CARD9 gene rs4077515 polymorphism is associated with the susceptibility of Hashimoto’s thyroiditis and the development of thyroid cancer

1

Introduction

Hashimoto’s thyroiditis (HT), also known as chronic lymphocytic thyroiditis (CLT), is an organ-specific autoimmune disease mediated by T cells [1] . HT is first reported by Japanese scholar Hashimoto in 1912 [2] . It is the most common type of autoimmune thyroiditis and mainly occurs in middle-aged women [3] . Clinically, diffuse lymphocyte infiltration in thyroid interstitial space and elevated anti-thyroid antibodies in blood can be observed in HT patients [4] . Thyroglobulin antibody (TGAb) and anti-thyroperoxidase antibody (TPOAb) are two main thyroid destructive antibodies that can lead to hypothyroidism and eventually to HT [5] . The mechanism of autoimmune damage of HT has not been fully clarified. Epidemiological data suggest that genetic susceptibility and environmental factors are the main causes of thyroid antigen immune tolerance abnormalities and disease development, in which genetic factors play a very important role in the pathogenesis of HT [6] .

Autoimmune disease is a pathological process that ultimately leads to inflammatory responses and damage to activated tissues [7] . Several genes involved in immune system regulation and inflammatory response have been shown to be associated with HT susceptibility, such as interleukin-23 receptor (IL-23R), IL-8, and transforming growth factor-β1 (TGF-β1) 8910 . The caspase recruitment domain family, member 9 (CARD9) is an inflammation-related molecule that initiates inflammatory cytokine cascades [11] . High activity and overexpression of CARD9 can lead to the imbalance of Th1/Th7, which is one of the contributors to the pathogenesis of HT [12] . It is well known that genetic mutations can lead to a range of biological consequences, including changes in expression and activity, structural modifications of proteins, or loss of function [13] . Single nucleotide polymorphism (SNP) is the most common form of genetic variation that can affect the human genome and regulate an individual’s susceptibility to certain diseases [14] . Due to its wide distribution and gradually revealed multiple biological functions, SNP has attracted the attention of many researchers [15] . The rs4077515 polymorphism of CARD9 brings the substitution of guanine (G) nucleotide to adenine (A) nucleotide, leading to the serine to be taken by asparagine. Interestingly, published genome-wide association analysis studies have shown that CARD9 rs4077515 polymorphism is closely associated with the development of several human autoimmune inflammatory diseases, such as IgA nephropathy, Crohn’s disease, and inflammatory bowel disease (IBD) [1617] . However, the genetic correlation between CARD9 rs4077515 and HT has not been examined.

At present, mainstream medical view is that HT is a risk factor for the occurrence of thyroid papillary carcinoma (PTC) [18] . A meta-analysis by Lai et al. has presented that the incidence of PTC in HT is 41.23 %, which is significantly higher than that in the control group (21.23 %) [19] . Another two pieces of research from Korea have reported that the incidence of PTC in HT is greater than 90 % [2021] . Therefore, in this study, polymerase chain reactor-restriction fragment length polymorphism (PCR-RFLP) was used to detect the polymorphism of CARD9 rs4077515. The frequency and distribution of CARD9 rs4077515 polymorphism among HT, PTC and healthy control groups were analyzed, so as to evaluate the predictive value of CARD9 rs4077515 polymorphisms in the occurrence and development of HT, and provide scientific basis for new diagnostic and therapeutic targets.