Family History of PAD Ass With Prevalance and Severity PAD

8/11/2019 Family History of PAD Ass With Prevalance and Severity PAD

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Family History of Peripheral Artery Disease

Is Associated With Prevalenceand Severity of Peripheral Artery Disease The San Diego Population Study

Christina L. Wassel, PHD,* Rohit Loomba, MD,* Joachim H. Ix, MD, MAS,*Matthew A. Allison, MD, MPH,* Julie O. Denenberg, MS,* Michael H. Criqui, MD, MPH*

La Jolla and San Diego, California

Objectives The purpose of this study was to determine the association of family history of peripheral artery disease (PAD) with

PAD prevalence and severity.

Background PAD is a signicant public health problem. Shared genetic and environmental factors may play an importantrole in the development of PAD. However, family history of PAD has not been investigated adequately.

Methods The San Diego Population Study enrolled 2,404 ethnically diverse men and women 29 to 91 years of age whoattended a baseline visit from 1994 through 1998 to assess PAD and venous disease. Ankle brachial indexmeasurement was performed at the baseline clinic examination, and family history of PAD was obtained viaquestionnaire . Family history of PAD was dened primarily as having any rst-degree relative with PAD. Preva-lent PAD was dened as ankle brachial index 0.90, and severe prevalent PAD was dened as ankle brachialindex 0.70, with both denitions also including any previous leg revascularization. Logistic regression was usedto evaluate the association of family history of PAD with prevalent PAD.

Results The mean age was 59 11 years, 66% were women, and 58% were Caucasian, with 42% representing otherracial or ethnic groups. Prevalence of PAD was 3.6%, and severe prevalent PAD was 1.9%. In fully adjusted mod-els, family history of PAD was associated with a 1.83-fold higher odds of PAD (95% condence interval: 1.03 to3.26, p 0.04), an association that was stronger for severe prevalent PAD (odds ratio: 2.42, 95% condenceinterval: 1.13 to 5.23, p 0.02).

Conclusions Family history of PAD is independently strongly associated with PAD prevalence and severity. This indicates arole for genetic factors or other shared environmental factors, or both, contributing to PAD. (J Am Coll Cardiol2011;58:138692) 2011 by the American College of Cardiology Foundation

Peripheral artery disease (PAD) is a signicant public healthissue, with approximately 8.5 million Americans currently

affected (1). PAD is associated with an increased risk of cardiovascular events and mortality (25). Morbidities re-sulting from PAD, including functional decline, intermit-tent claudication, critical leg ischemia, and amputation,severely affect quality of life (69). PAD prevalence differsby racial and ethnic group, with African Americans havingthe highest prevalence (10). Several studies have evaluatedpotential explanatory factors for this higher prevalence in African Americans and consistently have concluded that itcannot be explained entirely by differences in traditional ornovel cardiovascular disease (CVD) risk factors (1,1114). This result may indicate that genetic factors are importantin the development of PAD.

Genes, environment, and the interaction of these factorslikely play a role in the development of PAD. However, few genetic variants have been associated consistently with PAD(15). Familial aggregation also is likely an important factor

From the *Division of Preventive Medicine, Department of Family and PreventiveMedicine, University of California, San Diego, La Jolla, California; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California; Division of Epidemiology, Department of Family and PreventiveMedicine, University of California, San Diego, La Jolla, California; Division of Nephrology, Department of Medicine, University of California, San Diego, La Jolla,California; Nephrology Section, Veterans Affairs San Diego Healthcare System, SanDiego, California; and the Division of Cardiology, Department of Medicine,University of California, San Diego, La Jolla, California. This research was supportedby the National Heart, Lung, and Blood Institute, National Institutes of Health(grant 53487), and the National Institutes of Health General Clinical ResearchCenter Program (grant M01 RR0827), Bethesda, Maryland. Dr. Loomba is aconsultant for Daiichi Sankyo Inc., Gilead Inc., and Corgenix Inc. All other authorshave reported that they have no relationships relevant to the content of this paper to

disclose. Mark A. Creager, MD, served as Guest Editor for this paper.Manuscript received February 13, 2011; revised manuscript received June 14, 2011,accepted June 14, 2011.

Journal of the American College of Cardiology Vol. 58, No. 13, 2011 2011 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. doi:10.1016/j.jacc.2011.06.023

wnloaded From: http://umbrella.onlinejacc.org/ by Rosa Delima on 04/23/2014


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in determining PAD susceptibility (16); however, the asso-ciation of family history of PAD with prevalent PADlargely is unknown. To our knowledge, only 2 small studieshave previously examined this association, but only evalu-ated premature-onset PAD ( 49 years of age), and both were conducted in samples consisting almost exclusively of individuals of European descent (17,18).

Thus, we examined the association of family history of PAD with prevalent PAD in a large, ethnically diversecohort of men and women 29 to 91 years of age who wereparticipants in the San Diego Population Study. Addition-ally, we examined the association of family history of PAD with prevalent CVD and family history of CVD withprevalent PAD in this cohort.

Methods

Study participants. The San Diego Population Study en-rolled an ethnically diverse group of men and women who were current or former employees of the University of California, San Diego, and their signicant others who wereinvited to participate between 1994 and 1998 in a study of PAD and venous diseases. Briey, participants were chosenrandomly within age, sex, and ethnicity strata. Age strata were 29 to 49 years (primarily 40 to 49 years), 50 to 59 years,60 to 69 years, and 70 to 91 years (primarily 70 to 79 years). Women and ethnic minorities (African American, His-panic, Asian) were oversampled to have adequate power forhypotheses involving these groups. Additionally, a smallnumber of volunteers and their signicant others (n 193)heard about the study, asked to participate, and wereenrolled. The nal sample included persons of all levels of education and occupation and included working, unem-ployed, and retired persons. Further details of the study havebeen published elsewhere (13,19,20).

For all study procedures, participants provided signed,informed consent after a detailed introduction and descrip-tion of the study. The study received approval from theCommittee on Investigations Involving Human Subjects atthe University of California, San Diego.Family history of PAD. Family history of PAD wasobtained via interviewer-administered questionnaire prior tothe ankle brachial index (ABI) measurements. The family history questionnaire was ascertained by study personnel who were not performing the ABI measurement and who were blinded to the vascular examination results. Partici-pants were asked specically to exclude foster or adoptivefamily members and were asked about PAD history of allrst-degree relatives, including mother, father, brothers,sisters, sons, and daughters. The exact sequence of questions was as follows for parental history: Has your father ormother ever had any of the following? and then, Trouble with arterial circulation in the legs (peripheral arterialdisease) including bypass surgery in the legs and/or ampu-tation? These questions were repeated for brothers, sisters,sons, and daughters. This questionnaire has not been

validated previously for family history of PAD, which wouldinvolve contact of parents, broth-ers, sisters, sons, or daughters,and/or obtaining medical recordsof these family members withregard to PAD. All questionsregarding family history of PADcan be found in the Online Ap-pendix. Family history of CVDalso was assessed similarly viaquestionnaire and included questions regarding history of heart attack, stroke, angina, percutaneous transluminal cor-onary angioplasty, coronary artery bypass graft, and carotidendarterectomy of rst-degree relatives. ABI measurement. Systolic blood pressure was measuredin both arms with the participant in a supine position.Continuous-wave Doppler ultrasound was used to measuresystolic blood pressure twice in the posterior tibial artery; inthe rare event that there was no obtainable signal in theposterior tibial artery, thedorsalispedis was used.TheABIwascalculated as average systolic blood pressure in the posteriortibial artery (or dorsalis pedis) divided by the higher of thesystolic blood pressure in the 2 arms. For these analyses, the worst ABI was used and was dened as the minimum ABI value of the left and right leg. The higher arm systolicblood pressure was used because of previous studiesshowing a strong association between PAD and subclavian stenosis (21).Covariates. Age, sex, and race or ethnicity were deter-mined via questionnaire. Diabetes was dened as self-reportor use of antidiabetic medications or insulin. Current andpast cigarette smoking habits were ascertained via question-naire, and pack-years of smoking was calculated as theaverage number of cigarettes smoked per day over all the years cigarettes were smoked divided by 20, multiplied by the total number of years cigarettes were smoked. Smokingalso was dened as ever having smoked versus never havingsmoked. Hypertension was dened as a systolic pressure of 140 mm Hg or more or a diastolic pressure of 90 mm Hg ormore, or use of antihypertensive medications. Height (incentimeters) and weight (in kilograms) were measured, andthe body mass index was calculated as weight in kilogramsdivided by height in meters squared. A blood sample wasdrawn, and total and high-density lipoprotein (HDL)cholesterol were measured with standardized laboratory assays (Beckman Coulter analyzer, Beckman Coulter, Inc.,Carlsbad, California). Dyslipidemia was dened as a ratio of total cholesterol to HDL cholesterol of more than 5.0 or useof hyperlipidemic medications (22).Statistical analysis. Univariate associations were assessedusing the t test, chi-square test, or Wilcoxon rank sum test.Because pack-years of smoking was a skewed variable, thedifference between the PAD and non-PAD groups wasassessed using a Wilcoxon rank sum test. All other contin-uous variables (i.e., HDL cholesterol and systolic blood

Abbreviationsand Acronyms

ABI ankle brachial index

CVD cardiovascular

disease

HDL high-densitylipoprotein

PAD peripheral artery

disease

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pressure) were distributed normally, and thus differencesbetween the PAD and non-PAD groups for these variables were assessed using a t test.

To examine the multivariate association of family history of PAD with prevalent PAD, staged logistic regressionmodels were used, adding in adjustment variables forpotential confounders and mediators. Family history of PAD was dened 3 ways: 1) any family history of PAD(including any rst-degree relative); 2) parental history of PAD (either parent); and 3) number of rst-degree relatives with PAD as a continuous variable. Prevalent PAD wasdened as ABI of 0.90 or less or leg revascularization, andsevere prevalent PAD was dened as ABI of 0.70 or less orleg revascularization.

To compare associations of family history of PAD andfamily history of CVD with prevalent PAD and prevalentCVD outcomes, we dened family history of CVD or PADseparately as any parental history. Prevalent CVD wasdened as any previous myocardial infarction, stroke, per-cutaneous transluminal coronary angioplasty, or coronary artery bypass graft. Staged logistic regression models also were used for this analysis.

SAS software version 9.1.3 (SAS Institute, Cary, NorthCarolina) was used for all analyses, and p 0.05 wasconsidered statistically signicant.

Results

Participant characteristics. A total of 2,376 participantshad complete ABI and family history data and had an ABIof 1.4 or less in both legs. Overall, the mean age was 5911 years, and 66% were women, 58% were Caucasian, 14% were African American, 15% were Hispanic, and 14% wereother races or ethnicities. There were 87 cases of prevalentPAD, dened as ABI of 0.90 or less or leg revascularization,and 44 cases of severe prevalent PAD, dened as ABI of 0.70 or less or leg revascularization. PAD prevalence dif-fered signicantly by sex and ethnic group and was signif-icantly higher in men and African Americans ( Table 1).Participants with prevalent PAD had signicantly highersystolic blood pressure, total cholesterol, and pack-years of smoking and were more likely ever to have been smokers. Those with prevalent PAD also were more likely to havedyslipidemia, hypertension, diabetes, and CVD. Partici-pants with PAD were somewhat more likely to have any family history of PAD (p 0.06), but did not differsignicantly with regard to parental history of PAD orparental history of CVD or with regard to the distributionof the number of rst-degree relatives with PAD. Associations of family history of PAD with PAD prevalence and severity. In the fully adjusted analysis shown in Table 2, any family history of PAD, dened as any rst-degree relative with PAD, was signicantly associated with higher odds of PAD (odds ratio [OR]: 1.83, 95%condence interval [CI]: 1.03 to 3.26, p 0.04). Parentalhistory of PAD, dened as either mother or father with

PAD, similarly was associated with higher odds of PAD( Table 2). Both any family history of PAD and parentalhistory of PAD were associated strongly with severe prev-alent PAD, with approximately 2.4-fold higher odds of severe PAD for any family history and 2.9-fold higher oddsfor parental history of PAD ( Table 2). Dening smoking inpack-years instead of ever smoking or using HDL and totalcholesterol instead of dyslipidemia did not change theresults.

There were no statistically signicant interactions of sex(p 0.15), race or ethnicity (p 0.86), body mass index(p 0.20), pack-years of smoking (p 0.41), or eversmoking (p 0.95) with any family history of PAD forprevalent PAD. There was, however, a marginally signi-cant interaction of family history with diabetes (p 0.06)such that among those with no diabetes, any family history of PAD was associated signicantly with a 6.42-fold higherodds of prevalent PAD (95% CI: 3.35 to 12.35, p 0.001), whereas among those with diabetes, any family history of PAD was not associated signicantly with prevalent PAD(OR: 1.67, 95% CI: 0.46 to 6.03, p 0.44).

Because participants with prevalent PAD who had un-dergone a leg revascularization procedure would have beenaware of this at the time of the examination interview,

Baseline Characteristics by PADfor San Diego Population Study Cohort*Table 1

Baseline Characteristics by PADfor San Diego Population Study Cohort*

CharacteristicNo PAD

(n 2,289)PAD

(n 87) p Value

Age, yrs 59 11 69 10 0.001

Female 1,523 (67%) 45 (52%) 0.004

Ethnicity

Caucasian 1,328 (58%) 56 (64%) 0.001

Hispanic 341 (15%) 6 (7%)

African American 299 (13%) 22 (25%)

Other 321 (14%) 3 (3%)

Ever smoker 1,113 (49%) 60 (69%) 0.001

Pack-years of smoking 0 (0, 10) 15 (0, 45) 0.001

Body mass index, kg/m 2 27 5 27 6 0.46

Hypertension 1,057 (46%) 67 (77%) 0.001

Systolic BP, mm Hg 131 20 148 28 0.001

Diastolic BP, mm Hg 77 11 77 12 0.95

Dyslipidemia 702 (31%) 43 (49%) 0.001

Total cholesterol, mg/dl 210 41 226 54 0.009

HDL cholesterol, mg/dl 54 17 53 18 0.36

Diabetes 129 (6%) 26 (30%) 0.001

Cardiovascular disease 46 (2%) 15 (17%) 0.001

Parental history of CVD 1,366 (60%) 57 (66%) 0.28

Any family history PAD 335 (15%) 19 (22%) 0.06

Parental history of PAD 300 (13%) 16 (18%) 0.15

No. of rst relatives with PAD

0 1,954 (85%) 68 (78%) 0.14

1 303 (13%) 18 (21%)

2 32 (1%) 1 (1%)

Values are mean SD, n (%), or median (quartile 1, quartile 3). *Excluding those with ABI 1.4 ineither leg. Total cholesterol/HDL cholesterol 5.0. Includes mother and father only. Includesany rst degree relative, that is, mother, father, brothers, sisters, daughters, sons.

ABI anklebrachial index;BP bloodpressure;CVD cardiovasculardisease;HDL high-densitylipoprotein; PAD peripheral artery disease.

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which could have caused recall bias, we performed asensitivity analysis excluding the 10 participants with prev-alent PAD who had undergone revascularization proce-dures. Results were very similarfor example, any family history of PAD was associated with 1.91-fold higher oddsof prevalent PAD (95% CI: 1.04 to 3.52, p 0.04) and with a 2.64-fold higher odds of severe prevalent PAD (95%CI: 1.14 to 6.10, p 0.02).

Number of relatives with PAD was associated only marginally with prevalent PAD. Each increase in thenumber of relatives with PAD (i.e., 0 to 1, 1 to 2, 2 to 3) wasassociated with a 1.51-fold greater odds of prevalent PAD

(95% CI: 0.95 to 2.42, p 0.08). The number of relatives with PAD, however, was associated signicantly with severeprevalent PAD (OR: 1.91, 95% CI: 1.07 to 3.40, p 0.04)( Table 3). Associations of family history of PAD with prevalent CVD and family history of CVD with prevalent PAD.Figure 1 shows associations of parental history of PAD withprevalent CVD, of parental history of CVD with prevalentPAD, and of each with severe prevalent PAD. Associations were not statistically signicant for parental history of PADand prevalent CVD or for parental history of CVD andprevalent PAD (Fig. 1). The association of parental history

of CVD and severe prevalent PAD was signicant inunadjusted models (OR: 2.03, 95% CI: 1.02 to 4.04, p 0.04) and demographic adjusted models (OR: 2.06, 95% CI:

1.02 to 4.17, p 0.04); however, this association wasattenuated in models adjusted further for comorbidities,lifestyle factors, blood pressure, and dyslipidemia (Fig. 1).

Discussion

Using a large, ethnically diverse, well-characterized cohort, we report that having any rst-degree relative with PADand parental history of PAD are both associated signi-cantly with prevalent PAD; these familial associations arestronger for severe prevalent PAD. The number of rst-degree relatives with PAD is associated marginally with

higher odds of prevalent PAD and is associated signicantly with higher odds of severe prevalent PAD. Moreover, thisstudy demonstrated that family history of PAD is associatedmore strongly with prevalent PAD than with prevalentCVD, and similarly, that family history of CVD is associ-ated more strongly with prevalent CVD than with PAD,suggesting some specicity of the type of family history.

Results of the present study indicate that a signicantgenetic component exists for PAD. Studies have shown that ABI, a major criterion for PAD diagnosis, is moderately heritable, in the range of 0.20 to 0.50 (2325), but to date,results of candidate gene studies and genome-wide associ-

ation studies for ABI or PAD have been mixed, and/or not well replicated (15,26). Preliminary evidence suggests thatgenes in the inammatory pathways, the renin-angiotensin

Association of Family History of PAD With Prevalent PADTable 2 Association of Family History of PAD With Prevalent PAD

Any Family History* Parents Only*

OR (95% CI) p Value OR (95% CI) p Value

Prevalent PAD

Unadjusted 1.63 (0.972.75) 0.07 1.50 (0.862.61) 0.16

Demographics 1.90 (1.103.26) 0.02 1.88 (1.053.35) 0.03

Lifestyle/comorbidities 1.77 (1.003.11) 0.05 1.80 (0.993.28) 0.06

SBP, DBP, dyslipidemia 1.83 (1.033.26) 0.04 1.83 (1.003.41) 0.05

Severe prevalent PAD

Unadjusted 2.18 (1.114.28) 0.02 2.22 (1.114.43) 0.02

Demographics 2.60 (1.295.21) 0.008 2.92 (1.426.01) 0.004



*Any family history is any rst-degree relative with PAD (mother, father, brothers, sisters, sons, daughters); parents only is either mother or fatherhavingPAD.PADis ABI 0.90or legrevascularization; severe prevalentPAD is ABI 0.70or legrevascularization. Age,sex, and raceor ethnicity.Adding body mass index, ever smoker, diabetes, hypertension.

CI condence interval; DBP diastolic blood pressure; OR odds ratio; SBP systolic blood pressure; other abbreviations as in Table 1 .

Association of Number of First-Degree Relatives With PAD and Prevalent PAD*Table 3 Association of Number of First-Degree Relatives With PAD and Prevalent PAD*

Prevalent PAD Severe Prevalent PAD

OR (95% CI) p Value OR (95% CI) p Value

Unadjusted 1.37 (0.902.09) 0.15 1.70 (1.022.82) 0.04

Demographics 1.47 (0.961.12) 0.08 1.84 (1.103.06) 0.02



*Number of rst-degree relatives modeled as a continuous variable. Prevalent PAD is ABI 0.90 or leg revascularization; severe prevalent PAD isABI 0.70 or leg revascularization. Age, sex, and race or ethnicity. Adding body mass index, ever smoker, diabetes, hypertension.

Abbreviations as in Tables 1 and 2 .




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pathway, and genes important in nicotine metabolism anddependence are important determinants of PAD or ABI(2730), although it is unclear the extent to which theseassociations may be mediated through smoking status orpack-years of smoking. Previous studies also have suggestedinteractions of inammatory or nicotine dependence genes with smoking and diabetes, 2 of the major risk factors forPAD ( 27,29). In addition to the association of the 9p21locus with PAD (31), 9q33 also has been implicatedrecently, with higher odds for both abdominal aortic aneu-rysm and PAD (32).

It also is likely true that a complex interplay of geneticand environmental factors, including smoking, diabetes,obesity, diet, sex, and racial or ethnic group, lead to thedevelopment of PAD, although we did not nd any indi-cation of interaction of any family history of PAD and eversmoking, pack-years of smoking, sex, or race or ethnicity forprevalent PAD in the current study. This is likely because of the limited power to detect interactions with the relatively modest number of prevalent PAD cases within each sub-group in this study. We did nd a marginally signicantinteraction between any family history of PAD and diabetessuch that family history was associated with much higherodds of prevalent PAD among those without diabetes as

compared with those with diabetes. This may indicate thatthe set of genetic variants involved in diabetes could bedistinct from those involved in PAD; however, these resultsshould be interpreted with caution given the wide con-dence intervals.

Only 2 studies previously have examined the associationof family history of PAD with PAD or symptomatic CVD(17,18). One study found that participants with a sibling with premature PAD had 3-fold higher odds of PAD (17). A second study found that rst-degree relatives of individ-uals with premature PAD had higher odds of early onsetCVD events than relatives of healthy participants (18).However, these studies were in small, family-based samplesalmost exclusively of European descent, only studied pre-mature onset PAD (age 49 years), or concentrated onCVD events as an outcome. Results of the current study areconsistent with those of Valentine et al. (17). Our study extends the literature by showing the association of family history of PAD with both prevalent PAD and CVDconcurrently, conrming the relationship in a multiethnicand much larger community-living sample.

Our study suggests that having a parental history of CVDdoes not signicantly increase the odds of PAD, nor doeshaving a parental history of PAD signicantly increase the

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Parental History PAD andPrevalent CVD

Parental History CVD andPrevalent PAD

Parental History CVD and SeverePrevalent PAD

O d d s

R a

t i o

Model 1

Model 2

Model 3

Model 4

Figure 1 Association of Parental History of CVD With Prevalent PAD and Parental History of PAD With Prevalent CVD

Model 1 is in blue and represents unadjusted associations. Model 2 is in red and adjusts for age, sex, and ethnicity. Model 3 is in green and adjusts for model 2 plusbody mass index, diabetes, and ever smoking. Model 4 is in purple and adjusts for model 3 plus systolic and diastolic blood pressures and dyslipidemia. CVD cardio-

vascular disease; PAD peripheral artery disease.




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odds of CVD. These results are not consistent with those of Valentine et al. (18), who found that rst-degree relatives of individuals with premature PAD had higher odds of early onset CVD events than relatives of healthy participants;however, the present study was not restricted to prematurePAD cases. Our differing results could be the result of a lack of specicity of family history of CVD for PAD or vice versa. They also could be the result of the heterogeneity inherent in complex chronic diseases such as CVD andPAD or the genetic heterogeneity in these diseases. In thisregard, traditional risk factors do not entirely overlap forPAD and CVD; some traditional risk factors such assmoking and diabetes are stronger for PAD than CVD (2).Genetic risk factors also do not seem to overlap entirely orto be consistent ndings in all studies of PAD and CVD,suggesting that some genetic factors exclusive to PAD may exist. One study did nd 9p21, a well-replicated locus forcongenital heart disease and myocardial infarction (33), tobe associated signicantly with PAD and ABI after ac-counting for myocardial infarction (31). However, in an-other study, 9p21 was associated only marginally withclinical PAD (34), and after accounting for congenital heartdisease, the association was no longer marginally signicant.Study strengths and limitations. The San Diego Popula-tion Study is a population-based cohort of ethnically diversemen and women with a large age range and was designedspecically to study PAD. Careful ABI measurement wasperformed by trained vascular technicians, and ascertain-ment of other traditional risk factors was standard andcomplete. The current study also did not restrict thedenition of PAD to premature PAD only, but sought toexamine whether family history of PAD was importantfactors despite age at onset and despite severity of PAD. The study also has important limitations. Family history of PAD and CVD was obtained via an interview-administeredquestionnaire, which can result in misclassication, but thislikely would result in bias toward the null hypothesis.However, information on family history was obtained be-fore the ABI measurement to avoid recall bias. Results arefrom an actively employed and retired population, and somay not generalize fully to the overall population.

Conclusions

We found that family history of PAD was associatedsignicantly with PAD, but not with CVD. To date,signicant genetic risk factors for PAD are ORs generally inthe range of 1.1 to 1.3. Currently, familial aggregationseems to be the most strongly associated genetic risk factorfor PAD, with an OR similar in magnitude to those of smoking, hypertension, and diabetes, all of which rangefrom 2- to 4-fold greater odds for PAD (2). This ndingalso suggests that asking about family history of PADspecically (rather than CVD) may be more useful toidentify individuals at risk for PAD. Based on these nd-ings, future studies are warranted to identify genetic loci,

gene or environment interactions, or a combination thereof that may contribute to development of PAD.

Acknowledgments The authors thank the participants of the San DiegoPopulation Study for their cooperation.

Reprints requests and correspondence: Dr. Christina L. Wassel,Department of Family and Preventive Medicine, University of California, San Diego, 9500 Gilman Drive, MC 0965, San Diego,California 92093-0965. E-mail: [email protected].

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Key Words: ankle brachial index y family history y peripheral artery disease.

APPENDIX

For all questions regarding family history of PAD,please see the online version of this article.


Family History of PAD Ass With Prevalance and Severity PAD

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