research article the association between kif6 single...

Research ArticleThe Association between KIF6 Single Nucleotide Polymorphismrs20455 and Serum Lipids in Filipino-American Women

Irma B Ancheta1 Cynthia A Battie1 Dan Richard1 Christine V Ancheta2

Nancy Borja-Hart3 Annabelle S Volgman4 and Yvette Conley5

1 School of Nursing University of North Florida 1 UNF Drive Jacksonville FL 32224 USA2University of South Florida Tampa FL 33612 USA3 East Coast Institute for Research Jacksonville FL 32223 USA4Rush University Medical Center Chicago IL 60612 USA5University Pittsburgh Pittsburgh PA 15213 USA

Correspondence should be addressed to Irma B Ancheta ianchetaunfedu

Received 22 June 2013 Revised 21 September 2013 Accepted 21 October 2013 Published 23 January 2014

Academic Editor Adebowale A Adeyemo

Copyright copy 2014 Irma B Ancheta et alThis is an open access article distributed under theCreativeCommonsAttributionLicensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

The Trp719Arg allele of KIF6 rs20455 a putative risk factor for CHD especially in those with elevated low-density lipoproteincholesterol (LDL-C) was investigated in Filipino-American women (FAW 119899 = 235) participating in health screenings in fourcities The rs20455 genotype of each subject was determined by a multiplex assay using a Luminex-OLA procedure The riskallele Trp719Arg was present in 77 of the subjects The genotype distribution was 23 TrpTrp 51 ArgTrp and 26 ArgArgGenotype did not predict the presence of CHD risk factors Moreover LDL-C HDL-C and triglycerides mean values did notvary as a function of genotype However those with the ArgArg genotype on statin medication exhibited a significantly highermean triglycerides level (119875 lt 001) Approximately 60 of participants regardless of genotype exhibited LDL-C levels ge100mgdLbut were not taking medication Approximately 43 of those with the Trp719Arg risk allele on statins exhibited elevated LDL-Clevels Our study suggests that the Trp719Arg allele of KIF 6 rs20455 is common among Filipino-American women thus even withborderline LDL-C levels would benefit from statin treatment Secondly many participants did not exhibit guideline recommendedLDL-C levels including many who were on statin drugs

1 Introduction

Coronary heart disease is a multifactorial and complexdisease resulting from the interaction of genes and environ-mental factors [1ndash5] Genetics plays an important role indetermining the inherent CHD vulnerability and in deter-mining how a person responds to statin therapy KIF6 isa member of the kinesin family a class of motor proteinsthat are involved in the intracellular transport of membraneorganelles messenger RNArsquos and other protein complexesalong microtubules [6ndash10] Several studies focusing on Cau-casians have reported that the Trp719Arg allele of singlenucleotide polymorphism (SNP) rs20455 in the KIF6 geneis associated with CHD and that carriers who carry one ortwo copies of the risk allele respond better to statin therapy

than noncarriers [10ndash15] The prevalence among Caucasiansis about 59 and the risk ratio has been stated to be 122(95 confidence intervals 112ndash132) [15] This associationwith increased risk was present in African Americans whohave very high numbers (sim90) with the risk allele [15]Chinese and Japanese also have been reported to have a highfrequency (sim70) of the risk allele [15] Other investigatorswere unable to detect the association of the rs20455 allelewith increased CHD risk [16] even with a large sample size[17] Ference et al [18] carried out a large meta-analysis with88535 subjects in 8 randomized statin trials examining therole of KIF6 Trp719Arg allele in CHD and concluded thatthe risk allele increases the vulnerability to elevated LDL-CcholesterolThus the KIF6 genetic variant may be a predictor

Hindawi Publishing CorporationNursing Research and PracticeVolume 2014 Article ID 328954 8 pageshttpdxdoiorg1011552014328954

2 Nursing Research and Practice

of CHD in those who have elevated LDL-C Indeed carriersof the Trp719Argallele may have a greater increase in CHDrisk per unit increase in LDL and a greater reduction inCHD risk per unit decrease in LDL compared to noncarriers[18] Indeed the number needed to treat with statins toprevent a single CHD event ranged from 10 to 20 for theTrp719Arg carriers compared to gt80 for noncarriers in alarge meta-analysis [15] Furthermore the results of Ferenceet al [18] suggest that the differential vulnerability to LDL-C based upon genotype may explain the reason for the priordisagreement in studies

To the best of our knowledge despite a plethora ofevidence no studies of KIF6 Trp719Arg allele have beenconducted in the Filipino population Filipinos are the secondlargest minority population of Asians in America [19] andhave the highest prevalence of hypertension [20] type 2diabetes [21 22] and metabolic syndrome [23] comparedwith other Asian subgroups The heterogeneity of CHD riskfactors among Asians is well established [24] and the allelicfrequency distribution of rs20455 has been shown to varyacross populations [15] Scientific gaps still exist regardingthe role of genetics in the predisposition to CHD in variouspopulations Since the rs20455 variant has not been studiedin those of Filipino descent we investigated its prevalence inassociation with plasma lipid levels in a cohort of FilipinoAmerican women who attended community-based healthscreenings at various locations throughout the USA

2 Materials and Methods

21 Study Design Population and Recruitment ProcedureApproval of the University Institutional Research Board(IRB) was obtained prior to the conduct of this studyThis study is a descriptive cross-sectional study of FilipinoAmerican women (119899 = 234) who participated in a car-diovascular health screening at their places of worship orcultural centers during 2011ndash2013 Subjects were between 40and 65 years of age Health screenings were performed invarious US cities Jacksonville FL Chicago IL Tampa FLand San Francisco CA In order to recruit a wide varietyof subjects advertisements were posted in church bulletinsand at community organizations and stores frequently visitedby Filipino women These flyers specified inclusion andexclusion criteria and the need to be fasting for at least 12hours on the day of the study Participants were instructedto bring all prescription and nonprescription medications tothe study site

Participants were enrolled if they were women self-identified as Filipino by ethnicity agreed to volunteer for thestudy and were fasting for 12 hours Women who had severearthritis any autoimmune disorder and a recent cancerdiagnosis andor presented with any infection or severeinflammationwere excluded from the study important for themeasurement of inflammatory markers Informed consentwas obtained after the study purpose was carefully explainedPrior to giving consent participants were given ample timeto ask questions or state concerns regarding the study Total

time for participation in the study was approximately 45minper participant

22 Screening Protocol A demographic and clinical infor-mation questionnaire including participantsrsquomedical historyand current medications was completed for each subject bytrained research staff The clinical information questionnaireincluded family history smoking history participantrsquos med-ical history and current medications Upon completion ofthe survey blood pressure was obtained using a standardOmron digital HEM-705CP sphygmomanometer on thenondominant arm after the participant had been seated for10min Measurements were repeated three times with 5minin between each reading Subsequently weight and heightwere measured using a standard Tanita weighing scale (WB-3000) Waist circumference was measured using a tensiontape guided by the NHANES measurement protocol Lastlya licensed phlebotomist drew 5mL of blood via venipuncturefrom each participant for a series of tests including thestandard lipid panel hemoglobin A1C serum glucose acardiovascular inflammatory biomarker (high-sensitivity C-reactive protein or hs-CRP) and genetic assays The bloodwas captured in three test tubes containing EDTA Sampletubes were labeled with numbers only centrifuged andimmediately frozen At the end of each screening sessionfrozen samples were sent to a CLIA certified laboratory whereassays were performed using standard clinical protocolsThe lipid panel assay included total cholesterol triglycerideshigh-density lipoprotein (HDL) and low-density lipopro-tein (LDL-C) (Roche Modular methodology) performedat Berkeley Heartlab Inc (Alameda CA) Plasma hs-CRPconcentration was determined using an automated immuno-turbidimetric assay (Roche Modular methodology BerkeleyHeartlab Inc)

23 Cardiovascular Risk Factors The operational definitionfor CHD risk factors for the study was based on the fol-lowing guidelines For blood pressure values the AmericanHeart Association and the Joint National Committee forthe Prevention Detection Evaluation and Treatment ofHigh Blood Pressure (JNC 7) guidelines for the normalrange of blood pressure were used (ge120mmHg systolicandor diastolic blood pressure of le80mmHg) We usedthe criteria of the World Health Organization regardingcut-off for the body mass index (BMI) The NationalCholesterol Education Program (NCEP) Adult TreatmentPanel III guidelines were used to define the cholesterolnormal reference values namely total cholesterol (TC)ge200mgdL triglycerides (TGL) ge150mgdL high-densitylipoproteins cholesterol (HDL-C) le50mgdL low-densitylipoprotein cholesterol (LDL-C) ge100mgdL fasting bloodglucose (FBG) ge100mgdL (56mmolL) and waist cir-cumference ge35 inches (88 cm) The American DiabetesAssociation criteria for diabetes were used hemoglobin A1Cge65 and fasting plasma glucose ge126mgdL Metabolicsyndrome was defined using both the International Diabetesfederation and the National Cholesterol Education Program-Adult Treatment Panel III criteria

Nursing Research and Practice 3

Table 1 Demographic characteristics of the Filipino-Americanwomen subjects

Demographic characteristics Mean plusmn SD(119899 = 234) Frequency ()

Age 515 plusmn 7 mdashNo of years in the USA 240 plusmn 13 mdashAgemdasharrival in USA 310 plusmn 11 mdash

Marital statusSingle 8Married 73Divorcedwidow 19

Philippine-born 98Residency in the USAlt5 years 115ndash10 years 610ndash20 years 26Over 20 years 57

Incomelt$12000year 17$13000ndash$40000 47$41000ndash$69000 20$70000 and above 16

EducationHigh school 18Some college 214 year degree 52Graduate degree 9

OccupationHealth occupations 34

Healthcare insuranceWith insurance 87

24 Genetic Analysis Celera research reagents were usedto genotype the rs20455 SNP of each subject in a single-tube assay using a Luminex-OLA procedure as describedpreviously [25] The procedure included amplification ofgenomic DNA (sim3 ng) by multiplex PCR followed by mul-tiplex OLA The resulting ligation products were hybridizedto Luminex xMAP microspheres and labeled by the reportermolecule SA-PE The xMAP microspheres were analyzedon a Luminex 100 or a Luminex 200 systems Genotypeswere subsequently determined using the Celera allele callingsoftware as described in Iannone et al [25]

25 Data Analysis A confidential password-secureddatabase was used for data entry management and analysisInconsistencies were checked and the data descriptions wereverified by the principal investigator and the statisticianData were analyzed using the Statistical Package for theSocial Sciences (SPSS version 19) and GraphPad Prism 5software Means plusmn standard deviations were determinedfor all continuous variables and number and percentage

Table 2 Morphometric measurements and cardiovascular riskfactors of the Filipino-American women participants (119899 = 235)

Measurement Means plusmn SD Percent of group(risk level)

Weight (lbs) 151 plusmn 22

Height (inches) 61 plusmn 2

Body mass index 29 plusmn 437 (ge25 kgm2)15 (ge30 kgm2)

Waist circumference 40 plusmn 4 79 (ge35 inches)Systolic blood pressure 131 plusmn 19 64 (ge120mmHg)Diastolic blood pressure 87 plusmn 10 61 (le80mmHg)Fasting blood glucose 101 plusmn 25 38 (ge100mgdL)Hemoglobin A1C 60 plusmn 08 36 (ge65)Total cholesterol 201 plusmn 45 44 (ge200mgdL)Triglycerides 116 plusmn 67 19 (ge150mgdL)Low-density lipoprotein-C 122 plusmn 35 61 (ge100mgdl)High-density lipoprotein-C 62 plusmn 15 21 (le50mgdL)High-SensitivityC-Reactive protein 197 plusmn 30 13 (lt30mgL)

Metabolic syndrome 56Smoking 3Family history 48Note metabolic syndrome was defined by both the International DiabetesFederation (IDF) and the National Cholesterol Education ProgrammdashAdultTreatment Panel III (NCEPATP III) criteria

were determined for categorical variables Analysis ofvariance (ANOVA) was used to compare group means andmultiple stepwise linear regression determined whether riskalleles significantly predicted CHD risk factors controllingfor alternative predictors of CHD risks Dichotomousvariables were analyzed using Fisherrsquos chi-square tests forindependence with Yates continuity correction Statisticalsignificance was set at 119875 lt 005

3 Results

31 Demographic Characteristics Demographic characteris-tics of the nonrelated Filipino-American women (119899 = 234)enrolled in the study are shown in Table 1 The mean ageof the women was 554 plusmn 71 years old and the majority(98) were born in the Philippines with the mean lengthof residency in USA of 241 plusmn 131 years The mean ageupon arrival in the USA was 311 plusmn 109 years The majority(75)weremarried andmany had completed a college degreeand were employed in health-related professions Most ofthe participants (88) had some sort of insurance includingprivate insurance (49)

32 Cardiovascular Risk Factors Clinical and morphometricmeasurements are shown in Table 2 Participants had a meanheight of 51015840110158401015840 and mean weight of 151 lbs and 50 ofparticipants were considered either overweight or obese asindicated by BMI The majority were classified as prehy-pertensive because blood pressure was over the criterion


Table 3 Selective cardiovascular disease risk factors as a functionof the rs20455 genotype and statin medication usage

Risk factorsAA

TrpTrp119899 = 53

23

AGArgTrp119899 = 120

51

GGArgArg119899 = 62

26

ANOVA119875 value

AgeTotal 52 plusmn 7 54 plusmn 7 52 plusmn 69 009No statins 51 plusmn 10 52 plusmn 9 50 plusmn 10 028Statins 52 plusmn 4 54 plusmn 6 52 plusmn 7

HDL-CTotal 60 plusmn 14 64 plusmn 15 61 plusmn 16 021No statins 60 plusmn 16 65 plusmn 7 63 plusmn 15 006Statins 56 plusmn 11 61 plusmn 15 52 plusmn 14

LDL-CTotal 114 plusmn 36 113 plusmn 38 113 plusmn 37 071No statins 118 plusmn 39 119 plusmn 39 116 plusmn 34 059Statins 106 plusmn 32 101 plusmn 36 113 plusmn 40

TGTotal 119 plusmn 58 109 plusmn 67 130 plusmn 74

12 0009No statins 118 plusmn 60 107 plusmn 74 111 plusmn 54

Statins 121 plusmn 50 113 plusmn 39 177 plusmn 973 0002

Waist CircTotal 37 plusmn 7 37 plusmn 6 36 plusmn 7

No statins 36 plusmn 6 37 plusmn 4 37 plusmn 4 093Statins 37 plusmn 4 36 plusmn 7 37 plusmn 3

BMITotal 26 plusmn 4 28 plusmn 4 26 plusmn 4 006No statins 26 plusmn 4 27 plusmn 4 25 plusmn 5

Statins 30 plusmn 5 30 plusmn 4 27 plusmn 5 015Hs-CRP

Total 141 plusmn 15 186 plusmn 22 155 plusmn 21 045No statins 21 plusmn 39 22 plusmn 33 16 plusmn 17

Statins 16 plusmn 29 14 plusmn 19 22 plusmn 30 087HbA1c

Total 58 plusmn 046 58 plusmn 049 601 plusmn 097 039No statins 58 plusmn 048 58 plusmn 048 59 plusmn 066Statins 63 plusmn 12 61 plusmn 054 64 plusmn 15 017

Note HDL-C high-density lipoprotein cholesterol LDL-C low-densitylipoprotein-cholesterol TG triglycerides Waist Circ waist circumferenceBMI body mass index hs-CRP high-sensitivity C-reactive protein HbA1cHemoglobin A1c 1119875 lt 005TrpTrp versus ArgArg 2119875 lt 001ArgTrpversus ArgArg and 3ArgArg versus all other groups 119875 lt 0001 AA nostatins 119899 = 22 statins 119899 = 12 AG no statins 119899 = 48 statins 119899 = 21 GG nostatins 119899 = 26 statins 119899 = 16

set forth by the JNC 7 Approximately 36 of the womenhad diabetes as indicated by the levels of hemoglobin A1CA high percentage (61) of the participants had elevatedLDL-C but the percent of the group (21) with unhealthyHDL and elevated triglycerides (19) was much smallerElevated hs-CRPwas seen in 13of the groupApproximately50 of participants were classified as having metabolic

Table 4 Multiple regression analysis of cardiovascular risk factors

Variables TG T ratio(119875 value)

LDL T ratio(119875 value)

HDL T ratio(119875 value)

Genotype 057 (027) 018 (086) 111 (024)HbA1c 342 (00008) 075 (045) 336 (0001)hs-CRP 097 (034) 041 (068) 192 (006)Age 046 (064) 232 (002) 115 (025)BMI 056 (057) 123 (022) 022 (086)Note HbA1c hemoglobin A1c hs-CRP high-sensitivity C-reactive protein

syndrome About 50 of participants self-reported a familyhistory of heart disease indicated by stroke andor CHDevents of parents and immediate siblings Only 3 of theparticipants smoked and thus smoking was not thought to bea confounder in this study

33 KIF6 rs20455 Genotype and CHD Risk Factors Thedistribution of genotypes is as follows 23 AA (TrpTrp)51 AG (ArgTrp) and 26 GG (ArgArg) Thus a majority(77) of participants have at least one copy of the risk alleleThis SNP was found to be in Hardy Weinberg equilibriumThere were no differences in mean age BMI waist circum-ference hs-CRP or HbA1c between the groups (Table 3)

Differences in lipid risk factors as a function of thers20455 genotype and statin use are shown in Table 3 Themean value of TG was significantly elevated in the GGgenotype (ArgArg) group (119875 lt 0009) but further analysisindicated that this elevation was only seen in those ofthis genotype taking statin medication Multiple regressionanalyses confirmed a lack of association of genotype withTG levels but indicated a strong association with diabetes(119875 = 00008) indicated by HbA1c (Table 4) The prevalenceof high TG (ge150mgdL) as a function of genotype was 10of AA (TrpTrp) 16 of AG (TrpArg) and 38 of GG(ArgArg) genotype (Fisherrsquos exact 119875 lt 0001) indicatingthat those subjects with the GG (ArgArg) genotype weremore likely to have elevated TG levels Similar to TG therewas a lack of association of genotype with HDL-C levels butan association with diabetes (119875 = 0001) No differences inmean values of HDL-C between groups were apparent Noassociation of LDL-C with genotype nor differences in meanvalues were seen as a function of genotype or statin usage butan association of LDL-C with age was seen (119875 = 002)

We also investigated the prevalence of elevated LDL-C asa function of genotype and statin useMany participants (60ndash65 Table 5) had elevated LDL-C and were not being treatedwith statins including 65 of those with the Trp719Argallele Moreover many in each genotype who were on statinmedication exhibited elevated LDL-C including 43 of thosewith the Trp719Arg allele

4 Discussion

The major finding of this study is a high prevalence (070)of the Trp719Arg allele in the Filipino-American womenparticipantsMoreover a high percent of womenwith the risk


Table 5 Percent of participants with elevated LDL as a function of genotype and statin usage

Medications TrpTrp(AA)

ArgTrp(AG)

ArgArg(GG)

ArgTrpArgArg

(AG + GG)

Fisherrsquos exact test119875 Value

No statins 119899 = 22 119899 = 48 119899 = 26 119899 = 74

elevated LDL-C 69 67 62 65 041Statins 119899 = 12 119899 = 21 119899 = 16 119899 = 37

elevated LDL-C 58 33 56 43 031

allele and elevated LDL-C levels were not being treated withstatin medications and a significant number of those withthe risk allele on statin medications still exhibited elevatedLDL-C levels Results from the current study are novel sincean extensive search in the literature revealed no studiesdescribing the prevalence of rs20455 SNP of KIF6 and itsassociation with lipid levels in Filipino-American womenOur study may be the first in which the CVD rs20455 riskallele and its association to LDL-C were determined in thisgroup of understudied minority women Our current resultsshowed that the majority of the FAW participants carrieda single (heterozygote) or double (homozygote) copy of therisk allele The carrier frequency seen for Filipino-Americanwomen is similar to those reported by Li et al [15] for Asians(Japanese and Chinese) which was 72 based upon HapMapand Celera data Thus the carrier frequency may be higherin Asians than Caucasians who had a prevalence of 59 inone study [15] Peng et al [9] have reported differences in thers20455 allele frequencies across populations

Another finding of our study is that TG levels were signif-icantly elevated in individuals with theArgArg genotype andon statinmedicationThis result could be interpreted as thosewith ArgArg genotype have higher TG levels when theyhave elevated LDL-C but given the small subject numberfurther study is warranted Wu et al [10] in a case-controlstudy evaluated the association of KIF6 rs20455 SNP withangiographic CAD and serum lipid levels in the Han Chinesepopulation of northern China Their results demonstratedno significant differences in genotype and allele frequencybetween the cases (angiographic CAD) and controls (119875 gt005) However further analysis showed that nonfatalMI riskand TG levels were significantly higher in 719Arg carrierscompared to noncarriers (119875 lt 005) [10]

Our findings demonstrated that there were no differencesin HDL or LDL-C levels as a function of genotype howeverthis finding must be viewed with caution because the samplesize may not be sufficiently powered to discern an associationof genotype with lipid levels Importantly there were a signif-icant number of Filipino-American women including manywith the Trp719Arg allele who had elevated LDL-C but werenot being treated with statins Others were being treated buthad not achieved recommended levels of LDL-C Althoughstudies regarding KIF6rsquos polymorphism and risk for CHDare equivocal the KIF6 genetic variant may be a predictor ofCHD in those who have elevated LDL-C as described in theIntroduction [10ndash18] Given that the number needed to treat

with statins to prevent a single CHD event ranged from 10 to20 for the Trp719Arg carriers it is imperative that those withthis allele be treated for elevated LDL-C [15] The elevatedLDL-C in participants on statin medication could indicatenoncompliance with statin medications due to muscle painsor other side effects of the drugs however we did notcapture data about nonadherence to prescribed cholesterol-lowering medication [26 27] Additionally elevated LDL-C levels despite use of statins in this population may beconceivably due to genetic differences of this population [9]These results may also be due to the differential performanceof lipophilic and hydrophilic statins [28 29] Bonsu et al [28]conducted a systematic review andmeta-analysis of lipophilicand hydrophilic statins on heart failure patients The inves-tigators claimed that there are differences in the pleotropiceffects of statinmedications due to differences in lipophilicityin the type of statin medications Lipophilic statins utilizepassive diffusion for entering cells while hydrophilic statinsuse carrier-mediated process for uptake in the liver cellsAlthough there are controversial outcomes on the effects oflipophilic statins this group of statins appear to show morebeneficial effects than those of hydrophilic statins thoughimproved outcomes have been reported for rosuvastatin inthe Controlled Rosuvastatin in Multinational Trial in HeartFailure (CORONA) and the Gruppo Italiano per lo Studiodella Sopravvivenza nellrsquoInfarto Miocardico Heart Failure(GISSI-HF) trials [29] Regardless of cause further researchis required to determine why LDL-C is not at optimallevels among Filipino-American women even when takingcholesterol-lowering medications Our study indicates thatthis population needs to be more carefully monitored andtreated for elevated LDL-C Specific statin medications mayhave adverse effects in Asian populations [30] In 2005 theUSFood andDrugAdministration provided additional safetylabel warning for rosuvastatin since a pharmacokinetic studythat included a diverse population of Asians showed thatrosuvastatin drug levels were found to be approximatelytwofold higher when compared with the Caucasian controlgroup This in effect may produce increased risk of musclemyopathies and risk of kidney failure in Asians [30]

Many clinical trials have shown the benefit of lower-ing cholesterol levels even in those with relatively normalcholesterol levels and no previous myocardial infarctions[31ndash33] One clinical trial of participants with myocardialinfarction and plasma total cholesterollt240mgdL and LDL-C of 115ndash174mgdL randomized to 40mg of pravastatin


per day or placebo had 102 events in the pravastatingroup and 13 events in the placebo group indicating thatcholesterol-lowering treatment is beneficial for CAD patientswith borderline cholesterol levels [31] Pravastatin loweredcholesterol by 20 and LDL-C by 26 and reduced MIincidence inmen with hypercholesterolemia and no previousMI [32] These studies also suggest the need for cholesterollowering in carriers of the rs20455 allele For examplers20455 allele carriers had a hazard ratio of 150 in theCARE trial [31] and odds ratio of 155 (95CI 114ndash209) inWOSCOPS trial [32] For the rs20455 carriers the absoluterisk reduction by pravastatinwas 489 in theCARE trial and549 in the WOSCOPS trial In the PROSPER [33] studyamong the elderly population with previous CVD diseaseon pravastatin therapy there was an absolute risk reductionof 63 in KIF6 carriers versus 12 in noncarriers witha 336 reduction of relative risk among carriers with thenumber needed to treat with pravastatin significantly lower incarriers compared to noncarriers (16 versus 83) Thus thesethree trials demonstrated that KIF6 risk allele carriers hadan increased risk of developing coronary events and the useof pravastatin significantly reduced the risk Observationalstudies with multiple populations also found increased riskin allele carriers [34ndash38] Another study of 539 participantsshowed that the KIF6 risk variant was associated with cardiacevents with a hazard ratio of 133 after adjustment for agesex race high-sensitivity C-reactive protein and LDL-C [34]In the ARIC [35 36] study carriers of the KIF6 719Arg riskvariant had a higher incidence of CHD with a hazard ratio of122 aftermodel was adjusted for age and sex In theWHS [38]study carriers of the KIF67 719Arg risk variant had a greaterCHD risk with a hazard ratio of 124 and a hazard ratio of 134associated with risk for MI

In contrast other large studies have not found an associ-ation of Kif6 allele with statin response [39 40] The HeartProtection Study (HPS) with 18348 randomized patientsfound that there was no impact of KIF6 genotype on statintherapy and vascular events across all genotypes [39 40] InThe JUPITER Trial Caucasian participants with low LDL-Clt130mgdL and elevated high-sensitivity C-reactive proteinge2mgL were randomly assigned to rosuvastatin or placeboand followed for first major CVD event [12] There wereno differences in vascular event rates in KIF6 risk allelecarriers compared to noncarriers (hazard ratio of 091) noramount of LDL-C reduction Differences in study designbetween the earlier statin trials and more recent trials suchas HPS [39 40] and JUPITER [12] could help explain thedifferent findings In the HPS placebo patients have beenintensively treatedwith 40mg simvastatin for 6weeks prior torandomizationwhich substantially reduced LDL-C levels andaccording to Ference et al [18] could attenuate risk associatedwith KIF6 and therefore explain the lack of a differentialresponse to statin therapy in those with KIF6 genotype Andsimilarly in JUPITER only participants with low LDL-Clevels were enrolled in the study and were treated with high-dose rosuvastatin Such contradictory findings necessitatefurther investigation of the effect of KIF6 polymorphism oncardiovascular health

41 Limitations Certain study limitations merit commentFirst the study was based upon a small number of sub-jects and the significant genetic admixture of Filipinosalso presents a challenge when small population subsetsare studied The exclusion of Filipino-American men wasanother limitation to the study although it should be notedthat most studies include only men and women have beenan understudied gender Moreover we have developed asuccessful method of recruiting women for these sorts ofstudies in community settings It is not clear if this methodwould work for Filipino-American men

Third since this study was only conducted on the Filipinopopulation in the United States the generalizability to Fil-ipinos residing in other countries is not known Fourth theuse of the cross-sectional design limits examining risk factorsfor heart disease at a single point in time without the abilityto measure cardiovascular outcomes

5 Conclusion

Our results showed that 70 of a cohort of nonrelatedFilipino-American women are carriers of the Trp719Arg riskallele (rs20455 SNP of the KIF6 gene) Importantly manyof these women even those treated with statins did notachieve guideline recommended LDL-C levels Althoughlarger population studies are needed to confirm our findingsthe results indicate that Filipino-Americanwomen need to bemore carefully monitored and treated for elevated cholesterolin order to reduce the incidence of CHD in this population

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] J C Cohen ldquoGenetic approaches to coronary heart diseaserdquoJournal of the American College of Cardiology vol 48 no 9 ppA10ndashA14 2006

[2] A J Lusis A M Fogelman and G C Fonarow ldquoGenetic basisof atherosclerosis part II clinical implicationsrdquoCirculation vol110 no 14 pp 2066ndash2071 2004

[3] G H Gibbons C C Liew M O Goodarzi et al ldquoGeneticmarkers progress and potential for cardiovascular diseaserdquoCirculation vol 109 no 25 supplement 1 pp IV47ndashIV58 2004

[4] J F Peden and M Farrall ldquoThirty-five common variants forcoronary artery disease the fruits ofmuch collaborative labourrdquoHuman Molecular Genetics vol 20 no 2 pp R198ndash205 2011

[5] The IBC 50K CAD Consortium ldquoLarge-scale gene-centricanalysis identifies novel variants for coronary artery diseaserdquoPLoS Genetics vol 7 no 9 Article ID e1002260 2011

[6] NHirokawa ldquoKinesin and dynein superfamily proteins and themechanism of organelle transportrdquo Science vol 279 no 5350pp 519ndash526 1998

[7] H Miki M Setou K Kaneshiro and N Hirokawa ldquoAllkinesin superfamily protein KIF genes in mouse and humanrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 98 no 13 pp 7004ndash7011 2001


[8] S Seiler J Kirchner C Horn A Kallipolitou G Woehlke andM Schliwa ldquoCargo binding and regulatory sites in the tail offungal conventional kinesinrdquo Nature Cell Biology vol 2 no 6pp 333ndash338 2000

[9] P Peng J Lian R S Huang et al ldquoMeta-analyses of KIF6rs20455 in coronary heart disease and statin therapeutic effectrdquoPLoS ONE vol 7 no 12 Article ID e50126 2012

[10] G Wu G B Li and B Dai ldquoAssociation of KIF6 variant withlipid level and angiographic coronary artery disease events riskin the Han Chinese populationrdquo Molecules vol 17 no 9 pp11269ndash11280 2012

[11] D Shiffman D I Chasman R Y L Zee et al ldquoA kinesin familymember 6 variant is associated with coronary heart disease inthe Womenrsquos Health Studyrdquo Journal of the American College ofCardiology vol 51 no 4 pp 444ndash448 2008

[12] P M Ridker J G Macfadyen R J Glynn and D I ChasmanldquoKinesin-like protein 6 (KIF6) polymorphism and the efficacyof rosuvastatin in primary preventionrdquo Circulation Cardiovas-cular Genetics vol 4 pp 312ndash317 2011

[13] D Shiffman M S Sabatine J Z Louie et al ldquoEffect ofpravastatin therapy on coronary events in carriers of the KIF6719Arg allele from the cholesterol and recurrent events trialrdquoThe American Journal of Cardiology vol 105 no 9 pp 1300ndash1305 2010

[14] O A Iakoubova C H Tong C M Rowland et al ldquoAssociationof the Trp719Arg polymorphism in kinesin-like protein 6with myocardial infarction and coronary heart disease in 2prospective trials The CARE and WOSCOPS trialsrdquo Journal ofthe American College of Cardiology vol 51 no 4 pp 435ndash4432008

[15] Y Li O A Iakoubova D Shiffman J J Devlin J S Forresterand H R Superko ldquoKIF6 polymorphism as a predictor of riskof coronary events and of clinical event reduction by statintherapyrdquoThe American Journal of Cardiology vol 106 no 7 pp994ndash998 2010

[16] L A Bare E A Ruiz-Narvaez C H Tong et al ldquoInvestigationof KIF6 Trp719Arg in a case-control study of myocardialinfarction a Costa Rican populationrdquo PLoS ONE vol 5 no 9Article ID e13081 2010

[17] T Assimes H Holm S Katherisan et al ldquoLack of assoaitionbetween the rs20455 polymorphism in Kinesin-like protein-6and coronary artery disease in 19 case-control studiesrdquo Journalof the American College of Cardiology vol 56 no 9 pp 1552ndash1563 2010

[18] B A Ference W Yoo J M Flack and M Clarke ldquoAcommon KIF6 polymorphism increases vulnerability to low-density lipoprotein cholesterol two meta-analyses and a meta-regression analysisrdquo PLoS ONE vol 6 no 12 Article ID e288342011

[19] L J Larsen ldquoThe foreign born population in the UnitedStates 2003rdquo Current Population Reports US Census BureauWashington DC USA 2004

[20] R A Ursua N S Islam D E Aguilar et al ldquoPredictors ofhypertension among Filipino immigrants in the Northeast USrdquoJournal of Community Health vol 38 no 5 pp 847ndash855 2013

[21] M R G Araneta A Grandinetti and H K Chang ldquoA1Cand diabetes diagnosis among Filipino Americans JapaneseAmericans and Native Hawaiiansrdquo Diabetes Care vol 33 no12 pp 2626ndash2628 2010

[22] A T Holland B Zhao E C Wong S E Choi N D Wongand L P Palaniappan ldquoRacialethnic differences in control of

cardiovascular risk factors among type 2 diabetes patients in aninsured ambulatory care populationrdquo Journal of Diabetes andIts Complications vol 27 no 1 pp 34ndash40 2013

[23] I B Ancheta C A Battie T Tuason and C V AnchetaldquoA comparison of metabolic syndrome (MetS) risk factors inFilipino women and Filipino American women A Pilot StudyrdquoEthnicity amp Disease vol 22 no 4 pp 404ndash409 2012

[24] L P Palaniappan M R Araneta T L Assimes et al ldquoCall toaction cardiovascular disease in Asian Americans a scienceadvisory from the American Heart Associationrdquo Circulationvol 122 pp 1242ndash1252 2010

[25] M Iannone J Taylor J Chen et al ldquoMultiplexed singlenucleotide polymorphism genotyping by oligonucleotide liga-tion and flow cytometryrdquo Cytometry vol 39 pp 131ndash140 2000

[26] Y S Kim S Sunwoo H R Lee et al ldquoDeterminants ofnon-compliance with lipid-lowering therapy in hyperlipidemicpatientsrdquo Pharmacoepidemiology and Drug Safety vol 11 no 7pp 593ndash600 2002

[27] AM Peterson andW FMcGhan ldquoPharmacoeconomic impactof non-compliance with statinsrdquo PharmacoEconomics vol 23no 1 pp 13ndash25 2005

[28] K O Bonsu A Kadirvelu and D D Reidpath ldquoLipophilicversus hydrophilic statin therapy for heart failure a protocolfor an adjusted indirect comparison meta-analysisrdquo SystematicReviews vol 2 article 22 2013

[29] S Ganesan and M K Ito ldquoCoenzyme Q10 ameliorates thereduction in GLUT4 transporter expression induced by sim-vastatin in 3T3-L1 adipocytesrdquoMetabolic Syndrome and RelatedDisorders vol 11 no 4 pp 251ndash255 2013

[30] U S Food and Drug Administration FDA Public HealthAdvisory for Crestor (Rosuvastatin) 2013 httpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPati-entsandProvidersDrugSafetyInformationforHeathcareProfes-sionalsPublicHealthAdvisoriesucm051756htm

[31] F M Sacks M A Pfeffer L A Moye et al ldquoThe effectof pravastatin on coronary events after myocardial infarctionin patients with average cholesterol levelsrdquo The New EnglandJournal of Medicine vol 335 no 14 pp 1001ndash1009 1996

[32] J Shepherd S M Cobbe I Ford et al ldquoPrevention of coro-nary heart disease with pravastatin in men with hypercholes-terolemiardquo The New England Journal of Medicine vol 333 no20 pp 1301ndash1307 1995

[33] J Shepherd G J Blauw M B Murphy et al ldquoPravastatin inelderly individuals at risk of vascular disease (PROSPER) arandomised controlled trialrdquoThe Lancet vol 360 no 9346 pp1623ndash1630 2002

[34] M Cushman E S Cornell P R Howard E G Bovill andR P Tracy ldquoLaboratory methods and quality assurance in theCardiovascular Health Studyrdquo Clinical Chemistry vol 41 no 2pp 264ndash270 1995

[35] L P Fried N O Borhani P Enright et al ldquoThe CardiovascularHealth Study design and rationalerdquoAnnals of Epidemiology vol1 no 3 pp 263ndash276 1991

[36] M Szklo R Barnes A Folsom et al ldquoThe AtherosclerosisRisk in Communities (ARIC) Study design and objectivesTheARIC investigatorsrdquoAmerican Journal of Epidemiology vol 129no 4 pp 687ndash702 1989

[37] A D White A R Folsom L E Chambless et al ldquoCommunitysurveillance of coronary heart disease in the AtherosclerosisRisk in Communities (ARIC) Study methods and initial twoyearsrsquo experiencerdquo Journal of Clinical Epidemiology vol 49 no2 pp 223ndash233 1996


[38] P M Ridker N R Cook I-M Lee et al ldquoA randomized trialof low-dose aspirin in the primary prevention of cardiovasculardisease in womenrdquo The New England Journal of Medicine vol352 no 13 pp 1293ndash1304 2005

[39] J C Hopewell S Parish R Clarke et al ldquoNo impact of KIF6Genotype on vascular risk and statin response among 18348randomized patients in the heart protection studyrdquo Journal ofthe American College of Cardiology vol 57 no 20 pp 2000ndash2007 2011

[40] J C Hopewell S Parish A Offer et al ldquoImpact of commongenetic variation on response to simvastatin therapy among 18705 participants in the Heart Protection Studyrdquo European HeartJournal vol 34 pp 982ndash992 2013

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of CHD in those who have elevated LDL-C Indeed carriersof the Trp719Argallele may have a greater increase in CHDrisk per unit increase in LDL and a greater reduction inCHD risk per unit decrease in LDL compared to noncarriers[18] Indeed the number needed to treat with statins toprevent a single CHD event ranged from 10 to 20 for theTrp719Arg carriers compared to gt80 for noncarriers in alarge meta-analysis [15] Furthermore the results of Ferenceet al [18] suggest that the differential vulnerability to LDL-C based upon genotype may explain the reason for the priordisagreement in studies

To the best of our knowledge despite a plethora ofevidence no studies of KIF6 Trp719Arg allele have beenconducted in the Filipino population Filipinos are the secondlargest minority population of Asians in America [19] andhave the highest prevalence of hypertension [20] type 2diabetes [21 22] and metabolic syndrome [23] comparedwith other Asian subgroups The heterogeneity of CHD riskfactors among Asians is well established [24] and the allelicfrequency distribution of rs20455 has been shown to varyacross populations [15] Scientific gaps still exist regardingthe role of genetics in the predisposition to CHD in variouspopulations Since the rs20455 variant has not been studiedin those of Filipino descent we investigated its prevalence inassociation with plasma lipid levels in a cohort of FilipinoAmerican women who attended community-based healthscreenings at various locations throughout the USA

2 Materials and Methods

21 Study Design Population and Recruitment ProcedureApproval of the University Institutional Research Board(IRB) was obtained prior to the conduct of this studyThis study is a descriptive cross-sectional study of FilipinoAmerican women (119899 = 234) who participated in a car-diovascular health screening at their places of worship orcultural centers during 2011ndash2013 Subjects were between 40and 65 years of age Health screenings were performed invarious US cities Jacksonville FL Chicago IL Tampa FLand San Francisco CA In order to recruit a wide varietyof subjects advertisements were posted in church bulletinsand at community organizations and stores frequently visitedby Filipino women These flyers specified inclusion andexclusion criteria and the need to be fasting for at least 12hours on the day of the study Participants were instructedto bring all prescription and nonprescription medications tothe study site

Participants were enrolled if they were women self-identified as Filipino by ethnicity agreed to volunteer for thestudy and were fasting for 12 hours Women who had severearthritis any autoimmune disorder and a recent cancerdiagnosis andor presented with any infection or severeinflammationwere excluded from the study important for themeasurement of inflammatory markers Informed consentwas obtained after the study purpose was carefully explainedPrior to giving consent participants were given ample timeto ask questions or state concerns regarding the study Total

time for participation in the study was approximately 45minper participant

22 Screening Protocol A demographic and clinical infor-mation questionnaire including participantsrsquomedical historyand current medications was completed for each subject bytrained research staff The clinical information questionnaireincluded family history smoking history participantrsquos med-ical history and current medications Upon completion ofthe survey blood pressure was obtained using a standardOmron digital HEM-705CP sphygmomanometer on thenondominant arm after the participant had been seated for10min Measurements were repeated three times with 5minin between each reading Subsequently weight and heightwere measured using a standard Tanita weighing scale (WB-3000) Waist circumference was measured using a tensiontape guided by the NHANES measurement protocol Lastlya licensed phlebotomist drew 5mL of blood via venipuncturefrom each participant for a series of tests including thestandard lipid panel hemoglobin A1C serum glucose acardiovascular inflammatory biomarker (high-sensitivity C-reactive protein or hs-CRP) and genetic assays The bloodwas captured in three test tubes containing EDTA Sampletubes were labeled with numbers only centrifuged andimmediately frozen At the end of each screening sessionfrozen samples were sent to a CLIA certified laboratory whereassays were performed using standard clinical protocolsThe lipid panel assay included total cholesterol triglycerideshigh-density lipoprotein (HDL) and low-density lipopro-tein (LDL-C) (Roche Modular methodology) performedat Berkeley Heartlab Inc (Alameda CA) Plasma hs-CRPconcentration was determined using an automated immuno-turbidimetric assay (Roche Modular methodology BerkeleyHeartlab Inc)

23 Cardiovascular Risk Factors The operational definitionfor CHD risk factors for the study was based on the fol-lowing guidelines For blood pressure values the AmericanHeart Association and the Joint National Committee forthe Prevention Detection Evaluation and Treatment ofHigh Blood Pressure (JNC 7) guidelines for the normalrange of blood pressure were used (ge120mmHg systolicandor diastolic blood pressure of le80mmHg) We usedthe criteria of the World Health Organization regardingcut-off for the body mass index (BMI) The NationalCholesterol Education Program (NCEP) Adult TreatmentPanel III guidelines were used to define the cholesterolnormal reference values namely total cholesterol (TC)ge200mgdL triglycerides (TGL) ge150mgdL high-densitylipoproteins cholesterol (HDL-C) le50mgdL low-densitylipoprotein cholesterol (LDL-C) ge100mgdL fasting bloodglucose (FBG) ge100mgdL (56mmolL) and waist cir-cumference ge35 inches (88 cm) The American DiabetesAssociation criteria for diabetes were used hemoglobin A1Cge65 and fasting plasma glucose ge126mgdL Metabolicsyndrome was defined using both the International Diabetesfederation and the National Cholesterol Education Program-Adult Treatment Panel III criteria





















3 Results





Risk factorsAA

TrpTrp119899 = 53

23


51

GGArgArg119899 = 62

26

ANOVA119875 value

























4 Discussion





ArgTrp(AG)

ArgArg(GG)

ArgTrpArgArg

(AG + GG)


No statins 119899 = 22 119899 = 48 119899 = 26 119899 = 74













5 Conclusion




References

























































Advances in

Urology














Volume 2014






























3 Results





Risk factorsAA

TrpTrp119899 = 53

23


51

GGArgArg119899 = 62

26

ANOVA119875 value

























4 Discussion





ArgTrp(AG)

ArgArg(GG)

ArgTrpArgArg

(AG + GG)


No statins 119899 = 22 119899 = 48 119899 = 26 119899 = 74













5 Conclusion




References

























































Advances in

Urology














Volume 2014












Risk factorsAA

TrpTrp119899 = 53

23


51

GGArgArg119899 = 62

26

ANOVA119875 value

























4 Discussion





ArgTrp(AG)

ArgArg(GG)

ArgTrpArgArg

(AG + GG)


No statins 119899 = 22 119899 = 48 119899 = 26 119899 = 74













5 Conclusion




References

























































Advances in

Urology














Volume 2014













ArgTrp(AG)

ArgArg(GG)

ArgTrpArgArg

(AG + GG)


No statins 119899 = 22 119899 = 48 119899 = 26 119899 = 74













5 Conclusion




References

























































Advances in

Urology














Volume 2014















5 Conclusion




References

























































Advances in

Urology














Volume 2014



























































Advances in

Urology














Volume 2014










research article the association between kif6 single...

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