A study of biomarker analysis in association with type 1 diabetes and their shared features in rheumatoid arthritis

Type 1 diabetes (T1D) is mediated by abnormal immune system (autoimmunity) that targeting specifically to self insulin-producing cells (β-cells). People with T1D require treatments based on life-long insulin substitution. In addition to the damages in health caused by T1D complications, the complexity of insulin treatment and the fear of glucose dysregulation often place extra burden to the affected family. There is a current need for better understanding of the disease etiology therefore guide the construction of successful prediction and prevention strategies for the disease.

There are many immune-related genes playing important roles in T1D etiology. In addition, there is a trend of autoimmune diseases segregating within individuals and families where those genes are critically involved. Exploration of these genes can provide knowledge related to the disease pathogenesis. In my studies, we select two genes functioning in the immune system and explored their potential roles in T1D. In addition, we analyzed the association between HLA alleles and T1D autoimmune markers (autoantibodies) in rheumatoid arthritis patients.

Killer cell immunoglobulin like receptors (KIRs) is a group of receptors expressed on the surface of natural killer cells and subgroups of T cells. KIRs could accelerate autoimmune diabetes in rodent models. However their roles in human T1D are not clear. In Study I, we studied the T1D association of KIR genes and their combination with HLA-C ligand genes in Chinese Han population. Our results indicated that KIR modifies the T1D association of HLA-C ligand genes. Recent studies indicated that KIRs exert their function in a collective fashion and their effects can initiate as early as life in uterus by maternal-fetal interaction. Therefore in Study II, we studied the T1D association with the collection of maternal KIR genes and their combination with fetal HLA-C ligand genes in the Chinese Han population. Results from study II indicated that the accumulation of maternal activating KIRs along with fetal HLA-C2 genes predispose T1D in the fetus.

Alpha-B crystallin (encoded by CRYAB) is a major autoimmune target in multiple sclerosis (an autoimmune disease occurred in central nervous system). In Study III, we tested the association between CRYAB gene and islet autoantibodies in T1D using two well-established Swedish cohorts. Our results suggested that genetic variant in the promoter region of CRYAB is associated with increased T1D risk and islet autoantibodies in T1D patients.

In Study IV, we aimed to identify genetic factors that cause the aggregation of the two autoimmune disorders, T1D and rheumatoid arthritis (RA). We measured islet autoantibodies among RA patients and analyzed the association between HLA and islet autoantibodies in RA patients and in subgroups of RA positive for anti-citrullinated protein antibodies. We identified that HLA DR4 alleles were associated with increased islet autoantibodies in RA patients, however HLA DR3 alleles were the major genetic contributors toward elevated islet autoantibodies among RA patients positive for both anti-CCP and anti-CEP-1.

In conclusion, our studies indicated that KIR, CRYAB are among the genetic factors predisposing T1D. In addition, HLA alleles are the major contributors to the presence of islet autoantibodies among RA patients.

List of scientific papers

I. Zhi D, Sun C, Sedimbi SK, Luo F, Shen S, Sanjeevi CB. Killer cell immunoglobulin-like receptor along with HLA-C ligand genes are associated with type 1 diabetes in Chinese Han population. Diabetes/metabolism research and reviews. 2011 Nov;27(8):872-7.
https://doi.org/10.1002/dmrr.1264

II. Sun C, Luo F, Zhi D, Sanjeevi CB. Interactions between maternal killer cellimmunoglobulin receptor genes and fetal HLA ligand genes contribute toType 1 diabetes susceptibility. [Manuscript]

III. Sun C, Sedimbi SK, Ashok AK, Sanjeevi CB; Swedish Childhood Diabetes and the Diabetes Incidence in Sweden Study Groups. CRYAB-650 C>G (rs2234702) affects susceptibility to Type 1 diabetes and IAA-positivity in Swedish population. Human immunology. 2012 Jul;73(7):759-66.
https://doi.org/10.1016/j.humimm.2012.04.004

IV. Sun C, Ramelius A, Israelsson L, Lernmark Å, Klareskog L, Sanjeevi CB. Autoantibodies against Type 1 Diabetes autoantigens in RheumatoidArthritis. [Manuscript]