Molecular investigation of genetic factors associated with insulin resistance and obesity in a South African population

Vergotine, Zelda (2015-12)

Thesis (PhD)--Stellenbosch University, 2015.

Thesis

ENGLISH ABSTRACT: Background: The aetiopathogenesis of type 2 diabetes and the associated insulin resistance have been shown to have a strong genetic basis. Several genetic variants of the peroxisome proliferatoractivated receptor gamma (PPARG) and the insulin receptor substrate (IRS) 1 genes have been associated with the metabolic states of obesity, insulin resistance and type 2 diabetes in Caucasian populations. Furthermore, insulin resistance is strongly associated with diabetes and subsequent cardiovascular disease. These are increasingly common in low- to middle -income countries, including South Africa. Limited information is currently available regarding genetic associations with insulin resistance in African populations. Objectives: (1) To identify subjects with insulin resistance and determine the frequencies of the single nucleotide polymorphisms in the PPARG and IRS1 genes and examine the associated risk of insulin resistance and type 2 diabetes mellitus in a mixed-ancestry South African population. (2) To investigate the relationship between indices of insulin resistance and carotid intima media thickness, a marker of subclinical cardiovascular disease/atherosclerosis. Methods: A total of 856 (235 males) mixed-ancestry adults drawn from an urban community of Bellville South, Cape Town were genotyped for PPARG Pro12Ala (rs1801282, G>C), Pro115Gln (rs1800571, G>T), Val290Met (rs72551362, G>A), Pheu388Leu (rs72551363, T>A), Arg397Cys (rs72551364, C>T), His449His (rs3856806, C>T) and IRS1 Gly972Arg (rs 1801278, G>A). The oral glucose tolerance test was performed and cardiometabolic risk factors measured. Insulin resistance was estimated by the homeostasis model assessment of insulin resistance, the homeostasis model assessment of functional beta-cells, the quantitative insulin-sensitivity check index, the fasting insulin resistance index and the glucose/insulin ratio. Carotid intima media thickness was measured in longitudinal section at the far wall of the distal common carotid arteries, 2 cm from the bifurcation, at three consecutive end-points, 5-10 mm apart. Results: The genotype frequencies of PPARG Pro12Ala, IRS1 Gly972Arg and PPARG His449His were 10,4%, 7,7% and 23,8% respectively. No mutations were found for PPARG Pro115Gln, Val290Met, Pheu388Leu and Arg379Cys. In a model containing both PPARG Pro12Ala and IRS1 Gly972Arg alleles and their interaction term, the presence of the PPARG Pro12 resulted in a 64% risk of prevalent type 2 diabetes mellitus and was associated with higher 2 hour post-OGTT insulin levels in subjects with normoglycaemia. The PPARG Pro12 was associated with insulin resistance and interacted with IRS1 Gly972Arg, increasing the risk of type 2 diabetes mellitus. The PPARG His449His allele T frequency was about 14% and in an additive genetic model significantly reduced the risk of diabetes by 44%. After adjustment for age, gender, body mass index and diabetes status, the fasting plasma glucose (β=0,087;p=0,042) and glucose/insulin ratio (β=0,026; p=0,026) were associated with carotid intima media thickness. However, the effect on the overall model performance was marginal, R2<29,7%. Conclusion: The PPARG Pro12 was associated with insulin resistance and showed a gene-gene interaction with the unfavorable polymorphism IRS1 Gly972Arg, leading to an increased risk of type 2 diabetes mellitus. In contrast, the PPARG His449His T allele showed a protective effect against the risk of developing diabetes. Furthermore, indices of insulin resistance such as homeostatis model assessment of insulin resistance, quantitative insulin-sensitivity check index, fasting insulin resistance index and the glucose/insulin ratio were weakly associated with carotid intima media thickness in the risk stratification of cardiovascular disease in this population.

AFRIKAANSE OPSOMMING: Agtergrond: Die sterk genetiese grondslag van die etiopatogenese van tipe 2 diabetes en verwante insulienweerstand is reeds bevestig. Verskeie genetiese variante van die peroksisoomprolifereerder geaktiveerde reseptor gamma (PPARG) en die insulienreseptor substraat (IRS)1 gene hou verband met die metabolise sindroom van vetsug, insulienweerstand en tipe 2 diabetes in Kaukasiese bevolkings. Verder word insulienweerstand sterk verbind met gevolglike kardiovaskulêre siekte in diabetes mellitus. Laasgenoemde toestande neem toe in lae- en middelinkomste lande, Suid Afrika ingesluit. Beperkte inligting is tans beskikbaar aangaande die genetiese verwantskappe van insulienweerstand in Afrika bevolkings. Doel: (1) Om proefpersone met insulienweerstand te identifiseer, die voorkoms van enkelnukleotiedpolimorfismes in PPARG en IRS1 gene te bepaal en die verwante risiko vir insulienweerstand en tipe 2 diabetes in ‘n Suid-Afrikaanse bevolking van gemengde herkoms te ondersoek. (2) Om die verwantskappe tussen insulienweerstandsindekse en karotis intima media dikte as ‘n merker van subkliniese kardiovaskulêre siekte/aterosklerose te bepaal. Metode: ‘n Steekproef van 856 (235 mans) volwassenes van gemengde herkoms uit ‘n stedelike gemeenskap in Bellville Suid, Kaapstad, is gegenotipeer vir PPARG Pro12A1a (rs1801282, G>C), Pro115Gln (rs1800571, G>T), Val290Met (rs72551362, G>A), Pheu388Leu (rs72551363, T>A), Arg397Cys (rs72551364, C>T), His449His (rs3856806, C>T) en IRS1 Gly972Arg (rs 1801278, G>A). Orale glukosetoleransie toetse is uitgevoer en kardiometaboliese risikofaktore is gemeet. Insulienweerstand is geraam deur die homeostasemodel assessering vir insulienweerstand, die homeostasemodel assessering van funksionale betaselle, die kwantitatiewe insuliensensitiwiteit kontroleerindeks, die vastende insulienweerstandsindeks en glukose/insulien verhouding. Carotids intima media dikte is gemeet in longitudinale snit teen die verre wand van die distale gemene karotis arteries, 2 cm vanaf die bifurkasie, by drie opeenvolgende eindpunte, 5-10 mm uit mekaar. Resultate: Die voorkoms van PPARG Pro12Ala, IRS1 Gly972Arg and PPARG His449His genotipes was onderskeidelik 10,4%, 7,7% en 23,8%. Geen mutasies van PPARG Pro115Gln, Val290Met, Pheu388Leu of Arg379Cys is gevind nie. In ‘n model wat beide die PPARG Pro12Ala en IRS1 Gly972Arg allele en hul interaksieterm bevat het, het die teenwoordigheid van PPARG Pro12 gelei tot 64% risiko vir tipe 2 diabetes en verband gehou met verhoogde 2-uur post-OGTT insulienvlakke in studiepersone met normoglisemie. ‘n Verband is aangedui tussen PPARG Pro12 en insulienweerstand en daar was interaksie met IRS1 Gly972Arg wat die risiko vir tipe 2 diabetes verhoog. Die PPARG His449His T-allel se voorkoms was ongeveer 14% en het die diabetesrisiko met 44% verlaag in ‘n saamgestelde genetiese model.Na aanpassings vir ouderdom, geslag, liggaamsmassa indeks en diabetes status, is ‘n verband getoon tussen beide vastende plasmaglukose (β=0,087; p=0,042) en glukose/insulienverhouding (β=0,026; p=0,026), en karotis intima media dikte. Die uitwerking op die gehele model was egter gering, R2<29,7%. Gevolgtrekking: ‘n Verwantskap is getoon tussen PPARG Pro12 en insulienweerstand en ‘n geen-geen interaksie het voorgekom met die ongunstige IRS1 Gly972Arg polimorfisme wat lei tot verhoogde risiko vir tipe 2 diabetes. Die PPARG His449His T-allel het in teenstelling ‘n beskermende uitwerking getoon teen die risiko vir diabetes. Verder was daar ‘n swak verband tussen indekse van insulienweerstand soos homeostasemodel assessering, die kwantitatiewe insuliensensitiwiteit kontroleerindeks, die vastende insulienweerstandsindeks en glukose/insulien verhouding, en karotis intima media dikte vir risikogroepering vir kardiovaskulêre siekte in hierdie bevolking.

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