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

[摘要] ENGLISH ABSTRACT: Background: The aetiopathogenesis of type 2 diabetes and the associated insulin resistance havebeen shown to have a strong genetic basis. Several genetic variants of the peroxisome proliferatoractivatedreceptor gamma (PPARG) and the insulin receptor substrate (IRS) 1 genes have beenassociated with the metabolic states of obesity, insulin resistance and type 2 diabetes in Caucasianpopulations. Furthermore, insulin resistance is strongly associated with diabetes and subsequentcardiovascular disease. These are increasingly common in low- to middle -income countries,including South Africa. Limited information is currently available regarding genetic associationswith insulin resistance in African populations.Objectives: (1) To identify subjects with insulin resistance and determine the frequencies of thesingle nucleotide polymorphisms in the PPARG and IRS1 genes and examine the associated risk ofinsulin resistance and type 2 diabetes mellitus in a mixed-ancestry South African population. (2) Toinvestigate the relationship between indices of insulin resistance and carotid intima mediathickness, a marker of subclinical cardiovascular disease/atherosclerosis. Methods: A total of 856 (235 males) mixed-ancestry adults drawn from an urban community ofBellville 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). Theoral glucose tolerance test was performed and cardiometabolic risk factors measured. Insulinresistance was estimated by the homeostasis model assessment of insulin resistance, thehomeostasis model assessment of functional beta-cells, the quantitative insulin-sensitivity checkindex, the fasting insulin resistance index and the glucose/insulin ratio. Carotid intima mediathickness 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 His449Hiswere 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 andIRS1 Gly972Arg alleles and their interaction term, the presence of the PPARG Pro12 resulted in a64% risk of prevalent type 2 diabetes mellitus and was associated with higher 2 hour post-OGTTinsulin levels in subjects with normoglycaemia. The PPARG Pro12 was associated with insulinresistance and interacted with IRS1 Gly972Arg, increasing the risk of type 2 diabetes mellitus. ThePPARG His449His allele T frequency was about 14% and in an additive genetic model significantlyreduced the risk of diabetes by 44%. After adjustment for age, gender, body mass index anddiabetes 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 onthe overall model performance was marginal, R2<29,7%. Conclusion: The PPARG Pro12 was associated with insulin resistance and showed a gene-geneinteraction with the unfavorable polymorphism IRS1 Gly972Arg, leading to an increased risk oftype 2 diabetes mellitus. In contrast, the PPARG His449His T allele showed a protective effectagainst the risk of developing diabetes. Furthermore, indices of insulin resistance such ashomeostatis model assessment of insulin resistance, quantitative insulin-sensitivity check index,fasting insulin resistance index and the glucose/insulin ratio were weakly associated with carotidintima media thickness in the risk stratification of cardiovascular disease in this population.

[发布机构] Stellenbosch University