Increased risk of endocrine autoimmunity in first-degree relatives of patients with autoimmune Addison’s disease

Fichna, Marta; Małecki, Piotr; Młodzikowska, Mirela; Gębarski, Bolesław; Ruchała, Marek; Fichna, Piotr

doi:10.1530/eje-20-0150

Cited by 5 publications

(5 citation statements)

References 56 publications

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“…Apart from aTPO, which was more prevalent in females, no sex-related differences nor predisposition connected with relationship to the patient (parents, siblings, or offspring) were noted. However, as in previous analysis, relatives of the male AD patients, and of those suffering from polyendocrine autoimmunity appeared most prone to develop autoantibodies (9).…”

Section: Discussionsupporting

confidence: 76%

“…Our former study revealed that nearly 40% first-degree relatives of the AD patients displayed circulating serum autoantibodies to the endocrine gland-specific antigens compared to just 8.4% subjects with no family history of autoimmunity (9). Familial incidence of the autoimmune disease might be partially due to similar environmental exposures, but high concordance rates in monozygotic twins support substantial role of the genetic factors associated with the incidence of T1D, AD and autoimmune thyroid disease (AITD) (10)(11)(12).…”

Section: Introductionmentioning

confidence: 92%

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Genetic variants and risk of endocrine autoimmunity in relatives of patients with Addison’s disease

Fichna

Małecki

Żurawek

et al. 2023

Endocrine Connections

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Since individuals with Addison’s disease (AD) present considerable co-occurrence of additional autoimmune conditions, clustering of autoimmunity was also predicted among their relatives. The study was aimed to evaluate circulating autoantibodies in first-degree relatives of patients with AD and to correlate them with the established genetic risk factors (PTPN22 rs2476601, CTLA4 rs231775, and BACH2 rs3757247). Antibodies were evaluated using validated commercial assays and genotyping was performed with TaqMan chemistry. The studied cohort comprised 112 female and 75 male relatives. Circulating autoantibodies were found in 69 relatives (36.9%). Thyroid autoantibodies, aTPO and aTg were detectable in 25.1% and 17.1% relatives, respectively. Antibodies to 21-hydroxylase (a21OH) were found 5.8% individuals, and beta cell-specific antibodies to ZnT8, GAD and IA2 – in 7.5%, 8.0% and 2.7%, respectively. The prevalence of a21OH (p=0.0075; OR 7.68; 95% CI 1.903-36.0), aTPO (p<0.0001; OR 3.85; 95%CI 1.873-7.495) and aTg (p<0.0001; OR 7.73; 95% CI 3.112-19.65), as well as aGAD (p=0.0303; OR 3.38; 95% CI 1.180-9.123) and aZnT8 (p=0.032; OR 6.40; 95% CI 1.846-21.91) was significantly increased in carriers of rs2476601 T allele. Moreover, T allele appeared to be risk factor for multiple circulating autoantibody specificities (p=0.0009; OR 5.79; 95% CI 1.962-15.81). None of the studied autoantibodies demonstrated significant association with rs231775 in CTLA4 (p<0.05), and only weak association was detected between BACH2 rs3757247 and circulating aTPO (p=0.0336; OR 2.12; 95%CI 1.019-4.228). In conclusion, first-degree relatives of patients with AD, carriers of the PTPN22 rs2476601 T allele, are at particular risk of developing autoantibodies to the endocrine antigens.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 92%

Genetic variants and risk of endocrine autoimmunity in relatives of patients with Addison’s disease

Fichna

Małecki

Żurawek

et al. 2023

Endocrine Connections

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“…A family history of AD was reported in 10% of the Norwegian patients and 6% of the Swedish ones (1,3). A small case-control study from Poland reported that 3% of the family members were also diagnosed with AD and that thyroid AID was found in almost 30% of the family members (6). In our previous family studies, AD was associated with type 1 diabetes and Graves disease in family members (7,8).…”

Section: Introductionmentioning

confidence: 79%

“…Family studies on AD are rare and include the recent small hospital-based study from Poland and twin studies from Sweden, discussed in Introduction (6,11,12). However earlier studies on other AIDs have observed significant associations with AD in family members, including studies on vitiligo, thyroid diseases and multiple sclerosis (23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

Familial associations for Addison’s disease and between Addison’s disease and other autoimmune diseases

Thomsen

Sundquist

et al. 2020

Endocrine Connections

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Design: Addison disease (AD) is a rare autoimmune disease (AID) of the adrenal cortex, presenting as an isolated AD or part of autoimmune polyendocrine syndromes (APSs) 1 and 2. Although AD patients present with a number of AID co-morbidities, population-based family studies are scarce. We aimed to carry out an unbiased study on AD and related AIDs. Methods: We collected data on patients diagnosed with AIDs in Swedish hospitals, and calculated standardized incidence ratios (SIRs) in families for concordant AD and for other AIDs, the latter as discordant relative risks. Results: The number of AD patients was 2852, which accounted for 0.4% of all hospitalized AIDs. A total of 62 persons (3.6%) were diagnosed with familial AD. The SIR for siblings was remarkably high, reaching 909 for singleton siblings diagnosed before age 10 years. It was 32 in those diagnosed past age 29 years and the risk for twins was 323. SIR was 9.44 for offspring of affected parents. AD was associated with 11 other AIDs, including thyroid AIDs and type 1 diabetes, and some rarer AIDs such as Guillain-Barre syndrome, myasthenia gravis, polymyalgia rheumatica and Sjögren syndrome. Conclusions: The familial risk for AD was very high implicating genetic etiology, which for juvenile siblings may be ascribed to APS-1. The adult part of sibling risk was probably contributed to by recessive polygenic inheritance. AD was associated with many common AIDs; some of these were known co-morbidities in AD patients while some other appeared to more specific for a familial setting.

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“…In most instances, the etiology of these disorders remains obscure and combines some poorly determined environmental triggers with complex inherited susceptibility, conferred by numerous genetic polymorphisms [ 2 ]. Autoimmune conditions tend to cluster within families, although their inheritance pattern is rarely straightforward [ 3 , 4 ]. Furthermore, genetically predisposed individuals may develop several autoimmune diseases, traditionally categorized into four distinct autoimmune polyendocrine syndromes (APS) [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Polymorphism in BACH2 gene is a marker of polyglandular autoimmunity

et al. 2021

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Purpose Genetically predisposed individuals may develop several autoimmune diseases—autoimmune polyendocrine syndromes (APS). APS types 2–4, are complex disorders, which combine various organ-specific autoimmune conditions. Recent reports support the considerable role of the BACH2 gene in immune cell differentiation and shifting the T-cell balance towards regulatory T-cells. BACH2 polymorphisms are associated with autoimmune disorders, including Addison’s disease (AD), Graves’ disease (GD), and probably type 1 diabetes (T1D). Our study was aimed to investigate the BACH2 variant, rs3757247, in endocrine autoimmunity in the Polish population. Methods The analysis comprised 346 individuals with APS, 387 with T1D only, and 568 controls. Genotyping was performed using TaqMan chemistry. Results APS type 2 was found in 219 individuals, type 3 in 102, and type 4 in 25 subjects. Overall, AD was diagnosed in 244 subjects, Hashimoto’s thyroiditis—in 238, T1D—in 127, GD—in 58, vitiligo and chronic gastritis each in 40 patients, celiac disease—in 28, premature menopause in 18, and alopecia in 4 patients. Minor T allele at rs3757247 was found in 56.4% APS vs. 44.1% control alleles (OR 1.59; 95%CI: 1.30–1.95, p < 0.0001). The distribution of genotypes revealed excess TT homozygotes in the APS cohort (33.2 vs. 20.1% in controls, p < 0.0001). The frequencies of rs3757247 alleles and genotypes in T1D patients did not present significant differences vs. controls (p-values > 0.05). Conclusions These results provide evidence of the association between BACH2 polymorphism and polyglandular autoimmunity. Since carriers of rs3757247 display increased risk for additional autoimmune conditions, this variant could identify individuals prone to develop APS.

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Increased risk of endocrine autoimmunity in first-degree relatives of patients with autoimmune Addison’s disease

Cited by 5 publications

References 56 publications

Genetic variants and risk of endocrine autoimmunity in relatives of patients with Addison’s disease

Genetic variants and risk of endocrine autoimmunity in relatives of patients with Addison’s disease

Familial associations for Addison’s disease and between Addison’s disease and other autoimmune diseases

Polymorphism in BACH2 gene is a marker of polyglandular autoimmunity

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