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Translator: Liao Zhanlin The First Hospital of Nanping City, Fujian Province
Introduction: From September 19 to 23, 2022, the international conference in the field of endocrinology "2022 European Association for Diabetes Research Annual Meeting" was held
in Stockholm, Sweden in the form of "online + offline".
At the meeting, some scholars shared a study entitled "Hereditary Study of Serum C-peptides in Type 1 Diabetes", and found that the HLA regional variability of type 1 diabetes mellitus is related to C-peptide levels, while the DR-DQGRS score is not related to C-peptide levels, which may provide direction
for the final revelation of the mechanism of maintaining β cell function.
Correlation between genetic risk of type 1 diabetes mellitus and C-peptide
The genetic probability of type 1 diabetes serum C-peptide is 26%, and two previous independent genome-wide association analysis (GWAS) studies of type 1 diabetes C-peptide have identified multiple loci and one site on chromosome 1 in the human leukocyte antigen (HLA) region and insulin (INS) gene region
.
Although some of these sites were found to coincide with these sites for type 1 diabetes, the other part was independent, and these identified sites accounted for only a small fraction
of the C-peptide gene variant.
Therefore, in order to improve statistical power and find new sites, a large-scale C-peptide GWAS-meta-analysis was conducted and two previous GWAS studies
were included.
This study analyzed the correlation between the genetic risk (GRS) score for type 1 diabetes in the HLA region and C-peptides
.
Four trials involving a total of 7248 patients with type 1 diabetes mellitus of non-European descent were included in the study, including the SDRNT1BIO study (4824 cases with random C-peptide levels), the DCCT (sample size 1304 cases, fasting C-peptide level) study, the CACT1 study (sample size 529, fasting C-peptide level), and the WESDR study (sample size 591, randomized C-peptide level).
。 Genotyping in GWAS is done by the Illumina gene chip; Non-genotypic variants are done by the TOPMed platform, the largest reference template to date, which introduces smaller frequency gene variants and has better analytical capabilities
than previous reference templates.
Both the SDRNT1BIO study and the DCCT study showed their ability to analyze single nucleotide polymorphisms (SNPs) and high attribution analysis capabilities (INFO>0.
80) of small alleles with frequenc>ies of 8150645.
01, both of which were included in the GWAS-meta-analysis study with a sample size of cases
.
Use the multiracial HLA reference template from the Michigan estimation server to evaluate classic HLA alleles, amino acid sequences, and additionally discovered SNPs sites in the HLA region
.
The effect amount and standard error
of the study were assessed by multiple linear regression of C-peptide after correcting some covariates (sex, age at diagnosis, course of disease).
This GWAS-meta-analysis weights the amount of effect using the standard error reciprocal of
the METALv1.
5 tool.
The study examined the correlation
between the type 1 diabetes GRS score and C-peptide levels in the HLA region.
GRS scores in the HLA region of type 1 diabetes were co-analyzed and used to distinguish between DR-DQ and non-DR-DQ haploids
.
Non-DR-DQ haploids are divided into classical type 1, DPB1 and the inter-region gene located between DRB1 and DQA1 that is not located at the classical HLA site but regulates the expression of HLA-II genes
.
Type 1 diabetes mellitus HLA regional variability is associated with C-peptide levels, while DR-DQGRS scores are the opposite
The study identified relevant sites in the HLA region, including the rs9271349 gene (A/G, Chr6:32616053) (β(SE)=0.
57(0.
08), p=1.
62E-12).
In HLA attribution, DRB1*06:02 [β(SE)=0.
90(0.
11), p=1.
18E-16] gene and
DRB1*15:01 gene [β(SE)=0.
70(0.
10), p=1.
68E-12] is correlated
.
Five amino acid changes in HLA-DRB1, HLA-DQB1 and HLA-A reached the genome-wide significance threshold
.
In all four studies, the DR-DQGRS score was not associated with C-peptide levels, while the non-DR-DQGRS score was associated with low C-peptide levels, SDRNT1BIO (β=-0.
17, p=2.
00E-8), DCCT (β=-0.
06, p=0.
045), CACTI (β=-0.
08, p=0.
015), and WESDR (β=-0.
10, p=6.
44E-4).
。 The main ones come from HLAI genes (A*2402, B*3906, A*2902) and interm-region genes (rs9271346, rs116522341, rs1281934).
HLA-A*2402, HLA-B*3906, and intergene region GRS scores are associated with low C-peptide levels, while HLA-A*2902GRS scores correlate
with high C-peptide levels.
conclusion
In terms of correlation with C-peptide levels, HLA regional variability in type 1 diabetes mellitus is correlated with it, and type 1 diabetes DR-DQGRS scores are not correlated with C-peptide levels, which may provide direction for the eventual revelation of mechanisms that preserve β cell function and the possibility
of protecting β cell function.
Introduction of translators
Liao Zhanlin
Master of Medicine
He currently presides over a project of Fujian Provincial Science and Natural Foundation
Good at diabetes, thyroid disease, adrenal disease diagnosis and treatment
.