Genome-wide Association Study of Different Types of Diabetes and Construction of Genetic Risk Score

A Type 1 Diabetes Genetic Risk Score Discriminates Between Type 1 Diabetes and Type 2 Diabetes in Chinese

To enhance the genetic profile of T1D patients in China and construct a Chinese-specific GRS and evaluated its ability to differentiate between T1D and controls, as well as between T1D and T2D.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes

Detailed Description

Type 1 diabetes (T1D) is caused by autoimmune destruction of pancreatic beta cells, leading to severe insulin deficiency and requires life-long insulin therapy. Although traditionally viewed as a disease primarily affecting children and adolescents, recent epidemiological studies have demonstrated that over half of all new-onset T1D cases worldwide occur in adults. At present, methods to differentiate adult-onset T1D from T2D rely on the clinical phenotypes such as onset age and pattern, body mass index (BMI), C-peptide levels, and islet autoantibodies. However, the increasing rates of obesity in T1D, the presence of ketosis-prone T2D and idiopathic T1D, as well as unavailable autoantibody detection in some districts make it an increasing difficult challenge to accurately classify between adult-onset T1D and T2D. The discrimination of diabetes types is more challenging in the Chinese population due to the higher prevalence of early-onset T2D at a lower BMI than in European populations. Incorrectly identifying T1D as T2D can result in inadequate control of blood glucose levels, an elevated risk of ketoacidosis, and potentially severe and life-endangering complications. Therefore, it is crucial to search for new discriminative methods for different types of diabetes.

The genetic pathogenesis of T1D and T2D differ significantly, allowing for the differentiation of diabetes types based on genetic information. A T1D genetic risk score (GRS), comprising 31 HLA and non-HLA T1D-associated single nucleotide polymorphisms (SNPs), can be a useful tool to aid the discrimination between T1D and T2D. GRS2, which improved SNP capture of HLA DR-DQ risk including haplotype interactions and added non-DR-DQ loci, showed better discriminative power for the classification of diabetes type among multiethnic youth.

In this study, we employed GWAS to enhance the genetic profile of T1D patients in China. Additionally, our aim was to identify SNP tags for the HLA DR-DQ risk in the Chinese population, which could capture HLA DR-DQ risk and the interactions between these haplotypes. Using this information, we constructed a Chinese-specific GRS and evaluated its ability to differentiate between T1D and controls, as well as between T1D and T2D.

• Study Type: Observational
• Enrollment (Actual): 7000

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Subjects in these three groups were matched by age and sex.

Description

Inclusion Criteria:

• All diagnoses for diabetes were required to adhere to the 1999 World Health Organization diabetes diagnosis criteria. Type 1 diabetes mellitus patients needed to meet specific criteria, including insulin dependence in the first 6 months and the presence of at least one designated islet autoantibody: glutamic acid decarboxylase antibody (GADA), protein tyrosine phosphatase antibody (IA-2A) and zinc transporter 8 antibody (ZnT8A). Type 2 diabetes mellitus patients also needed to show negative results for all three islet autoantibodies at onset. Controls were defined as individuals without diabetes or a family history of diabetes within the same geographic area who had normal oral glucose tolerance test results.

Exclusion Criteria:

• Subjects with the following conditions were excluded: severe gastrointestinal, cardiovascular, cerebrovascular, liver or kidney diseases; other autoimmune diseases; a history of gastrointestinal surgery; tumours; pregnancy; treatments with oral hypoglycaemic agents or immunomodulators; and use of probiotics, prebiotics or antibiotics within one month.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Controls; Controls were defined as individuals without diabetes or a family history of diabetes within the same geographic area who had normal oral glucose tolerance test results
Type 1 diabetes; All diagnoses for diabetes were required to adhere to the 1999 World Health Organization diabetes diagnosis criteria. Type 1 diabetes mellitus patients needed to meet specific criteria, including insulin dependence in the first 6 months and the presence of at least one designated islet autoantibody: glutamic acid decarboxylase antibody (GADA), protein tyrosine phosphatase antibody (IA-2A) and zinc transporter 8 antibody (ZnT8A).
Type 2 diabetes; All diagnoses for diabetes were required to adhere to the 1999 World Health Organization diabetes diagnosis criteria. Type 2 diabetes mellitus patients also needed to show negative results for all three islet autoantibodies at onset, including glutamic acid decarboxylase antibody (GADA), protein tyrosine phosphatase antibody (IA-2A) and zinc transporter 8 antibody (ZnT8A).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identified single nucleotide polymorphisms that reach genome-wide significance	Single nucleotide polymorphisms should reach the genome-wide significance，which is defined as a P value of smaller than 5e-8.	at baseline

Collaborators and Investigators

• Sponsor: Second Xiangya Hospital of Central South University

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2010
• Primary Completion (Actual): April 1, 2024
• Study Completion (Actual): April 1, 2024

Study Registration Dates

• First Submitted: January 20, 2025
• First Submitted That Met QC Criteria: January 20, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 20, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: type 2 diabetes; type 1 diabetes; genetic risk score; genome-wide association study
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: 2019GRS

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No