The <i>TCF7L2</i> Locus: A Genetic Window Into the Pathogenesis of Type 1 and Type 2 Diabetes

Grant, Struan F A

doi:10.2337/dci19-0001

Cited by 48 publications

(43 citation statements)

References 51 publications

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“…The potential relationship between obesity-induced inflammation and autoimmune disease, including islet autoimmunity, could also underlie our previous observations that the type 2 diabetesassociated TCF7L2 genetic variant, which may be involved in fatty acid metabolism (39), accelerates antigen spreading in individuals with a single positive ICA512/IA-2 or insulin autoantibody who are obese or overweight (40). In this smaller study of pediatric and adult TrialNet participants who had available ImmunoChip data, the effect of ceBMI or age strata was not evaluated.…”

Section: Discussionmentioning

confidence: 73%

Excess BMI Accelerates Islet Autoimmunity in Older Children and Adolescents

et al. 2020

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Sustained excess BMI increases the risk of type 1 diabetes (T1D) in autoantibodypositive relatives without diabetes of patients. We tested whether elevated BMI also accelerates the progression of islet autoimmunity before T1D diagnosis. RESEARCH DESIGN AND METHODS We studied 706 single autoantibody-positive pediatric TrialNet participants (ages 1.6-18.6 years at baseline). Cumulative excess BMI (ceBMI) was calculated for each participant based on longitudinally accumulated BMI ‡85th age-and sex-adjusted percentile. Recursive partitioning analysis and multivariable modeling defined the age cut point differentiating the risk for progression to multiple positive autoantibodies. RESULTS At baseline, 175 children (25%) had a BMI ‡85th percentile. ceBMI range was 29.2 to 15.6 kg/m 2 (median 21.91), with ceBMI ‡0 kg/m 2 corresponding to persistently elevated BMI ‡85th percentile. Younger age increased the progression to multiple autoantibodies, with age cutoff of 9 years defined by recursive partitioning analysis. Although ceBMI was not significantly associated with progression from single to multiple autoantibodies overall, there was an interaction with ceBMI ‡0 kg/m 2 , age, and HLA (P 5 0.009). Among children ‡9 years old without HLA DR3-DQ2 and DR4-DQ8, ceBMI ‡0 kg/m 2 increased the rate of progression from single to multiple positive autoantibodies (hazard ratio 7.32, P 5 0.004) and conferred a risk similar to that in those with T1D-associated HLA haplotypes. In participants <9 years old, the effect of ceBMI on progression to multiple autoantibodies was not significant regardless of HLA type. CONCLUSIONS These data support that elevated BMI may exacerbate islet autoimmunity prior to clinicalT1D, particularly inchildren with lower risk based on age and HLA.Interventions to maintain normal BMI may prevent or delay the progression of islet autoimmunity. The global rise in incidence of type 1 diabetes (T1D) has intensified efforts to identify modifiable risk factors in order to prevent or delay onset of clinical diabetes (1). Although there are several genetic loci for T1D susceptibility, heritability does not completely predict appearance of islet autoantibodies or disease development (2), highlighting the role of other influences such as the environment (3). The parallel rise in obesity (4,5) and T1D incidence suggests a potential link between elevated body weight and T1D progression (6-9). The accelerator hypothesis proposes that obesity-induced insulin resistance triggers the autoimmune-mediated b-cell

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Section: Discussionmentioning

confidence: 73%

Excess BMI Accelerates Islet Autoimmunity in Older Children and Adolescents

et al. 2020

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“…In the current study, long-term weight gain of participants modified the effects of nut consumption on the MetS risk, based on rs12255372 and rs7903146 polymorphisms of the TCF7L2 gene, suggesting an interplay of BMI and genetic susceptibility on the association of nut consumption and MetS incidence. The effect of TCF7L2 variants on risk of type 2 diabetes and obesity as well as modulation effect of BMI on the association between diabetes and TCF7L2 variants, have been controversial [ 26 , 27 , 43 ]. This discrepancy, at least in part, may be attributed to the extent of linkage disequilibrium in different population [ 8 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

TCF7L2 polymorphisms, nut consumption, and the risk of metabolic syndrome: a prospective population based study

et al. 2021

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Background The aim of this study was to investigate whether two variants of the TCF7L2 (rs7903146 and rs12255372) modify the association between nut consumption and the risk of metabolic syndrome (MetS). Additionally, the modifying effect of weight change during follow-up on these associations was investigated. Material and methods We prospectively studied 1423 participants of the Tehran Lipid and Glucose study aged 19–74 years who were followed-up for dietary assessment using a validated, semi-quantitative food frequency questionnaire. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) for MetS events. Genotyping was performed by Human Omni Express-24-v1-0 chip. Results Over a median 8.9 years of follow-up, 415 new cases of MetS were documented. The median nut consumption was 20.0 g/week (Interquartile Range (IQR): 8.6–38.9 g/week). Regarding the rs7903146 genotype, in carriers of T allele (CT + TT), highest tertile of nut consumption was associated with a reduced risk of MetS after adjusting for confounders (HR: 0.67 (0.50–0.91)). Regarding the rs12255372 genotype, highest versus lowest tertile of nut consumption in participants with T allele (GT + TT) resulted in 34% reduction of MetS risk after adjustment for confounders (HR: 0.66 (0.49–0.69)). After stratification by weigh change (< 7% or ≥ 7% weight gain), in individuals with ≥ 7% weight gain, highest tertile of nut consumption was associated with reduced risk of MetS among the risk allele of rs7903146. In the risk allele of rs12255372, among individuals with < 7% weight gain, third tertile of nuts intake reduced the risk of MetS, after adjustment for confounders. Conclusion Higher consumption of nuts may reduces the risk of MetS in T-risk allele of the TCF7L2 rs7903146 and rs12255372 variants and weight change may modify this association.

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“…84,103,129,130 However, there are an increasing molecular evidence that emphasized on the role of some variants in coding regions as causative genes that associated with T2D. 112,131,132 The sibling-relative risk for T2D is 3 compared with 15 for T1D. 84,133 Genetic studies revealed the concordance of T2D in monozygotic twins is about 70% to 90%, while it is only 20% to 30% in dizygotic twins.…”

Section: Genetics and Architecture Of T2dmentioning

confidence: 99%

“…So far, many susceptibility and predisposition genetic loci have been described and found to be influenced by other environmental factors such as obesity and life style effects 84,103,129,130 . However, there are an increasing molecular evidence that emphasized on the role of some variants in coding regions as causative genes that associated with T2D 112,131,132 …”

Section: Overview Of T2dmentioning

confidence: 99%

Genetic predisposition in type 2 diabetes: A promising approach toward a personalized management of diabetes

Sirdah

Reading

2020

Clinical Genetics

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Diabetes mellitus, also known simply as diabetes, has been described as a chronic and complex endocrine metabolic disorder that is a leading cause of death across the globe. It is considered a key public health problem worldwide and one of four important non-communicable diseases prioritized for intervention through world health campaigns by various international foundations. Among its four categories, Type 2 diabetes (T2D) is the commonest form of diabetes accounting for over 90% of worldwide cases. Unlike monogenic inherited disorders that are passed on in a simple pattern, T2D is a multifactorial disease with a complex etiology, where a mixture of genetic and environmental factors are strong candidates for the development of the clinical condition and pathology. The genetic factors are believed to be key predisposing determinants in individual susceptibility to T2D. Therefore, identifying the predisposing genetic variants could be a crucial step in T2D management as it may ameliorate the clinical condition and preclude complications. Through an understanding the unique genetic and environmental factors that influence the development of this chronic disease individuals can benefit from personalized approaches to treatment. We searched the literature published in three electronic databases: PubMed, Scopus and ISI Web of Science for the current status of T2D and its associated genetic risk variants and discus promising approaches toward a personalized management of this chronic, non-communicable disorder.

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The TCF7L2 Locus: A Genetic Window Into the Pathogenesis of Type 1 and Type 2 Diabetes

Cited by 48 publications

References 51 publications

Excess BMI Accelerates Islet Autoimmunity in Older Children and Adolescents

Excess BMI Accelerates Islet Autoimmunity in Older Children and Adolescents

TCF7L2 polymorphisms, nut consumption, and the risk of metabolic syndrome: a prospective population based study

Genetic predisposition in type 2 diabetes: A promising approach toward a personalized management of diabetes

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