Development of a novel pre-screen algorithm for cardio-metabolic risk management using a genomics database resource

Luckhoff, Hilmar Klaus (2016-03)

Thesis (MSc)--Stellenbosch University, 2016.

Thesis

ENGLISH ABSTRACT: The timely assessment and treatment of dyslipidaemia is an important component of cardiovascular risk screening and intervention. The apolipoprotein E (APOE) ε-2/ε-3/ε-4 polymorphism associated with impaired lipid homeostasis provides a genetic link between cardiovascular disease (CVD) and late-onset Alzheimer’s disease (AD). Realization that the phenotypic expression of the risk associated APOEε-2 and ε-4 alleles may be dependent on non-genetic factors supports the inclusion of APOE genotyping in chronic disease screening programs. The lack of well-defined selection criteria for APOE genotyping, however, limits the use of this biomarker in clinical practice. The aim of the present study was to develop a pre-screen algorithm for identification of a target population most likely to benefit from APOE genotyping, performed in conjunction with a clinical and lifestyle assessment. Towards this goal, comprehensive patient data were evaluated from a total of 580 unrelated Caucasians enrolled in a chronic disease screening program over a five-year period (2010-2015), using an ethically approved study questionnaire. Biochemical tests performed according to standard laboratory protocols were extracted from the research database. All study participants were genotyped for the APOE ε- 2/ε-3/ε-4 polymorphism. APOE genotype distribution differed significantly (p<0.05) between study participants with and without a family history of AD. A positive association between dietary fat intake and lowdensity lipoprotein (LDL) cholesterol (p=0.001), as well as an inverse association with highdensity lipoprotein (HDL) cholesterol (p=0.002), were observed in patients with a family history of AD. Body mass index (BMI) was positively associated with LDL cholesterol and inversely associated with HDL cholesterol levels (p<0.001), irrespectively of an AD family history. Smoking was associated with higher triglycerides (p<0.001) and lower HDL cholesterol levels (p=0.004) in the total study group. Alcohol intake was positively associated with BMI (p=0.008) as well as triglyceride levels (p=0.021) in patients with a positive family history of AD. The clinical expression of a hypercholesterolaemic phenotype in APOE ε-4 allele carriers, as well as apparent mitigation by regular physical activity, were dependent on the interaction between a family history of AD and APOE genotype (p<0.001). APOE ε-2 carriers without an AD family history showed a significant increase in triglyceride levels (p=0.014). The modulating influence of APOE ε-4 on the relationship between alcohol intake and BMI as well as total cholesterol levels was also dependent on the presence or absence of AD family history (p<0.05). This study resulted in the addition of a family history of AD as a novel component to the prescreen algorithm developed for selection of at-risk individuals prior to APOE genotyping performed as part of a chronic disease screening program. The lifestyle questionnaire used in this study furthermore facilitated interpretation of the clinical relevance of variation detected in the APOE gene. This is important to prioritize the use of lipid-lowering medication towards patients with severe subtypes of dyslipidaemia such as familial hypercholesterolaemia (FH), which remains largely undiagnosed and untreated in the highrisk South African population. Incorporating the research findings into clinical practice would suggest that physical activity may be the most effective risk reduction strategy in carriers of the APOEε-4 allele, as supported by international studies.

AFRIKAANSE OPSOMMING: Die tydige opsporing en behandeling van dislipidemie is 'n belangrike komponent van kardiovaskulêre risikobepaling en intervensie. Die apolipoproteïn E (APOE) ε-2/ε-3/ε-4 polimorfisme wat geassosieer is met abnormale lipied metabolisme toon ‘n genetiese verband tussen kardiovaskulêre siekte (KVS) en laat- aanvang Alzheimer se siekte (AD). Die bevinding dat die fenotipiese uitdrukking van die risiko geassosieerde APOE ε-2 en ε-4 allele afhanklik mag wees van nie-genetiese faktore ondersteun die insluiting van APOE genotipering in kroniese siekte siftingsprogramme. Die gebrek aan goed-gedefinieerde seleksie kriteria vir APOE genotipering beperk egter die gebruik van hierdie biomerker in kliniese praktyk. Die doel van hierdie studie was om 'n pre-toets algoritme te ontwikkel vir identifikasie van ‘n teiken populasie waar APOE genotipering waarde kan byvoeg, tesame met die evaluering van kliniese en leefstyl risikofaktore. Om hierdie doel te bereik is pasiëntdata geanaliseer van ‘n totaal van 580 nie-verwante Koukasiërs wat deelneem aan ‘n kroniese siekte siftingsprogram oor ‘n vyf-jaar periode (2010-2015), met gebruik van ‘n eties goedgekeurde studievraelys. Biochemiese toetse wat uitgevoer is volgens standaard laboratorium protokolle is geëekstraheer uit die navorsingsdatabasis. Genotipering van alle studiedeelnemers is uitgevoer vir die APOE ε-2/ε-3/ε-4 polimorfisme. APOE genotipe verspreiding het betekenisvol verskil (p<0.05) tussen studiedeelnemers met en sonder ‘n familiegeskiedenis van AS. ‘n Positiewe assosiasie is waargeneem tussen vetinname in die dieet en lae-digtheid lipoproteïen (LDL) cholesterol (p=0.001), terwyl ‘n omgekeerde assosiasie met hoë-digtheid lipoproteïen (HDL) cholesterol (p=0.002) waargeneem is in deelnemers met ‘n familiegeskiedenis van AS. Liggaamsmassa-indeks (BMI) was positief geassosieer met LDL cholesterol en omgekeerd geassosieer met HDL cholesterolvlakke (p<0.001), ongeag van AS familiegeskiedenis. Rook was geassosieer met verhoogde trigliserides (p<0.001) and laer HDL cholesterolvlakke (p=0.004) in die totale studiegroep. Alkohol inname was positief geassosieer met BMI (p=0.008) asook trigliseriedvlakke (p=0.021) in deelnemers met ‘n positiewe familiegeskiedenis van AS. Die kliniese uitdrukking van ‘n hipercholesterolemiese fenotipe in APOE ε-4 alleel draers, asook die verlaagde cholesterolvlakke met gereëlde fisiese aktiwiteit, was afhankik van die interaksie tussen AS familiegeskiedenis en APOE genotipe (p<0.001). APOE ε-2 draers sonder ‘n AS familiegeskiedenis het ‘n betekenisvolle verhoging in trigliseriedvlakke getoon (p=0.014). Die modulerende invloed van APOE ε-4 op die verhouding tussen alkohol inname en BMI asook totale cholesterolvlakke is ook bepaal deur die teenwoordigheid al dan nie van ‘n AS familiegeskiedenis (p<0.05). Hierdie studie het gelei tot die byvoeging van ‘n familiegeskiedenis van AS as ‘n nuwe komponent tot die pre-toets algoritme wat ontwikkel is om hoë-risiko individue te selekteer voor APOE genotipering as deel van n kroniese risiko bestuur program. Die leefstyl vraelys wat gebruik is vergemaklik die interpretasie van die kliniese relevansie van die genotipe resultate. Dit is belangrik sodat die noodsaaklikheid van lipied-verlagende farmakoterapie geprioritiseer kan word in deelnemers met erge subtipes van dislipidemie soos familiële hipercholesterolaemie (FH), wat meestal ongediagnoseer en onder-behandel bly in die hoërisiko Suid-Afrikaanse populasie. Inkorporering van die navorsingsresultate in kliniese praktyk behels die aanbeveling van fisiese aktiwiteit as die mees effektiewe risikoverlagende strategie in draers van die APOE ε-4 alleel, soos ook ondersteun word deur intenasionale studies.

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