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Risk stratification of patients with familial hypercholesterolemia in a multi-ethnic cohort Allard, Matthew D; Saeedi, Ramesh; Yousefi, Masoud; Frohlich, Jiri Apr 8, 2014

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RESEARCH Open AccessRisk stratification of patients with familialhypercholesterolemia in a multi-ethnic cohortMatthew D Allard1, Ramesh Saeedi1, Masoud Yousefi3 and Jiri Frohlich1,2*AbstractBackground: Heterozygous Familial hypercholesterolemia (FH) is a common autosomal dominant disorder resulting inin very high blood cholesterol levels and premature cardiovascular disease (CVD). However, there is a wide variation inthe occurrence of CVD in these patients. The aim of this study is to determine risk factors that are responsible for thevariability of CVD events in FH patients.Methods: This is a retrospective analysis of a large multiethnic cohort of patients with definite FH attending theHealthy Heart Prevention Clinic in Vancouver, Canada. Cox proportional hazard regression analysis was used toassess the association of the risk factors to the hard cardiovascular outcomes.Results: 409 patients were identified as having “definite” FH, according to the Dutch Lipid Clinic Network Criteria(DLCNC), with 111 (27%) having evidence of CVD. Male sex, family history of premature CVD, diabetes mellitus, lowhigh density lipoprotein cholesterol (HDL-C) and high lipoprotein (a) (Lp (a)) were significant, independent riskfactors for CVD. In men, family history, diabetes and low levels of HDL-C were significant risk factors while inwomen smoking, diabetes mellitus and high Lp (a) were significant risk factors for CVD. There were no significantdifferences in risk factors between ethnicities.Conclusion: In conclusion, men and women differ in the impact of the risk factors on the presence of CVD withfamily history of CVD and low HDL-C being a significant factor in men while smoking and increased Lp (a) weresignificant factors in women. Diabetes was a significant factor in both men and women.Keywords: Familial hypercholesterolemia, Cardiovascular disease (CVD), Risk factors, Gender differences and ethnicityBackgroundHeterozygous familial hypercholesterolemia (FH) is anautosomal dominant disease with a prevalence of 1:500in the general population. Major causes of FH are loss-of-function mutations in the low-density lipoprotein(LDL) receptor (LDL-R) or apolipoprotein B-100 (apo B)gene, or gain-of-function mutations in proprotein conver-tase subtilisin/kexin type 9 (PCSK9), resulting in very highblood cholesterol levels and premature CVD [1,2]. If leftuntreated, it is estimated that about 50% of men and 12%of women will suffer a coronary episode before the ageof 50 [1,2]. FH has been shown to decrease one’s lifeexpectancy by approximately 20-30 years [1,2]. Thevariation in phenotypic expression, and specifically theoccurrence of CVD in FH is affected by contributionsof additional metabolic, environmental and genetic riskfactors, acting in conjunction with severe hypercholes-terolemia. Treatment of FH with lipid lowering therapyhas proven to be both highly effective and cost efficient[3,4]. Despite the proven benefits of early diagnosis andtreatment of FH, only a minority of patients are diagnosedand treated adequately and the majority remains untreatedor improperly treated at the present time. Both lay peopleand health professionals currently lack full awareness ofFH, its diagnostic features, and its consequences. Moreover,standard assessment tools (eg. Framingham) do not ac-curately quantify risk in these patients. Thus, a bettermeans of identifying and characterizing risk in thesepatients is required. The aim of this study was to investigatethe effects of risk factors that may contribute to CVD inFH patients.* Correspondence: jifr@mail.ubc.ca1Healthy Heart Program Prevention Clinic, St Paul’s Hospital, Vancouver,University of British Columbia, Vancouver, Canada2Pathology and Laboratory Medicine, University of British Columbia, St. Paul’sHospital, Rm 180 - 1081 Burrard Street, Vancouver, BC V6Z 1Y6, CanadaFull list of author information is available at the end of the article© 2014 Allard et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (, which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver ( applies to the data made available in this article,unless otherwise stated.Allard et al. Lipids in Health and Disease 2014, 13:65 of study populationFour hundred and nine patients were identified ashaving “definite” FH as determined by the DLCNC(Table 1). There were more women (229) than men(180). 111 (27%) patients had hard evidence of CVDwith more men affected (58.6%). The mean age of onset ofCVD was 49.5 (±12.4) in men and 56.9 (±16.0) in women.Coronary artery disease (n = 92, 82.8%), cerebrovascu-lar disease (n = 9, 7.8%), peripheral ischemic disease(n = 4, 3.4%) or aortic valve disease (n = 6, 6.0%) werethe underlying pathologies. According to data obtainedfrom BC Vital Statistics, 24 patients (12 men, 12 women)died. 13 of these patients (52.0%) died of a cardiovascularevent.Demographics and clinical characteristics of the patientswith and without CVD are shown in Tables 2 and 3.Patients with CVD were older, men and smokers, witha higher prevalence of hypertension, diabetes mellitusand family history of premature CVD. HDL-C levels weresignificantly lower in patients with CVD. Paradoxically,the LDL-C levels were significantly higher in the non-CVDgroup. We speculate that this may have resulted from sev-eral factors including referral bias, lifestyle changes, higherLp (a) levels or different size of LDL particles in the twogroups. Also, patients with CVD tended to have higher Lp(a) (349 mg L-1 (IQR: 122.0,841.2) vs. 262.6 mg L-1( IQR:104.4,605.1)). Demographics and clinical characteristics ofthe patients with and without CVD (only those untreated)are shown in Tables 4 and 5. The same significant differ-ences remain except for family history of premature CVD.Females tended to have higher Lp (a) (298 mg L-1 (IQR:129.0, 709.8) vs. 264 mg L-1(IQR: 88.8, 594.8)) than men.Men with CVD were younger (64 ± 13 vs. 71 ± 13) andhad their first CVD event 7 years earlier than women withCVD (50 vs. 57). Men with CVD had significantly lowerHDL-C levels (1.1 mmol/L (0.3) vs. 1.4 mmol/L (0.4)) andsignificantly higher TC/HDL ratio (7.8 ± 4.0 vs. 6.2 ± 2.4),while, women with CVD had significantly higher medianLp (a) levels (512 mg L-1 (IQR: 163, 925) vs. 289 mg L-1(IQR: 87, 604)) than men.The median (interquartile range) was 288.2 (IQR:109.679.9) mg L-1, and there was no significant differenceTable 1 Dutch lipid clinic network criteriaScoreFamily historyFirst degree relative with known prematurecoronary and vascular disease (Men <55 yrs,Females <60 yrs),1ORFirst degree relative with LDL cholesterol abovethe 95th percentile for age and sexFirst degree relative with tendionous xanthomataand/or arcus cornealis,2ORChildren <18 yrs with LDL cholesterol above the95th percentile for age and sexClinical historyPatient with premature coronary artery disease(ages as above)2Patient with premature cerebral or peripheralvascular disease (ages as above)1Physical examinationTendinous xanthomata 6Arcus cornealis prior to age 45 yrs 4LDL cholesterol (mmol/L)LDL-C≥ 8.5 8LDL-C 6.5-8.4 5LDL-C 5.0-6.4 3LDL-C 4.0-4.9 1DNA analysis- functional mutation in the LDLR,APOB, or PCSK9 gene8Stratification Total scoreDefinite FH ≥8Probable FH 6-7Possible FH 3-5Unlikely FH <3Modified from Civeira [3] with permission from Elsevier.Table 2 Characteristics of the entire cohort stratified bypresence or absence of cardiovascular diseaseRisk factorWith CVD Without CVD P-valueN = 111 N = 298Age (years)66.6(±13.5) 58.6(±15.2) <0.001Mean (SD)Age at 1st CVDendpoint (yrs) 52.6(±14.6) NA NAMean (SD)Sex (M/F,%) 60.4/39.6 38.6/61.4 <0.001BMI (kg/m2) 26.2(±4.5) 26.1(±4.9) 0.456Mean (SD)Diabetes (%) 13.5 3.7 0.001Family history (%) 0.019No family history ofpre-mature CVD39.5 49.8Family history of CVD;pre-mature60.5 50.2Smoking (%) <0.001Never smoked 39.6 63.4Ever smoked 60.4 36.6Hypertension (%) 34.2 18.5 0.001Deaths (%) 15.3 2.3 <0.001Allard et al. Lipids in Health and Disease 2014, 13:65 Page 2 of 7 the median Lp (a) concentration between men andwomen (P = 0.36, Mann–Whitney test). There were 205patients whose Lp (a) concentration was categorized aslow (<600 mg L-1) and 79 as high (>600 mg L-1). Of these,55 patients (26.8%) in the low group had a first CVD eventin the follow-up period compared with 29 (36.7%) in thehigh group. The mean age at the first CVD event was53.9 years (range, 23–84 years) in the cohort as a whole:54.8 years in the low Lp (a) group (range, 23– 84 years)and 52.3 years (range, 32–73 years) in the high Lp (a)group (P = 0.59).Relation between CVD and risk factorsTable 6 shows the relative risks and 95% confidence in-tervals for the risk factors in univariate and multivariateanalyses for the entire cohort. In both univariate andmultivariate Cox hazard analysis, male sex, prematurefamily history of CVD, diabetes mellitus and high Lp (a)all significantly increased CVD risk, while higher levelsof HDL-C at first visit decreased risk for CVD. Smokingonly significantly increased CVD risk in univariate analysis.In a paradoxical finding LDL-C at first visit appearedto decrease risk for CVD. We speculate that this haveresulted from several factors including, referral bias,lifestyle changes, higher Lp (a) levels or different size ofLDL particles in the two groups.Table 7 shows the relative risks and 95% confidenceintervals for the risk factors in univariate and multivariateanalyses for the entire cohort without anyone on treat-ment at baseline. The same significant results are seen asin the entire cohort except for family history of prematureTable 4 Characteristics of the entire cohort stratified bypresence or absence of cardiovascular disease (onlyuntreated patients)Risk factorWith CVD Without CVD P-valueN = 74 N = 221Age (years)67.7 (±13.3) 58.0 (±15.8) <0.001Mean (SD)Age at 1st CVDendpoint (yrs) 53.6 (±14.5) NA NAMean (SD)Sex (M/F,%) 58.1/41.9 37.6/62.4 <0.001BMI (kg/m2) 26.2 (±4.6) 25.6 (±4.8) 0.355Mean (SD)Diabetes (%) 13.5 3.6 0.001Family history (%) 0.420No family history ofpre-mature CVD45.9 51.6Family history of CVD;pre-mature54.1 47.5Smoking (%) <0.001Never smoked 41.9 65.2Ever smoked 58.1 34.8Hypertension (%) 32.4 16.3 0.001Deaths (%) 16.2 2.7 <0.001Table 5 Laboratory results of the entire cohort at apatient’s first clinic visit (only untreated patients)Risk factorWith CVD Without CVD P-valueN = 74 N = 221Total cholesterol (mmol/L)8.2(1.8) 9.1(2.1) <0.001Mean (SD)HDL cholesterol (mmol/L)1.2(0.3) 1.4(0.4) 0.001Mean (SD)LDL-cholesterol (mmol/L)6.1(1.8) 7.0(1.9) <0.001Mean (SD)Triglycerides (mmol/L)1.7(0.9) 1.7(1.2) 0.968Mean (SD)TC/HDL 7.5(3.5) 7.3(2.8) 0.684Mean (SD)Lp (a) (mg/L)* 331.5 278.8 0.480Median (IQR) (111.2,691.6) (102.6,569.7)Fasting blood sugar (mmol/L)5.4(0.6) 5.1(0.5) 0.001Mean (SD)Lipid lowering therapy (%) 0.0 0.0 NATable 3 Laboratory results of the entire cohort at apatient’s first clinic visitRisk factorWith CVD Without CVD P-valueN = 111 N = 298Total cholesterol (mmol/L)7.8(2.1) 8.7(2.0) <0.001Mean (SD)HDL cholesterol (mmol/L)1.2(0.4) 1.3(0.4) 0.001Mean (SD)LDL-cholesterol (mmol/L)5.7(2.0) 6.6(1.9) <0.001Mean (SD)Triglycerides (mmol/L)1.6(0.9) 1.7(1.2) 0.509Mean (SD)TC/HDL 7.1(3.5) 7.0(2.7) 0.724Mean (SD)Lp (a) (mg/L)* 349.0 262.6 0.166Median (IQR) (122.0,841.2) (104.4,605.1)Fasting blood sugar (mmol/L)5.4(0.6) 5.1(0.5) 0.001Mean (SD)Lipid lowering therapy (%) 33.3 25.8 0.139*:Lp (a) analysis carried out on the 84 FH patients with CVD and Lp (a) dataavailable and the 200 FH patients with no CVD and Lp (a) data available.Allard et al. Lipids in Health and Disease 2014, 13:65 Page 3 of 7 and high Lp (a) which were not significant in eitherunivariate or multivariate analysis.Table 8 provides the relative risks and 95% confidenceintervals of the risk factors in univariate and multivariateanalyses stratified by sex. In men, in univariate Cox hazardregression analysis, diabetes mellitus, and premature familyhistory of CVD significantly increased CVD risk, whileHDL-C at first visit decreased risk for CVD. In multivari-ate Cox hazard regression analysis family history and dia-betes mellitus were significant risk factors for CVD, whileHDL-C at first visit decreased risk for CVD. In women,in univariate Cox hazard regression analysis, diabetesmellitus, high Lp (a) and smoking, significantly increasedCVD risk. In multivariate Cox hazard regression analysis,diabetes mellitus, high Lp (a), and smoking were signifi-cant risk factors for CVD.DiscussionWe assessed the contribution of risk factors to the de-velopment of CVD in a large, multi-ethnic cohort of FHpatients to identify those most susceptible to the devel-opment of CVD. Our study confirms earlier identifiedassociations by a number of other similar FH cohortstudies (9-17). Risk factors found to be significant, indecreasing order of importance, were male sex, diabetes,high Lp (a), family history of pre-mature CVD, and lowHDL-C. Of note is that hypertension, a well-known riskfactor in the general population, was not an independentrisk factor in our study.Although a number of the risk factors explored usingthe Cox multivariate survival analysis were significantwithin the entire cohort, of particular interest were the fewrisk factors that were sex specific. For instance, familyhistory of pre-mature CVD was a significant risk factorof CVD only in men with a relative risk of 2.1 (95% CI,1.3-3.6). Despite family history of premature CVD being anestablished independent risk factor for CVD and athero-sclerosis in the general population, no similar FH cohortstudies have explored it as a risk factor. We found it to be asignificant and independent risk factor for CVD in ourentire cohort but interestingly it was significant only inmen. It is likely a combination of the family’s lifestyle(diet, smoking, physical activity) and the inherited geneticpredisposition that contribute to the increased risk in thosewith a family history of premature CVD. A study by deJong et al. [5] found that endothelial function, a predictorof future cardiovascular events, was impaired in childrenwith FH having family history of premature cardiovas-cular events. Additionally, HDL-C, with a relative riskof 0.3 (95% CI, 0.1-0.8) was of significance only in men.Table 6 Relative risks (RR) and 95% confidence intervals (95% CI) for the presence of a risk factor for cardiovasculardisease in the entire cohortUnivariate Multivariate (n = 409)RR 95% CI P value RR 95% CI P valueDiabetes (present vs. absent) 3.2 1.9-5.6 <0.001 3.6 2.0-6.5 <0.001Male sex 2.9 2.0-4.3 <0.001 2.4 1.6-3.7 <0.001Lp (a) (high vs. low)* 1.6 1.0-2.6 0.033 1.8 1.1-2.9 0.014HDL-C (mmol L-1) 0.2 0.1-0.4 <0.001 0.4 0.2-0.7 0.004Family history pre-mature CVD 1.5 1.1-2.3 0.026 1.8 1.2-2.7 0.005LDL-C (mmol L-1) 0.8 0.6-0.9 0.002 0.8 0.7-0.9 0.001Smoking (ever vs. never) 2.1 1.4-3.0 <0.001 - - -*:Lp (a) analysis carried out on the 276 FH patients with Lp (a) data available.Table 7 Relative risks (RR) and 95% confidence intervals (95% CI) for the presence of a risk factor for cardiovasculardisease in the entire cohort (only untreated patients)Univariate Multivariate (n = 295)RR 95% CI P value RR 95% CI P valueDiabetes (present vs. absent) 3.8 2.0-7.1 <0.001 3.8 2.0-7.5 <0.001Male sex 2.7 1.7-4.3 <0.001 1.9 1.1-3.2 0.018Lp (a) (high vs. low)* - - - - - -HDL-C (mmol L-1) 0.2 0.1-0.4 <0.001 0.3 0.1-0.7 0.008Family history pre-mature CVD - - - - - -LDL-C (mmol L-1) 0.8 0.7-0.9 0.001 0.8 0.6-0.9 0.002Smoking (ever vs. never) 1.8 1.1-2.9 0.014 - - -*:Lp (a) analysis carried out on the 199 untreated FH patients with Lp (a) data available.Allard et al. Lipids in Health and Disease 2014, 13:65 Page 4 of 7 contrast, smoking, with a relative risk of 2.5 (95%CI, 1.4-4.7) and Lp (a), with a relative risk of 2.8 (95%CI, 1.4-5.3), were of significance only in women. Theseresults suggest that there are certain risk factors moredetrimental to one sex and identifying their presence canidentify an FH patient more susceptible to developingCVD.In accordance with Holmes et al. [6] the median Lp (a)levels in this FH cohort were significantly higher than inpatients without FH. Interestingly, in our study medianLp (a) levels between men and women with FH whencomparing Lp (a) values within our total FH study cohortwere similar. However, when comparing Lp (a) levels be-tween women with CVD to men with CVD, the women’sLp (a) level was significantly higher. This is consistent withour previous findings [7]. In accordance with this finding,Lp (a) level was found to be a significant risk factor inwomen but not in men. A study by Nenseter et al. [8] ofLp (a) in CVD resistant vs. CVD susceptible FH patientssimilarly found that Lp (a) levels were more importantin women. They found that CVD-susceptible womenhad significantly higher levels of Lp (a) compared toCVD-resistant women, and CVD-resistant women hadsignificantly lower Lp (a) levels compared to CVD-resistant men [8]. The findings of our study and thoseby Nenseter et al., suggest that Lp (a) is a more importantrisk factor in women.Despite the introduction of statins, 50% of mortality inthis cohort was due to CVD- almost twice as much asexpected in the general population.In contrast to other FH cohort studies [9-17], we studiedan ethnically heterogeneous population of FH patients.Thus, these results are more applicable to the type ofFH patients seen in lipid clinics across North America.We used only CVD endpoints that were unambiguoussuch as myocardial infarction (MI), coronary artery bypassgraft surgery (CABG), percutaneous coronary transluminalangioplasty (PCTA)/ stent, stroke, carotid endartarectomy,femoral-popliteal bypass, cardiac death, aortic valve re-placement and positive coronary angiogram with greaterthan 50% occlusion. This allowed for avoidance of anyendpoints that might be open to interpretation such asangina, transient ischemic attack (TIA), nuclear medicinetests, and exercise stress tests. Although this certainlylimited the number of subjects defined as having CVD,it makes the results more meaningful.The present study has a number of limitations mainlydue to its retrospective nature. We relied on the accuracyof the physician’s written record. Other FH studies recordedlipid levels in patients who were not using lipid loweringtherapy for a period of time whereas, due to the retro-spective nature of data collection, we recorded lipid valuesat a patient’s first visit. The patients in the CVD groupwere being more aggressively treated, thus, confoundingthe lipid values we recorded. Due to this, the non-CVDgroup had a less optimal lipid panel than the CVD group.There was also a recruitment bias present in this study asa result of the manner we chose to diagnose patients withFH. Genetic information/diagnosis was unavailable onmost patients and as a result we used clinical criteria toTable 8 Relative risks (RR) and 95% confidence intervals (95% CI) for the presence of a risk factor for cardiovasculardisease in men and womenUnivariate Multivariate (n, men = 180, n, women = 229)RR 95% CI P value RR 95% CI P valueDiabetes (present vs. absent)Men 2.7 1.1-6.3 0.024 3.1 1.2-8.0 0.018Women 5.4 2.5-11.6 <0.001 4.3 2.0-9.4 <0.001Family history pre-mature CVDMen 2.0 1.2-3.2 0.009 2.1 1.3-3.6 0.004Women 1.4 0.8-2.6 0.235 - - -HDL-C (mmol L-1)Men 0.3 0.1-0.8 0.014 0.3 0.1-0.8 0.022Women 0.5 0.2-1.1 0.066 - - -Smoking (ever vs. never)Men 1.2 0.7-2.0 0.441 - - -Women 2.9 1.6-5.3 0.001 2.5 1.4-4.7 0.003Lp (a) (high vs. low)*Men 1.1 0.5-2.2 0.814 - - -Women 2.8 1.4-5.3 0.002 2.8 1.4-5.3 0.003*:Lp (a) analysis carried out on the 123 male FH patients with Lp (a) data available and 161 female FH patients with Lp (a) data.Allard et al. Lipids in Health and Disease 2014, 13:65 Page 5 of 7 FH. We limited our cohort those diagnosed as“Definite FH” based upon the DLCNC. Also there mayhave been a selection bias as the cohort of patientsconsisted of those referred to the lipid clinic.ConclusionIn conclusion, in our ethnically diverse cohort of FHpatients the significant risk factors for CVD in decreasingorder of importance were, male sex, diabetes, high Lp (a),family history of pre-mature CVD, and low HDL-C. Menand women differed in the impact of the individual riskfactors on the development of CVD.MethodsPatients and study designThis is a retrospective cohort study using data from theHealthy Heart Prevention Clinic at St. Paul’s Hospital.Patients included in the study were anyone who visitedthe clinic since 1970 and were 18 years or older and diag-nosed as “Definite” FH based upon the DLCNC (Table 1).Each patient included in the study signed “consent forresearch form” in his or her chart in accordance withhospital and/or government regulations. Patients excludedfrom the study were those aged less than 18 yrs, thosewith a diagnosis of homozygous FH, those with secondarycauses of dyslipidemia, including hypothyroidism, liverdisease, renal disease, HIV-induced dyslipidemia, anddrug-induced dyslipidemia. Other patients excluded fromthe study were those who were seen at the clinic onlyonce. The patients were followed at the lipid clinic for aminimum of 6 months and a maximum of 28 years. A de-tailed phenotypic characterization was completed using adesigned template. The study protocol was approved bythe UBC Committee of Medical Ethics.The demographic and clinical characteristics includingage, sex, family history of pre-mature CVD, body massindex (BMI), smoking, diabetes, and hypertension wererecorded. Family history of pre-mature CVD was definedas the presence of a hard cardiovascular endpoint in amale 1st degree relative younger than 55 or a female 1stdegree relative younger than 60. Smoking history wasdefined dichotomously as “ever smoked” or “never smoked”.Hypertension was defined as a blood pressure readinggreater than 140/90 mmHg that was confirmed at a followup appointment or patient’s treatment history. Diabetesmellitus was defined as fasting blood glucose readingsgreater than 7.0 mmol/L on 2 separate occasions and/orhemoglobulin A1C greater or equal than 6.5% or patient’streatment history.The baseline fasting lipid profile was recorded TC,HDL-C, TG and calculated LDL-C using the Freidewaldformula. Lp (a) levels were also recorded. Prior to 2005Lp (a) levels were measured using an immunometric im-munoassay ((reference range (RR) < 400 U/L). After 2005Lp (a) levels were measured using the commercially avail-able direct-binding double mAb-based method (MercodiaLp (a) ELISA) (RR < 300 mg/L). The results are expressedin mg/dl, where 1 U of apo (a) is approximately equal to0.7 mg of Lp (a) (Mercodia Mannual). Due to the retro-spective nature of the study approximately 28% of subjectsdid not have an untreated lipid profile. The individuals inthe CVD group have been more aggressively treated andas a result their TC and LDL-C are significantly lowerthan those in the non-CVD group. To account for this thesame analyses were performed on the cohort on no lipidlowering medication at baseline.CVD endpointsCardiovascular endpoints were MI, CABG, PCTA stent,stroke, angiogram with >50% occlusion, carotid endarter-ectomy, femoral popliteal bypass, aortic valve replacementand cardiac death. Both the type and year of the first CVDendpoint were recorded.Statistical analysesAll statistical analyses were performed using the SPSSpackage (Version 21.0). For normally distributed continu-ous characteristics data were presented as means andstandard deviations. The continuous clinical characteristicswith skewed distributions were presented as medians andinterquartile ranges. Categorical variables were presented asnumbers with corresponding percentages. Differences inclinical characteristics between patients with and withoutCVD were tested with chi-square statistics for categoricalvariables, the non-parametric test Mann Whitney U Testfor Lp (a) and triglycerides, and t-tests for the normallydistributed continuous characteristics.Cox proportional hazard regression analysis was usedto assess the association of risk factors to hard cardiovas-cular outcomes in univariate and multivariate analyses.Follow-up started from the date of birth and ended at thedate of first CVD event. Patients without CVD werecensored at the date of the last lipid clinic visit or at thedate of death attributable to other causes.The following variables were entered into the analyses:sex, BMI, smoking history, family history of pre-matureCVD, diabetes, hypertension, LDL-C at first visit, HDL-C atfirst visit, TG at first visit, and Lp (a) (very high: >600 mg/Lor low: <75th percentile, <600 mg/L).AbbreviationsFH: Familial hypercholesterolemia; CVD: Cardiovascular disease; DLCNC: Dutchlipid clinic network criteria; HDL-C: High density lipoprotein cholesterol; Lp(a): Lipoprotein (a); LDL: Low density lipoprotein; LDL-R: Low density lipoproteinreceptor; Apo-B: Apolipoprotein B100; PCSK9: Proprotein convertase subtilin/kexin 9; TG: Triglycerides; MI: Myocardial infarction; CABG: Coronary artery bypassgraft; PCTA: Percutaneous transluminal angioplasty; TIA: Transient ischemic attack;BMI: Body mass index.Competing interestsThe authors declared that they have no competing interest.Allard et al. Lipids in Health and Disease 2014, 13:65 Page 6 of 7’ contributionsMA reviewed patient’s medical charts to collect the data, helped carry outstatistical analysis and drafted the manuscript. RS participated in the designand coordination of the study and helped to draft the manuscript. MYcarried out statistical analysis. JF conceived of the study, and participated inits design and coordination and helped to draft the manuscript. All authorsread and approved the final manuscript.AcknowledgementWe are grateful to Dr. Dan Holmes for his intellectual support.FundingThis research was funded by Genzyxme Inc.Author details1Healthy Heart Program Prevention Clinic, St Paul’s Hospital, Vancouver,University of British Columbia, Vancouver, Canada. 2Pathology andLaboratory Medicine, University of British Columbia, St. Paul’s Hospital, Rm180 - 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada. 3Department ofMedicine, University of British Columbia, Vancouver, Canada.Received: 5 February 2014 Accepted: 25 March 2014Published: 8 April 2014References1. DeMott K, Nherera L, Shaw E: Clinical guidelines and evidence review forfamilial hypercholesterolaemia: the identification and management of adultsand children with familial hypercholesterolaemia. London: NationalCollaborating Centre for Primary Care and Royal College of GeneralPractitioners; 2008.2. 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Heart 2004, 90:1431–1437.doi:10.1186/1476-511X-13-65Cite this article as: Allard et al.: Risk stratification of patients withfamilial hypercholesterolemia in a multi-ethnic cohort. Lipids in Healthand Disease 2014 13:65.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at et al. Lipids in Health and Disease 2014, 13:65 Page 7 of 7


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