The Association of CTLA-4 rs231775 and rs3087243 Polymorphisms with Latent Autoimmune Diabetes in Adults: A Meta-Analysis

Abstract Objective: Latent autoimmune diabetes in adults (LADA) has been shown in recent studies to have heterogeneous pathophysiology and phenotype. Although insulin is considered as the therapeutic choice for these patients, other antidiabetic drugs have been studied in terms of glycemic control and beta cell function preservation. In particular, dipeptidyl peptidase-4 (DPP-4) inhibitors have shown immunomodulatory effects in animal models since it was demonstrated a higher DPP-4 activity in patients with LADA compared to patients with Type 1 and Type 2 diabetes suggesting a possible effect on autoimmunity found in LADA. This study aims to review the outcomes of the included studies and evaluate the efficacy of DPP-4 inhibitors in the treatment of LADA. Methods: We searched Medline, Embase, PubMed and Cochrane Library Databases and ClinicalTrials.gov for studies concerning the use of DPP4 inhibitors in patients with latent autoimmune diabetes in adults (LADA). Results: Preclinical studies demonstrated drug’s immunomodulatory effects in terms of suppression of inflammatory processes and oxidative stress providing endothelial protection leading to improved metabolic control and prevention of vasculopathy. From this meta-analysis, pooled data from 8 randomized controlled trials revealed that the use of DPP-4 inhibitors in LADA patients resulted in an improved glycemic control, decreased insulin requirement and increased beta cell function as assessed by a decrease in GADA titers, increased C peptide levels and HOMA B. Conclusion: Beneficial effects of DPP4 inhibitors are shown by the included studies indicating that they are promising therapeutic agents for patients with LADA. However, caution should still be exercised since there is still much to learn about the disease itself and larger scale prospective randomized trials are needed to assess the efficacy and safety of DPP4 inhibitors for these patients.

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Prevalence of latent autoimmune diabetes in adults in China: a systematic review and meta-analysis

The Lancet Diabetes & Endocrinology ◽

10.1016/s2213-8587(16)30392-8 ◽

2016 ◽

Vol 4 ◽

pp. S37

Author(s):

Bin Wang ◽

Jianghong Yuan ◽

Qiuming Yao ◽

Ling Li ◽

Ni Yan ◽

...

Keyword(s):

Systematic Review ◽

Autoimmune Diabetes ◽

Meta Analysis ◽

Latent Autoimmune Diabetes

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Sugary beverages consumption and latent autoimmune diabetes in adults: systematic review and meta-analysis

Clinical Diabetology ◽

10.5603/dk.2020.0007 ◽

2020 ◽

Vol 9 (2) ◽

pp. 118-127

Author(s):

Ahmed Mahmoud El-Malky ◽

Ramachandra G Naik ◽

Azza A Elnouman

Keyword(s):

Systematic Review ◽

Autoimmune Diabetes ◽

Meta Analysis ◽

Latent Autoimmune Diabetes ◽

Sugary Beverages

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The Association of CTLA-4 rs231775 and rs3087243 Polymorphisms With Latent Autoimmune Diabetes in Adults: A Meta-analysis

10.21203/rs.3.rs-744970/v1 ◽

2021 ◽

Author(s):

Haipeng Pang ◽

Shuoming Luo ◽

Gan Huang ◽

Xia Li ◽

Zhiguo Xie ◽

...

Keyword(s):

Genetic Model ◽

Autoimmune Diabetes ◽

Meta Analysis ◽

Control Group ◽

Case Control Studies ◽

Recessive Genetic Model ◽

Latent Autoimmune Diabetes ◽

Genotype Frequencies ◽

Dominant Genetic Model ◽

Subgroup Analyses

Abstract BackgroundPolymorphisms rs231775 and rs3087243 of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) gene have been associated with risk of latent autoimmune diabetes in adults (LADA). However, the results were inconsistent. The purpose of this study was to quantitatively assess the relationship between polymorphisms rs231775 and rs3087243 of CTLA-4 and LADA in a larger pooled population by performing a meta-analysis. MethodsSystematic search for eligible studies was conducted in PubMed, Web of Science, and Embase. Case-control studies containing genotype frequencies of polymorphisms rs231775 or rs3087243 of CTLA-4 gene were selected, and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the associations between polymorphisms of CTLA-4 and LADA in allelic genetic model, dominant genetic model, and recessive genetic model. ResultsA total of eleven studies, in which five studies reported rs231775, two studies reported rs3087342, and four studies reported both rs231775 and rs3087243, were identified. Among them, one study wasn’t included in the following meta-analysis because the distribution of genotypes in the control group didn’t comply with Hardy-Weinberg equilibrium. Significant associations with susceptibility to LADA were detected for rs231775 (785 cases and 3435 controls, allelic genetic model OR 1.53, 95%CI 1.22-1.92; dominant genetic model OR 2.16, 95%CI 1.43-3.28; recessive genetic model OR 1.49, 95%CI 1.13-1.97) and for rs3087243 (820 cases and 4824 controls, allelic genetic model OR 1.26, 95%CI 1.03-1.55; dominant genetic model OR 1.11, 95%CI 0.88-1.40; recessive genetic model OR 1.41, 95%CI 1.07-1.86) in overall population. Further subgroup analyses for ethnicity (Asian, Caucasian, and African) have also indicated the positive association between rs231775 and LADA. As for rs3087243, subgroup analyses detected the association between polymorphism and LADA in Caucasian population under recessive model. ConclusionsPolymorphisms rs231775 and rs3087243 of CTLA-4 gene are potential risk factors for LADA and may serve as novel genetic biomarkers of LADA.

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HLA-DQB1 and HLA-DRB1 Variants Confer Susceptibility to Latent Autoimmune Diabetes in Adults: Relative Predispositional Effects among Allele Groups

Genes ◽

10.3390/genes10090710 ◽

2019 ◽

Vol 10 (9) ◽

pp. 710 ◽

Cited By ~ 1

Author(s):

Zhang ◽

Lin ◽

Yuan ◽

Lin ◽

Huang

Keyword(s):

Autoimmune Diabetes ◽

Meta Analysis ◽

Human Leukocyte ◽

Protective Effects ◽

Case Control Studies ◽

Leukocyte Antigen ◽

Latent Autoimmune Diabetes ◽

Close Relationship ◽

The Relationship ◽

Autoimmune Diabetes Mellitus

Latent autoimmune diabetes in adults (LADA) was recently demonstrated to be the most frequent form of adult-onset autoimmune diabetes mellitus. Case–control studies have investigated the relationship between human leukocyte antigen (HLA)-DQB1 and HLA-DRB1 polymorphisms and LADA risk, but their conclusions are inconsistent. This study aimed to more precisely explore the correlation between these HLA gene variants and LADA development. Eight databases, including PubMed, Embase, and Medline, were systematically searched for relevant studies up to September 15, 2018. We performed this retrospective study using meta-analysis and relative predispositional effect (RPE) methods. The meta-analysis results indicated that DQB1*02 (odds ratio (OR) = 1.685, pc < 0.005) and DQB1*06 (OR = 0.604, pc = 0.010) have opposite effects on susceptibility to LADA, while a significant decrease in LADA risk caused by DQB1*05 (OR = 0.764, pc = 0.100) disappeared upon Bonferroni correction. The RPE method confirmed the roles of DQB1*02 (χ² = 46.475, p < 0.001) and DQB1*06 (χ² = 17.883, p < 0.001) and further suggested protective effects of DQB1*05 (χ² = 16.496, p < 0.001). Additionally, the meta-analysis results showed that DRB1*03 (OR = 2.685, pc < 0.013), DRB1*04 (OR = 1.954, pc < 0.013), and DRB1*09 (OR = 1.346, pc < 0.013) are associated with increased LADA risk, while DRB1*12 (OR = 0.600, pc < 0.013) and DRB1*13 (OR = 0.583, pc < 0.013) carriers have a decreased risk of developing LADA. Furthermore, the RPE method revealed that DRB1*03 (χ² = 98.754, p < 0.001), DRB1*04 (χ² = 94.685, p < 0.001), DRB1*09 (χ² = 40.489, p < 0.001), DRB1*01 (χ² = 12.181, p < 0.001), DRB1*07 (χ² = 10.882, p = 0.001), and DRB1*08 (χ² = 5.000, p = 0.025) play protective roles against LADA. LADA showed a close relationship with genetic polymorphisms of HLA-DQB1 and WHLA-DRB1, which could contribute to a better understanding of disease pathogenesis and the identification of predisposing loci in the diagnosis and treatment of LADA.

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