Genetic Predisposition to Central Obesity and Risk of Type 2 Diabetes: Two Independent Cohort Studies (original) (raw)
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Scientific Reports
Obesity, parental history (PH) of type 2 diabetes (T2D), and genes play an important role in T2D development. However, the influence of each factor on T2D variability is unclear. This study aimed to investigate the influence of obesity (body mass index [BMI], waist/hip ratio), PH, and 16 singlenucleotide polymorphisms (SNPs) associated with T2D on T2D variability in Mexico, comparing 1234 non-diabetic controls and 1219 diabetic patients. To replicate the data, a case-control (n = 2904) and a cross-sectional (n = 1901) study were also included. In a multivariate logistic regression model, all factors accounted for only 27.3% of T2D variability: SNPs (8.4%); PH (11.8%) and obesity (7.1%). These factors contributed more in men (33.2%) than in women (25%), specifically when the disease was diagnosed before the age of 46 (46.7% vs. 30%). Genes played a substantially more important role in men than in women (14.9% vs. 5.5%), while obesity and PH played a similar role in both genders. Genes and PH appeared to play a greater role than obesity in T2D. However, obesity contribution was calculated at the time of recruitment and may be underestimated in patients because the BMI decreased linearly with the number of years with the disease. The data suggest that sexual hormones may play important roles in genes that are associated with T2D. The aetiology of type 2 diabetes (T2D) includes factors such as genes, genetic predisposition, ethnicity, poor nutrition, sedentary lifestyle, obesity, and dyslipidaemia 1. Several family-based studies of disease heritability have indicated that T2D is strongly heritable 2-4 , and the heritability is on average 25% 5. However, insufficient information exists on the heritability of T2D in non-twin families, and little is known regarding how much of this heritability is due to genes and other heritable factors, such as epigenetic factors 6. Historical studies of linkage, candidate genes, and genome-wide association studies (GWAS) have discovered more than 100 variants of genes associated with T2D 7,8. However, the influence of these genes on the disease is unclear. Based on their low individual odds ratios (ORs), most genes have very little influence on the development of the disease 8. According to the results of a European case-control study, only approximately 10% of the T2D variability can be explained by T2D-susceptible loci 9-11. Obesity is a modifiable factor that is clearly associated with the development of the disease. It is well known that the risk of T2D increases linearly as the body mass index (BMI) increases 12. In fact, obesity has been promoted as the main risk factor for diabetes 13. However, the relationship between T2D and
Predisposition of Obesity through Genetic and Non-Genetic Risk Fac- tors
2021
Article history Received: 4 January 2021 Accepted: 28 January 2021 Published Online: 31 January 2021 Globally there is an increase in the number of people affected by obesity. This has increased the count of individuals to double, triple, and even quadruple. Obesity is a complex disease that has a genetic, behavioural, socioeconomic, and environmental effect. This raises morbidity and mortality in obesity. It is an important predisposition for diabetes as well as the current pandemic COVID-19. The rationale of this case-control observational study is to identify obese individuals among the diabetic and non-diabetic population. The study includes non genetic factors like lipid profiles with genetic factors in form of SNP as a predisposition factor. The amplified portion of the ADIPOQ gene sequence revealed the presence of SNPs rs2241767 in 46.3% population and showed increased lipid profile values. It can be concluded that these are important predisposing factors for obesity.
Diabetes care, 2016
Type 2 diabetes (T2D) is associated with increased mortality in ethnically diverse populations, though the extent to which this association is genetically determined is unknown. We sought to determine whether T2D-related genetic variants predicted all-cause mortality, even after accounting for BMI, in the Third National Health and Nutrition Examination Survey. We modeled mortality risk using a genetic risk score (GRS) from a weighted sum of risk alleles at 38 T2D-related single nucleotide polymorphisms. In age-, sex-, and BMI-adjusted logistic regression models, accounting for the complex survey design, we tested the association with mortality in 6,501 participants. We repeated the analysis within ethnicities (2,528 non-Hispanic white [NHW], 1,979 non-Hispanic black [NHB], and 1,994 Mexican American [MA]) and within BMI categories (<25, 25-30, and ≥30 kg/m(2)). Significance was set at P < 0.05. Over 17 years, 1,556 participants died. GRS was associated with mortality risk (OR ...
International Journal of Obesity, 2012
Obesity is the major determinant of type 2 diabetes (T2D), presumably through its effect on insulin resistance. Genomewide association studies reported many single-nucleotide polymorphisms (SNPs) that increase obesity risk and body mass index (BMI), but their impact on T2D-related traits and risk is unclear. OBJECTIVE: We aimed at analyzing the effect of 24 obesity risk alleles, separately and in combination, on variation of both insulin resistance and b-cell dysfunction, and on T2D risk. DESIGN: We genotyped 24 obesity-associated SNPs and calculated an obesity genotype score (sum of the obesity risk alleles per individual). We analyzed the contribution of each SNP and this score to the variation of four metabolic indices: homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of the pancreatic b-cell function (HOMA-B), insulin sensitivity index (ISI) and insulinogenic index (II) (in up to 8050 nondiabetic French individuals) and to T2D risk (in 2077 T2D cases and 3085 controls). RESULTS: We found a highly significant effect of the obesity genotype score on increased insulin resistance adjusted for age and gender (b ¼ 0.02; P-value ¼ 7.16 Â 10 À 9 for HOMA-IR). Individually, we identified nominal or significant association between increased insulin resistance and risk alleles in FAIM2, FTO, GNPDA2, MC4R, NPC1, PTER and SH2B1. Most signals, including the obesity genotype score and FTO SNP, were also associated with increased b-cell function (b ¼ 0.01; P-value ¼ 1.05 Â 10 À 6 and b ¼ 0.04; P-value ¼ 3.45 Â 10 À 4 , respectively). In our T2D case-control study, only the obesity genotype score and the well-known FTO locus significantly contributed to T2D risk (OR ¼ 1.03; P-value ¼ 9.99 Â 10 À 3 and OR ¼ 1.15; P-value ¼ 9.46 Â 10 À 4 , respectively). Adjustment for BMI abolished all significant associations. CONCLUSIONS: Genetic predisposition to obesity contributes to increased insulin resistance and to its compensation through increased b-cell function, and weakly increases the T2D risk. These associations are mediated by BMI.
Biomarkers in medicine, 2016
Generally, obese and overweight individuals display higher free fatty acid levels, which stimulate insulin resistance. The combination of overweight or obesity with insulin resistance can trigger Type 2 diabetes mellitus (T2DM) and are primary contributing factors to the development of uncontrolled T2DM. Genetic polymorphisms also play an important role as they can impact a population's susceptibility to becoming overweight or obese and developing related chronic complications, such as uncontrolled T2DM. This review specifically examines the genetic polymorphisms associated with overweight and obesity in patients with uncontrolled T2DM. Particularly, gene polymorphisms in ADIPOQ (rs1501299 and rs17300539), LepR (rs1137101 and rs1045895), IRS2 (rs1805092), GRB14 (rs10195252 and rs3923113) and PPARG (rs1801282) have been associated with overweight and obesity in uncontrolled T2DM.
Genetic determinants of obesity heterogeneity in type II diabetes
Nutrition & Metabolism, 2020
Background Although obesity is considered as the main cause of Type II diabetes (T2DM), non-obese individuals may still develop T2DM and obese individuals may not. Method The mRNA expression of PI3K/AKT axis from 100 non-obese and obese participants with insulin sensitivity and insulin resistance states were compared in this study toward the understanding of obesity heterogeneity molecular mechanism. Result In present study, there was no statistically significant difference in gene expression levels of IRS1 and PTEN between groups, whereas PI3K, AKT2 and GLUT4 genes were expressed at a lower level in obese diabetic group compared to other groups and were statistically significant. PDK1 gene was expressed at a higher level in non-obese diabetic group compared to obese diabetic and non-obese non-diabetics groups. No statistically significant difference was identified in gene expression pattern of PI3K/AKT pathway between obese non-diabetics and non-obese non-diabetics. Conclusion The ...