Newly identified set of obesity‐related genotypes and abdominal fat influence the risk of insulin resistance in a Korean population

Kim, Minjoo; Jeong, Sarang; Yoo, Hye Jin; An, H M; Jee, Sun Ha; Lee, Jong Ho

doi:10.1111/cge.13509

Cited by 6 publications

(3 citation statements)

References 44 publications

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“…Previous human studies on FARP1 and fatty liver suggested that FARP1 rs9584805 might be related to NAFLD pathology 36 . Another study has demonstrated that other SNPs in FARP1, like rs2127779, were associated with obesity in the Korean population 37 . Our data suggest strong support regarding the role of FARP1 in the pathophysiology of NAFLD, which might be mediated by the effects of rs9584805 on liver fat.…”

Section: Discussionsupporting

confidence: 69%

“…36 Another study has demonstrated that other SNPs in FARP1, like rs2127779, were associated with obesity in the Korean population. 37 Our data suggest strong support regarding the role of FARP1 in the pathophysiology of NAFLD, which might be mediated by the effects of rs9584805 on liver fat. Although the Causal Inference Test 38 did not robustly support the causal role of DNA methylation as a mediator between genotype and outcome (IHF%) in our sample set, methylation-genetic variation cross talk should be considered, 39 by, eg, transcription factors binding to gene target promoters gated by promoter methylation.…”

Section: Discussionsupporting

confidence: 61%

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Effects of lifestyle interventions on epigenetic signatures of liver fat: Central randomized controlled trial

Meir

Keller

Müller³

et al. 2021

Liver International

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Background and Aims In the CENTRAL trial context, we found diverse liver fat dynamics in response to different dietary interventions. Epigenetic mechanisms may contribute to the intraindividual variation. Moreover, genetic factors are involved in developing nonalcoholic fatty‐liver disease (NAFLD), a disease reflected by an increase in intrahepatic fat (IHF). In this exploratory analysis, we primarily aimed to examine the effect of lifestyle interventions on DNA‐methylation of NAFLD related genes associated with IHF. Methods For 120 participants from the CENTRAL trial, an 18‐month regimen of either low‐fat (LF) or Mediterranean‐low carbohydrate (MED/LC) diets, with or without physical activity (PA+/PA−), was instructed. Magnetic resonance imaging was used to measure IHF%, which was analysed for association with CpG specific DNA‐methylation levels of 41 selected candidate genes. Single‐nucleotide polymorphisms known to be associated with NAFLD within the studied genes were genotyped by TaqMan assays. Results At baseline, participants (92% men; body mass index = 30.2 kg/m2) had mean IHF of 10.7% (59% NAFLD). Baseline‐IHF% was inversely correlated with DNA‐methylation at individual CpGs within AC074286.1, CRACR2A, A2MP1, FARP1 (P < .05 for all multivariate models). FARP1 rs9584805 showed association with IHF, with the prevalence of NAFLD and baseline methylation level of the CpG site (cg00071727) associated with IHF%. Following 18‐month lifestyle intervention, differential DNA‐methylation patterns were observed between diets at cg14335324 annotated to A2MP1 (P = .04, LF vs. MED/LC), and differential DNA‐methylation between PA groups within AC074286.1, CRACR2A, and FARP1 CpGs (P < .05 for all, PA−vs. PA+). Conclusions This study suggests epigenetic markers for IHF and potential epigenetic remodeling after long‐term lifestyle interventions.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionsupporting

confidence: 61%

Effects of lifestyle interventions on epigenetic signatures of liver fat: Central randomized controlled trial

Meir

Keller

Müller³

et al. 2021

Liver International

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“…Kim et al [58] reported that a 20-SNP obesity GRS showed a significantly greater effect on fasting insulin concentration for men with waist circumferences ≥90 cm and women with waist circumferences ≥85 cm (β = 0.037 ± 0.03) than in less centrally obese subjects (β = 0.003 ± 0.016, p interaction < 0.001). The corresponding effect sizes for HOMA-IR were β = 0.044 ± 0.027 in the wider-waisted participants versus β = 0.001 ± 0.015 in the narrowerwaisted participants (p interaction < 0.001).…”

Section: Adipositymentioning

confidence: 99%

Quantile-Dependent Heritability of Glucose, Insulin, Proinsulin, Insulin Resistance, and Glycated Hemoglobin

Williams¹

2021

Lifestyle Genomics

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Background: “Quantile-dependent expressivity” is a dependence of genetic effects on whether the phenotype (e.g., insulin resistance) is high or low relative to its distribution. Methods: Quantile-specific offspring-parent regression slopes (βOP) were estimated by quantile regression for fasting glucose concentrations in 6,453 offspring-parent pairs from the Framingham Heart Study. Results: Quantile-specific heritability (h2), estimated by 2βOP/(1 + rspouse), increased 0.0045 ± 0.0007 (p = 8.8 × 10−14) for each 1% increment in the fasting glucose distribution, that is, h2 ± SE were 0.057 ± 0.021, 0.095 ± 0.024, 0.146 ± 0.019, 0.293 ± 0.038, and 0.456 ± 0.061 at the 10th, 25th, 50th, 75th, and 90th percentiles of the fasting glucose distribution, respectively. Significant increases in quantile-specific heritability were also suggested for fasting insulin (p = 1.2 × 10−6), homeostatic model assessment of insulin resistance (HOMA-IR, p = 5.3 × 10−5), insulin/glucose ratio (p = 3.9 × 10−5), proinsulin (p = 1.4 × 10−6), proinsulin/insulin ratio (p = 2.7 × 10−5), and glucose concentrations during a glucose tolerance test (p = 0.001), and their logarithmically transformed values. Discussion/Conclusion: These findings suggest alternative interpretations to precision medicine and gene-environment interactions, including alternative interpretation of reported synergisms between ACE, ADRB3, PPAR-γ2, and TNF-α polymorphisms and being born small for gestational age on adult insulin resistance (fetal origin theory), and gene-adiposity (APOE, ENPP1, GCKR, IGF2BP2, IL-6, IRS-1, KIAA0280, LEPR, MFHAS1, RETN, TCF7L2), gene-exercise (INS), gene-diet (ACSL1, ELOVL6, IRS-1, PLIN, S100A9), and gene-socioeconomic interactions.

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Sexual Dimorphism of a Genetic Risk Score for Obesity and Related Traits among Chinese Patients with Type 2 Diabetes

et al. 2019

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Background: Obesity is more prevalent in men than in women in China, especially within the middle-aged population. Objectives: The present study aims to determine the contribution of sexual dimorphisms to obesity and related traits in terms of the mechanisms involving the obesity-related genetic variants among patients of Chinese Han ancestry with type 2 diabetes. Method: In the Chinese National Diabetes and Metabolic Disorders Study, 2,555 out of 4,036 patients with type 2 diabetes were treatment naive, including 1,142 men and 1,413 women. Single-nucleotide polymorphisms (SNP) from 18 genomic loci previously found to be associated with obesity-related traits were successfully genotyped, and a genetic risk score (GRS) was constructed by summing the risk alleles for obesity. Results: Single SNP analysis showed that genetic variants in SLC30A10, TMEM18, GNPDA2, PRL, TFAP2B, BDNF, MTCH2, FTO, and MC4R were nominally associated with waist circumference (WC), BMI, and risk for abdominal or general obesity in the untreated patients with type 2 diabetes, as well as in the total group of patients with type 2 diabetes (untreated and treated) (p < 0.05). Interactions between sex and SNP in PRL, MTCH2,and FTO were detected (p < 0.05). In the untreated patients with diabetes, the GRS was nominally associated with WC (β = 0.0032, SE = 0.0011; p = 0.003), BMI (β = 0.0030, SE = 0.0013; p = 0.027), and increased risk for abdominal (OR = 1.08; 95% CI 1.02–1.13; p = 0.004) or general obesity (OR = 1.07; 95% CI 1.02–1.13; p = 0.011) in men but not in women. GRS-sex interactions were detected in the determinant of WC (p = 0.019) and abdominal obesity (p = 0.016). Among patients aged 30–60 years, GRS was found to be significantly associated with WC (β = 0.0050, SE = 0.0016; p = 0.002) and abdominal obesity (OR = 1.10; 95% CI 1.04–1.17; p = 0.001) and nominally associated with BMI (β = 0.0057, SE = 0.0020; p = 0.005) and general obesity (OR = 1.07; 95% CI 1.01–1.14; p = 0.027) in men, whereas in women none of the associations were detected. GRS-sex interactions were present in the determinant of WC (p = 0.015), BMI (p = 0.032), and abdominal obesity (p = 0.012). Among patients aged 60 years or older, neither an association of GRS with obesity-related traits nor GRS-sex interactions were detected. Conclusions: Genetic factors contribute to obesity-related traits in a sex-dependent pattern among middle-aged Chinese, and men tend to be more susceptible to the genetic risk of obesity.

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Newly identified set of obesity‐related genotypes and abdominal fat influence the risk of insulin resistance in a Korean population

Cited by 6 publications

References 44 publications

Effects of lifestyle interventions on epigenetic signatures of liver fat: Central randomized controlled trial

Effects of lifestyle interventions on epigenetic signatures of liver fat: Central randomized controlled trial

Quantile-Dependent Heritability of Glucose, Insulin, Proinsulin, Insulin Resistance, and Glycated Hemoglobin

Sexual Dimorphism of a Genetic Risk Score for Obesity and Related Traits among Chinese Patients with Type 2 Diabetes

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