| 1. |
- Eriksson, Daniel, et al.
(författare)
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GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility
- 2021
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune Addison's disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10-8). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7-4.3), P = 9.0 × 10-25) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35-41% of heritability (h2).
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| 2. |
- Berglund, Linnea Hergot, et al.
(författare)
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Testosterone levels and psychological health status in men from a general population : the Troms circle divide o study
- 2011
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Ingår i: The Aging Male. - : Informa UK Limited. - 1368-5538 .- 1473-0790. ; 14:1, s. 37-41
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Tidskriftsartikel (refereegranskat)abstract
- Methods. aEuro integral Total testosterone and sex hormone-binding globulin levels were analysed and free testosterone levels was calculated in 3413 men participating in the fifth Troms circle divide o study in 2001. Self-administered questionnaires including information about education, marital status, smoking habits and the Hopkins Symptom Checklist-10 (SCL-10, a 10-item psychological health questionnaire) were completed. The cross-sectional data were analysed with partial association and analysis of variance and covariance. Results. aEuro integral The complete SCL-10 was not associated with total or free testosterone, but symptoms of anxiety were negatively associated with both total and free testosterone (p < 0.05). Men presumed to be testosterone deficient, with testosterone levels in the lowest 10th percentile, had increased SCL-10 score compared to men with higher testosterone levels (p == 0.021), before and after adjusting for age, waist circumference, marital status, education and smoking. There was an even stronger association between men presumed to be testosterone deficient and symptoms of anxiety (p < 0.001). However, men with more pronounced symptoms indicating mental disorder did not have lower testosterone levels. Conclusions. aEuro integral Men presumed being testosterone deficient had a higher symptom score, in particularly regarding anxiety, but they did not have pathological symptoms. Thus, lower testosterone levels was only associated with subthreshold symptoms of anxiety and depression.
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| 3. |
- Bruserud, Oyvind, et al.
(författare)
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A Longitudinal Follow-up of Autoimmune Polyendocrine Syndrome Type 1
- 2016
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 101:8, s. 2975-2983
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Tidskriftsartikel (refereegranskat)abstract
- Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disease defined by the presence of two of the three major components: hypoparathyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis (CMC). Information on longitudinal follow-up of APS1 is sparse. Objective: To describe the phenotypes of APS1 and correlate the clinical features with autoantibody profiles and autoimmune regulator (AIRE) mutations during extended follow-up (1996-2016). Patients: All known Norwegian patients with APS1. Results: Fifty-two patients from 34 families were identified. The majority presented with one of the major disease components during childhood. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. With age, most patients presented three to five disease manifestations, although some had milder phenotypes diagnosed in adulthood. Fifteen of the patients died during follow-up (median age at death, 34 years) or were deceasedsiblingswithahighprobability of undisclosed APS1. All except three had interferon-omega) autoantibodies, and allhadorgan-specific autoantibodies. The most common AIRE mutation was c.967_979del13, found in homozygosity in 15 patients. A mild phenotype was associated with the splice mutation c.879+1G>A. Primary adrenocortical insufficiency and type 1 diabetes were associated with protective human leucocyte antigen genotypes. Conclusions: Multiple presumable autoimmune manifestations, in particular hypoparathyroidism, CMC, and enamel hypoplasia, should prompt further diagnostic workup using autoantibody analyses (eg, interferon-omega) and AIRE sequencing to reveal APS1, even in adults. Treatment is complicated, and mortality is high. Structured follow-up should be performed in a specialized center.
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| 4. |
- Erichsen, Martina M, et al.
(författare)
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Clinical, Immunological, and Genetic Features of Autoimmune Primary Adrenal Insufficiency: Observations from a Norwegian Registry.
- 2009
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 94, s. 4882-4890
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Primary adrenal insufficiency [Addison's disease (AD)] is rare, and systematic studies are few, mostly conducted on small patient samples. We aimed to determine the clinical, immunological, and genetic features of a national registry-based cohort. Design: Patients with AD identified through a nationwide search of diagnosis registries were invited to participate in a survey of clinical features, health-related quality of life (HRQoL), autoantibody assays, and human leukocyte antigen (HLA) class II typing. Results: Of 664 registered patients, 64% participated in the study. The prevalence of autoimmune or idiopathic AD in Norway was 144 per million, and the incidence was 0.44 per 100,000 per year (1993-2007). Familial disease was reported by 10% and autoimmune comorbidity by 66%. Thyroid disease was most common (47%), followed by type 1 diabetes (12%), vitiligo (11%), vitamin B12 deficiency (10%), and premature ovarian insufficiency (6.6% of women). The mean daily treatment for AD was 40.5 mg cortisone acetate and 0.1 mg fludrocortisone. The mean Short Form 36 vitality scores were significantly diminished from the norm (51 vs. 60), especially among those with diabetes. Concomitant thyroid autoimmunity did not lower scores. Anti-21-hydroxylase antibodies were found in 86%. Particularly strong susceptibility for AD was found for the DR3-DQ2/ DRB1*0404-DQ8 genotype (odds ratio, 32; P = 4 x 10(-17)), which predicted early onset. Conclusions: AD is almost exclusively autoimmune, with high autoimmune comorbidity. Both anti-21-hydroxylase antibodies and HLA class II can be clinically relevant predictors of AD. HRQoL is reduced, especially among diabetes patients, whereas thyroid disease did not have an impact on HRQoL. Treatment modalities that improve HRQoL are needed.
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| 5. |
- Linnér, Carl, et al.
(författare)
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Estrogen receptor alpha single nucleotide polymorphism as predictor of diabetes type 2 risk in hypogonadal men.
- 2013
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Ingår i: The Aging Male. - : Informa UK Limited. - 1473-0790 .- 1368-5538. ; 16:2, s. 52-57
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Estradiol (E2) is, apart from its role as a reproductive hormone, also important for cardiac function and bone maturation in both genders. It has also been shown to play a role in insulin production, energy expenditure and in inducing lipolysis. The aim of the study was to investigate if low circulating testosterone or E2 levels in combination with variants in the estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2) genes were of importance for the risk of type-2 diabetes. The single nucleotide polymorphisms rs2207396 and rs1256049, in ESR1 and ESR2, respectively, were analysed by allele specific PCR in 172 elderly men from the population-based Tromsø study. The results were adjusted for age. In individuals with low total (≤11 nmol/L) or free testosterone (≤0.18 nmol/L) being carriers of the variant A-allele in ESR1 was associated with 7.3 and 15.9 times, respectively, increased odds ratio of being diagnosed with diabetes mellitus type 2 (p = 0.025 and p = 0.018, respectively). Lower concentrations of E2 did not seem to increase the risk of being diagnosed with diabetes. In conclusion, in hypogonadal men, the rs2207396 variant in ESR1 predicts the risk of type 2 diabetes.
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| 6. |
- Skjaerpe, Paal Andre, et al.
(författare)
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Androgen receptor gene polymorphism and sex hormones in elderly men: the Tromso study
- 2009
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Ingår i: Asian Journal of Andrology. - : Medknow. - 1008-682X .- 1745-7262. ; 11:2, s. 222-228
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to examine whether CAG/GGN repeats are significant modulators of serum concentrations of total and free testosterone (T) as well as of luteinizing hormone (LH) in elderly men. Sixty-nine 60- to 80-year-old men with subnormal T levels (<= 11.0 nmol L-1) and 104 men with normal T levels taking part in a nested case-control study were used for these analyses. Sex hormones were measured and free T was calculated. The CAG and GGN polymorphisms in the androgen receptor gene were determined by polymerase chain reaction and subsequent direct sequencing. There were no differences in the CAG and GGN repeat lengths between the groups. In cross-sectional analyses of the whole cohort, total and free T were positively associated with CAG length (all P < 0.05) before, but not after, waist circumference or body mass index was added to the model. CAG repeat lengths were weakly, but not independently, associated with total and free T. These findings indicate that when clinically evaluating T and LH levels in elderly men, the CAG and GGN repeat lengths do not need to be taken into consideration.
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| 7. |
- Skjaerpe, Paal, et al.
(författare)
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Androgen receptor gene polymorphism and the metabolic syndrome in 60-80 years old Norwegian men
- 2010
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Ingår i: International Journal of Andrology. - : Wiley. - 0105-6263 .- 1365-2605. ; 33:3, s. 500-506
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Tidskriftsartikel (refereegranskat)abstract
- The metabolic syndrome (MS) includes a clustering of metabolic derangements. Low testosterone levels have been shown to be associated with both components of MS and MS per se. As most androgen-related effects are mediated thorough the androgen receptor (AR), we wanted to investigate to which degree the AR CAG and GGN repeat polymorphisms might be related to MS. Sixty-eight men, 60-80 years old, with subnormal total testosterone levels (< 11.0 nmol/L) and 104 men with normal levels (> 11.0 nmol/L), participating in a nested case-control study were investigated in this study. Body weight, height, waist circumferences and blood pressure were measured. Fasting blood samples were drawn and an oral glucose tolerance test (OGTT) was performed. The CAG and GGN polymorphisms in the AR gene were determined by direct sequencing of leucocyte DNA. Men with MS had lower CAG repeat number than healthy men (p = 0.007). There were, however, no difference in CAG or GGN repeats length between the groups with subnormal or normal testosterone concentrations. In cross-sectional analyses, men with CAG repeat lengths < 21 had significantly higher fasting glucose, C-peptide and glycosylated haemoglobin (HbA1c) levels (all p < 0.05). In multiple regression analyses, CAG repeat length was an inverse and independent predictor of glucose after an OGTT and of HbA1c levels. We also found that men with more than one component of MS had shorter CAG repeat number (p for trend 0.013) than those with only one component. In conclusion, there were no associations with GGN repeat length, while short CAG repeat length seems to be associated with increased risk of MS.
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