mexican Americanscompared to their native counterparts isthought to derive from adoption of a Westernlifestyle, highlighting the importance of modi-fiable risk factors in the etiology of T2DM. 4 Inaddition, nonmodifiable risk factors includingage, sex, and family history remain importantdeterminants. The heritability (a measure of ge-netic influence) of T2DM and individual MetScomponents is well-established, 5–8 while theheritability of MetS as a cluster of traits is lesswell studied.Despite decades of research yielding numer-ous linkages and hundreds of candidate loci,few genes have been convincingly shown to beassociated with T2DM or MetS. One reason forthe observed inconsistencies in genetic associ-ations across populations might be failure totake into account the modifying effects of en-vironment (nongenetic factors). With this inmind, we sought to evaluate nongenetic effectmodifiers of family history in the etiology of  both T2DM and the MetS as a means of in-forming future genetic association studies byidentifying important covariates to consider inanalysis of gene-environment interaction. METHODS Study population Subjects were drawn from Proyecto SALSA , across-sectional study of gene-environment in-teraction in the development of the MetS. Thisstudy was established in 2003 with approvalfrom the Institutional Review Board of SanDiego State University. Study participantswere recruited between April 2004 and Octo- ber 2005 from the San Ysidro Health Center inSan Diego County, a clinic serving a predomi-nantly low income Mexican American com-munity just north of the border. Any adultLatino patient who was present at the clinicduring the morning hours for the purpose of a blood draw and in a fasting state was eligibleto participate. In addition, clinic patients wererecruited through advertisement at the clinicfor heart-disease risk-factor screening. A totalof 599 patients were enrolled in the study.Three hundred ninety-four participants wereexcluded because of missing values on vari-ables required in the study, including 357 sub- jects with missing data on family history andan additional 37 subjects with missing data onone or more MetS traits. The remaining 205subjects served as the study’s population foranalysis. Data collection An interviewer-administered questionnairewas used to obtain demographics, medical his-tory, medication use, and risk factor informa-tion on subjects. Additional risk factor data, in-cluding family history, was collected during afollow-up telephone interview several weeksafter enrollment. Medical records were ab-stracted to confirm diagnosis and medicationuse for diabetes and hypertension. Anthropo-metric measures—height (inches), weight(pounds), blood pressure (mmHg), and waistand hip circumferences (centimeters)—werecollected by trained research assistants. Bloodpressure readings and waist and hip circum-ferences were measured twice, and the averageused. Lastly, participants’ fasting glucose andlipids were measured from a sample of whole blood collected at enrollment, using standardprocedures. Dependent variables T2DM status was defined by self-reporteddiabetes, and was in strong agreement withmedical record data and fasting glucose levelstaken on the day of enrollment. In addition,subjects who reported no history of diabetes, but who had documented history in their med-ical records or elevated fasting plasma glucoseon enrollment, were classified as diabetic. MetSwas defined in two ways. First, we used theNational Cholesterol Education Program’sAdult Treatment Panel III (NCEP-ATPIII) def-inition of presence of three or more of the fol-lowing abnormalities: Waist circumference  102 cm in men or  88 cm in women; triglyc-erides  150 mg/dL; HDL-C  40 mg/dL in  men or  50 mg/dL in women; fasting plasmaglucose  110 mg/dL or on antidiabetic ther-apy; and blood pressure  130/85 mmHg or onanti-hypertensive meds. 3 Second, MetS was de-fined as a continuous trait of the scores derivedfrom principal components analysis using thefirst principal component (that which ex-plained the greatest amount of variance). Traitsentered into the analysis included triglycerides(log transformed), HDL-C (log transformed),waist circumference, fasting plasma glucose(log transformed), and hypertension (yes/no).Traits loading highly on each principal com-ponent were defined to be those with correla-tion greater than 0.5 in magnitude with thatcomponent (calculations not shown). Analysisof individual MetS components was carried outon traits defined both continuously (for all buthypertension status) and categorically, usingthe cutoffs listed above. Independent variables Family history of diabetes, the main expo-sure of interest in this study, was defined as thepresence of diabetes in at least one parent, asreported by patients. Smoking status was clas-sified as past, current, and never. Educationlevel was considered low if subjects had lessthan a high school education or equivalent.Low income was defined as less than $18,000per year. Acculturation was measured in twoways: first with a language usage scale and sec-ond as the number of years that the U.S. has been the main home of study participants. Thelanguage scale was shown to have little vari-ability in this study population because mostsubjects used only Spanish; thus, this tool wasnot considered further. Years in the U.S. waskept as a continuous variable. Statistical analysis All statistical analyses were performed usingSAS version 8.1 (SAS Institute Inc., Cary, NC).To assess the association between family his-tory of diabetes and T2DM or MetS (NCEP-ATPIII definition), logistic regression analysiswas carried out in a minimally adjusted modelincluding age and sex. MetS was also analyzedas a continuous trait using linear regression ina similar fashion. To determine whether the as-sociation between diabetes family history andT2DM or MetS varied at different levels of co-variates, interaction terms for family historyand risk factors were entered into each model,along with the main effect of the risk factor.Risk factors included age, sex, smoking status,education, income, and years in the US. Inter-action terms were entered into the model si-multaneously and removed if not significant.The likelihood ratio test was used to determineif a change to the model was statistically sig-nificant. RESULTS We evaluated a total of 205 adult MexicanAmerican subjects with complete data for as-sociation between diabetes family history andthe MetS. Family history data were missing ona substantial number of subjects, but a com-parison of subjects included and excluded fromthe analysis revealed no relevant differences(all P  .05). The prevalence of individual MetStraits in the SALSA study population is shownin Figure 1 for men and women. Each trait wasvery common in both sexes, occuring in over30% of subjects. The most common traits werehigh blood pressure (61%) in men and abdom-inal obesity (68%) in women. Using the NCEP-ATPIII MetS criteria of presence of 3 or moretraits, 39% of the subjects in SALSA were clas-sified as having MetS.Table 1 shows the demographic and clinicalcharacteristics of the subjects stratified by MetSstatus. Family history of T2DM was much more NELSON ET AL.264 100   A   b  d  o  m   i  n  a   l   O   b  e  s   i   t  y   H  y  p  e  r   t  r   i  g    l  y  c  e  r   i  d  e  m   i  a   L  o  w    H   D   L  -  C   H   i  g    h    B   l  o  o  d    P  r  e  s  s  u  r  e   H   i  g    h   G   l  u  c  o  s  e MenWomen9080706050    %   o   f  s  u   b   j  e  c   t  s  w   i   t   h  e  a  c   h   t  r  a   i   t 403020100 FIG. 1. Prevalance of individual metabolic syndrometraits in men and women from proyecto SALSA.  FAMILY HISTORY AND METABOLIC SYNDROME265 common among subjects with MetS comparedto those without MetS. In addition, subjectswith MetS were significantly older and hadlived in the U.S. a greater number of years thanthose without MetS. Differences in smokingstatus, income level and education level werenot significant.Principal components analysis was used todefine MetS as a quantitative trait. As shownin Table 2, the first principal component,PRIN1, explained the most variance and loadedhighly on all five traits: fasting glucose, waistcircumference, HDL-C (negative weighting),triglycerides, and hypertension, consistentwith a MetS phenotype. PRIN1 was a normallydistributed, continuous trait with range from  4.25 to  3.25. Higher numbers of PRIN1 areassigned to subjects that load most strongly onthe five component traits and thus, have a MetSphenotype. Conversely, subjects with low (neg-ative) values of PRIN1 are characterized by nothaving the MetS phenotype. The other princi-pal components explained less of the varianceand showed clustering of traits inconsistentwith a MetS phenotype.Table 3 shows the association between fam-ily history of diabetes and individual MetScomponents, T2DM and MetS defined in twoways. As expected, family history of diabeteswas significantly associated with T2DM in ageand sex-adjusted models, conferring a greaterthan 3-fold increased odds. In addition, familyhistory was a significant, independent predic-tor of high fasting plasma glucose ( P  .0002)and low HDL-C ( P  .001) measured as cate-gorical traits, and less so with waist circumfer-ence ( P  .01) measured as a continuous trait.Family history of diabetes was also signifi-cantly associated with MetS in age and sex-ad- justed models, conferring a significant 3.57-foldincreased odds of MetS, defined by NCEP-ATPIII criteria. These results held even when T ABLE 1.D EMOGRAPHIC AND R ISK F ACTOR P ROFILE OF S UBJECTS IN P ROYECTO SALSA BY M ETABOLIC S YNDROME (NCEP-ATPIII D EFINITION ) TotalNo MetSMetSCharacteristic(N  205)(N  129)(N  76)P value Family History T2DM28%19%42%.0005Age (years)54.6  14.052.0  14.559.1  11.8.0004Income (yearly).09$18,000 or more27%32%20%Less than $18,00073%68%80%Education.09High School graduate24%28%18%  High school graduate76%72%82%Smoking Status.15Never58%62%50%Past30%26%39%Current12%12%11%No. of years in U.S.25.7  16.423.0  16.230.3  15.9.006Data are percentages of totals, except age and number of years in US, which are mean  standard deviation.T ABLE 2.R ESULTS OF P RINCIPAL C OMPONENTS A NALYSIS S HOWING E IGENVECTORS FOR THE F IVE P RINCIPAL C OMPONENTS D ERIVED FROM A NALYSIS OF M EXICAN A MERICANS IN P ROYECTO SALSA VariablePRIN1PRIN2PRIN3PRIN4PRIN5 Log glucose0.36   0.330.86   0.07   0.13Waist Circumference0.480.41   0.03   0.630.45Log triglycerides0.48   0.44   0.250.470.54Log HDL-C   0.490.290.440.260.65Hypertension0.420.660.090.55   0.27% Variance43%18%17%12%10%explained  subjects with diabetes were removed: amongnondiabetic subjects, family history of diabetesconferred a strong and significant increasedodds of MetS (age and sex-adjusted OR  2.71;95% CI: 1.10, 6.77), while among diabetic sub- jects, the association was somewhat stronger but failed to reach statistical significance(OR  3.08; 95% CI: 0.82, 11.60). In addition, weobserved a similar association between familyhistory and MetS defined as a continuous com-posite trait, PRIN1, ( P  .003).Next, we examined possible effect modifiersof the association between family history of di-abetes and T2DM, MetS (more than 3 traits) andMetS (PRIN1). Among the effect modifierstested, including age, sex, income, education,smoking status, and acculturation (measured by number of years living in the U.S.), only ac-culturation was found to be a significant mod-ifier of family history effects (Table 4). This re-lationship was significant using both theNCEP-ATPIII definition ( P  .04) and the traitderived from principal components analysis,PRIN1 ( P  .03). Specifically, as the number of years subjects have lived in the U.S. increased,the effect of family history on the metabolicsyndrome increased. Figure 2 illustrates thiseffect modification for MetS defined byNCEP-ATPIII. In contrast, the relationship be-tween family history of diabetes and T2DMwas not significantly modified by accultura-tion ( P  0.19), or any of the other risk factorsexamined. DISCUSSION The results of our study reveal that familyhistory of diabetes is a strong, independent pre-dictor of not only T2DM, but specific individ- NELSON ET AL.266 T ABLE 3.A SSOCIATION BETWEEN F AMILY H ISTORY OF D IABETES AND I NDIVIDUAL C OMPONENTS (C ATEGORICAL AND C ONTINUOUS ) AND C LUSTERING (MetS) OF M ETABOLIC S YNDROME T RAITSAMONG M EXICAN A MERICANS IN P ROYECTO SALSA ContinuousCategoricalFamily historyTraitPresentAbsentP valueOdds ratio95% CIP value HDL-C* ‡ 49.55  12.2453.65 , 5.67.001Triglycerides*160.61  80.86152.58 , 1.88.56Waist circumference* ‡ 100.65  16.0197.49 , 2.67.89Fasting glucose* ‡ 125.28  47.98114.02 , 9.01.0002Hypertension* ‡ –––0.780.36, 1.70.43MetS (PRIN1) ‡ 0.26  0.16   0.29  0.13.003–––T2DM  –––3.271.64, 6.54.0008MetS (NCEP)  –––3.571.82, 7.01.0002Family history entries are means (SD). – indicates not applicable.*NCEP cutoffs were used to define categorical HDL-C, triglycerides, waist circumference and fasting glucose † Models are adjusted for age and sex alone ‡ Adjusted for age, sex and other individual MetS traitsT ABLE 4.P-V ALUES FOR I NTERACTIONS BETWEEN F AMILY H ISTORY OF D IABETES AND S ELECTED C OVARIATES IN THE D EVELOPMENT OF D IABETES (T2DM) AND M ETABOLIC S YNDROME (MetS) AMONG M EXICAN A MERICANS IN P ROYECTO SALSA Interaction TermsT2DMMetS (NCEP)MetS (PRIN1) Family history * Age0.220.480.20Family history * Sex0.740.310.73Family history * Income0.880.800.61Family history * Education0.150.220.82Family history * Smoking0.470.670.94Family history * Acculturation0.190.030.04
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