Identifying relevant novel markers of cardiometabolic risk in the Cardiovascular Risk in Black South Africans (CRIBSA) Study

De Buys, Keren (2019-04)

Thesis (MSc)--Stellenbosch University, 2019.

Thesis

ENGLISH ABSTRACT: Non-communicable diseases are the second leading cause of death in South Africa. In South African Black individuals, risk factors for cardiovascular disease, such as hypertension, obesity and type 2 diabetes mellitus, are common. These individual risk factors for cardiovascular disease (dyslipidaemia, hypertension, obesity and type 2 diabetes) are the focus of the present study in the Black isiXhosa-speaking population of Cape Town. Previous studies, in European and North American populations, have identified single nucleotide polymorphisms (SNPs) in various genes to be associated with non-communicable diseases that are risk factors for cardiovascular disease. However, few studies have been conducted in sub-Saharan Africa and even fewer have been conducted in South Africa. Identifying genes that contribute to the development of cardiovascular disease may help to understand its pathophysiology, identify individuals at higher risk and novel targets may aid preventative and treatment strategies. The aim of this study was to determine if selected genetic markers in genes encoding the angiotensin-converting enzyme (ACE), angiotensinogen (AGT), angiotensin II type I receptor (AT1R), transcription factor 7-like 2 (TCF7L2), fat-mass and obesity associated (FTO), melanocortin 4 receptor (MC4R) and tumour necrosis factor-alpha (TNFα) are associated with cardiovascular disease risk in South African Black individuals. Of the 1 116 samples available for this study, DNA was extracted from 936 samples. SNPs in each of these genes were selected based on previous findings of association with disease in other African populations. Genotypes were analysed under additive, dominant and recessive association models using the R Statistical Package, snpassoc. The I/I genotype of rs4646994 of ACE was associated with blood pressure (p=0.014) and LDL-C (p=0.038) under a recessive inheritance model, while the D/D genotypes was associated with obesity and waist circumference under additive (p=0.047 and p=0.044, respectively) and dominant (p=0.04351 and p=0.04437, respectively) inheritance models. rs17782313 of MC4R was nominally associated with type 2 diabetes mellitus under dominant (T/C and C/C genotypes) (p=0.054) and recessive (T/T genotype) (p=0.075) inheritance models; and rs229616 (A/A genotype) was nominally associated with HDL-C (p=0.059) and rs1297034 was nominally associated with type 2 diabetes mellitus (p=0.075) under recessive inheritance models. Suggestive evidence of association with disease was observed for many of the genes, but further studies are needed to confirm this. Genetic associations with obesity and type 2 diabetes mellitus, risk factors for cardiovascular disease, observed in other African, as well as European and American populations, were replicated in this study. Novel associations with disease in South Africa and sub-Saharan Africa are reported and cross-phenotype associations were observed. This study suggests that these genes are potentially causal in disease predisposition and progression in the South African Black population, where the prevalence of these diseases is high. This study suggests that this is an important population to study and further studies are warranted.

AFRIKAANSE OPSOMMING: Nie oordraagbare siekte is die tweede hoofoorsaak van dood in Suid Afrika. In Suid Afrikanse Swart mense, risiko faktore vir hart siekte, soos hoë bloeddruk, vetsug en suiker siekte, is algemeen. Metaboliese sindroom beskryf die groepering van hierdie risiko faktore, wat ʼn individu plaas met hoër risiko vir hart siekte. Voorige studies, in Europa en Amerika, het enkel nukleotied polimorfismes (ENP) in verskeie gene geidentifiseer wat verband hou met nie oordraagbare siektes, wat risiko faktore is vir hart siekte. Maar min studies is in sub-Sahariese Afrika gedoen, en nog minder in Suid Afrika. Die identifikasie van gene wat bydra tot die ontwikeling van hart siekte mag dalk help om die patofisiologie te verstaan, en om hoë risiko individu te identifiseer. Nuwe genetiese teikens mag ook dalk voorkomende en behandelings strategieë help. Die doel van hierdie study was dus om te bepaal of spesfieke genetiese teikens (die angiotensienomskekling ensiem (ACE), angiotensinogen (AGT), angiotnsien II tipe I reseptor (AT1R), transkripsiefator 7, 2-agtige (TCF7L2), vetmassa en vetsugverwante (FTO), melanocortine 4 reseptor (MC4R) en tumor nekrose factor-alfa (TNFα) gene) is verband met hart siekte risiko in Suid Afrikanse Swart mense. Uit 1 116 monsters beskikbaar vir die study, DNS van 936 monsters was onttrek. ENP gekies in elk van die gene was gebasseer op voorige vindings van verbanding met siekte in Afrika lande. Genotipes was ontleed onder toevoeging, dominante en ressesiewe assosiasie modelle met die R statistike paket, snpassoc. Die I/I genotype van rs4646994 van ACE was met hoë bloeddruk (p=0.014) en LDL-C (p=0.038) geassosieer onder ʼn resessiewe model, terwyl die D/D genotype met vetsug en middellyf omtrek onder toevoeging (p=0.047 en p=0.044, onderskeidelik) en dominante (p=0.044 en p=0.044, onderskeidelik) modelle geassosieer was. Rs17782313 van MC4R was nominal geassosieer met suiker siekte geassosieer onder dominante (T/C en C/C genotype) (p=0.054) en resessiewe (T/T genotype) (p=0.075) modelle; rs229616 (A/A genotype) was nominaal geassosieer met HDL-C (p=0.059) en rs1297034 was nominaal geassosieer met suiker siekte (p=0.075) onder toevoeging modelle. Aanduidende bewyse vie assosiasie met hart siekte risiko faktore was waargeneem vir baie van die gene, maar meer studies is nodig om dit te bevestig. Genetiese assosiasies met vetsug en suiker siekte, risiko faktore vir hart siekte, waargeneem in ander Afrika, sowel as Europese en Noord Amerikanse mense, was herhaal in dié study. Nuwe assosiasies met siekte in Suid Afrika is berig en kruis-fenotipe assosiasies waargeneem. Dié study dui daarop dat hierdie gene moontlik oorsaaklik in die vatbaarheid en vordering van siekte is in Suid Afrikanse Swart mense, waar die voorkoms van hierdie siektes hoog is. Dié study dui ook daarop dat die Swart mense van Suid Afrika belangrik is om te studeer en meer studies geregverdig is.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/105641
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