AUTHOR=Robino Antonietta , Bevilacqua Elena , Aldegheri Luana , Conti Andrea , Bazzo Valentina , Tornese Gianluca , Catamo Eulalia 

TITLE=Next-generation sequencing reveals additional HLA class I and class II alleles associated with type 1 diabetes and age at onset

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1427349

DOI=10.3389/fimmu.2024.1427349

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p>Type 1 diabetes is an autoimmune disease with an significant genetic component, played mainly by the <italic>HLA</italic> class II genes. Although evidence on the role of <italic>HLA</italic> class I genes in developing type 1 diabetes and its onset have emerged, current <italic>HLA</italic> screening is limited to determining DR3 and DR4 haplotypes. This study aimed to investigate the role of <italic>HLA</italic> genes on type 1 diabetes risk and age of onset by extensive typing.</p></sec><sec><title>Methods</title><p>This study included 115 children and young adults with type 1 diabetes for whom typing of <italic>HLA-A</italic>, <italic>-B</italic>, <italic>-C</italic>, <italic>-DRB1</italic>, <italic>-DRB3/4/5</italic>, <italic>-DQA1</italic>, <italic>-DQB1</italic>, <italic>-DPA1</italic> and <italic>-DPB1</italic> genes was conducted using Next Generation Sequencing.</p></sec><sec><title>Results</title><p>We observed that 13% of type 1 diabetes subjects had non-classical <italic>HLA</italic> haplotypes that predispose to diabetes. We also found that compared to type 1 diabetes subjects with classical <italic>HLA</italic> haplotypes, non-classical <italic>HLA</italic> subjects had a significantly higher frequency of <italic>HLA-B*39:06:02</italic> (p-value=0.01) and <italic>HLA-C*07:02:01</italic> (p-value=0.03) alleles, known to be involved in activating the immune response. Non-classical <italic>HLA</italic> subjects also presented peculiar clinical features compared to classical HLA subjects, such as multiple diabetic antibodies and the absence of other autoimmune diseases (i.e., coeliac disease and thyroiditis). We also observed that subjects with early onset had a higher frequency of DQ2/DQ8 genotype than late-onset individuals. Moreover, subjects with late-onset had a higher frequency of alleles <italic>HLA-B*27</italic> (p-value=0.003), <italic>HLA-C*01:02:01</italic> (p-value=0.027) and <italic>C*02:02:02</italic> (p-value=0.01), known to be associated with increased protection against viral infections.</p></sec><sec><title>Discussion</title><p>This study reveals a broader involvement of the <italic>HLA</italic> locus in the development and onset of type 1 diabetes, providing insights into new possible disease prevention and management strategies.</p></sec>