Genome-wide association analysis suggests novel loci underlying thyroid antibodies in Hashimoto’s thyroiditis

Abstract

Thyroid antibodies against thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) are key markers of Hashimoto’s thyroiditis (HT), the most common autoimmune thyroid disorder. Genetic determinants of thyroid antibodies are still poorly known, especially as they were not studied in patients with thyroid diseases. We performed the first genome-wide association analysis of thyroid antibodies in 430 HT patients that may be considered as population extremes for thyroid antibodies distribution. We detected two suggestively associated genetic variants with TgAb, rs6972286 close to ANKRD7 and LSM8 (P = 2.34 × 10 −7 ) and rs756763 inside CA10 (P = 6.05 × 10 −7 ), and one with TPOAb, rs12507813 positioned between TRIM61 and TRIM60 (P = 4.95 × 10 −7 ). Bivariate analysis resulted with three suggestively associated genetic variants that predispose to both antibodies: rs13190616 inside RP11-138J23.1 (P = 2.01 × 10 −6 ), rs561030786 close to DUBR (P = 7.33 × 10 −6 ) and rs12713034 inside FSHR (P = 7.66 × 10 −6 ). All identified genomic regions have a substantial literature record of involvement with female-related traits, immune-mediated diseases and personality traits that are all characterized by increased thyroid antibody levels. Our findings demonstrate the existence of genetic overlap between thyroid autoimmunity in HT and different non-thyroid diseases characterized by the presence of thyroid antibodies. We also suggest that genetic variants that regulate antibody levels may differ between HT patients and individuals with normal thyroid function.

The Role of Thyroid Hormones and Autoantibodies in Metabolic Dysfunction Associated Fatty Liver Disease: TgAb May Be a Potential Protective Factor

“…Here, we tentatively bring forward two possible mechanisms. To begin with, a recent study found that carbonic anhydrase (CA) is genetically related to TgAb ( 47 ). Decreased CA activity may induce the production of TgAb via high levels of iodine uptake ( 48 ).…”

Genetic Susceptibility to Joint Occurrence of Polycystic Ovary Syndrome and Hashimoto’s Thyroiditis: How Far Is Our Understanding?

“…Numerous studies have been performed using small cohorts or patients with HT and GD grouped together (128,161). In total, six GWAS included separate groups of patients with HT (134,140,146,147,154,159), while three included patients with hypothyroidism, a typical feature of HT (133,135,158). Together, 16 putative HT susceptibility loci have been identified; however, the most convincing evidence for associations is limited to HLA (6p21), CTLA4 (2q33.2), PTPN22 (1q13.2), and FOXE1 (9q22.33) variants.…”

“…Several other FSHR polymorphisms have been shown to correlate with ovarian function, including SNPs identified by GWAS in Han Chinese population ( Table 1) and by fine mapping of 2p16.3 region in a population of European ancestry (271); however, they seem to be associated with FSH levels and the PCOM phenotype rather than with disease risk (33,47). Recent GWAS among patients with HT identified SNP rs12713034 in the FSHR gene that is associated with the presence of anti-thyroid antibodies (146). In addition, hypothyroidism has been found to decrease FSH and E 2 levels and alter FSHR-mediated expression of CYP51, a key enzyme involved in sterols and steroids biosynthesis during folliculogenesis and oocyte maturation, which is regulated by FSH (272); thus providing a further link between the functions of the ovaries and thyroid gland.…”

Genetic relationship between Hashimoto`s thyroiditis and papillary thyroid carcinoma with coexisting Hashimoto`s thyroiditis

“…Risk factors for HT include environmental factors, such as exposure to ionizing radiation, carcinogenic chemicals, iodine deficiency, and infections, as well as nonenvironmental risk factors, such as genetic susceptibility, that can be linked in certain cases with a history of inherited autoimmune diseases [4,5]. Genome-wide association studies (GWAS) have identified a number of genetic susceptibility loci that are associated with autoimmunity, especially with development of thyroid autoantibodies [6,7]. A systematic review on studies, carried out in their majority on Caucasian populations, reported that incidence of hypothyroidism, which is commonly associated with HT, is 350/100,000/year in women and 80/100,000/year in men [8].…”