FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease.

Autoimmune thyroid disease is the most common autoimmune disease and is highly heritable1. Here, by using a genome-wide association study of 30,234 cases and 725,172 controls from Iceland and the UK Biobank, we find 99 sequence variants at 93 loci, of which 84 variants are previously unreported2-7. A low-frequency (1.36%) intronic variant in FLT3 (rs76428106-C) has the largest effect on risk of autoimmune thyroid disease (odds ratio (OR) = 1.46, P = 2.37 × 10-24). rs76428106-C is also associated with systemic lupus erythematosus (OR = 1.90, P = 6.46 × 10-4), rheumatoid factor and/or anti-CCP-positive rheumatoid arthritis (OR = 1.41, P = 4.31 × 10-4) and coeliac disease (OR = 1.62, P = 1.20 × 10-4). FLT3 encodes fms-related tyrosine kinase 3, a receptor that regulates haematopoietic progenitor and dendritic cells. RNA sequencing revealed that rs76428106-C generates a cryptic splice site, which introduces a stop codon in 30% of transcripts that are predicted to encode a truncated protein, which lacks its tyrosine kinase domains. Each copy of rs76428106-C doubles the plasma levels of the FTL3 ligand. Activating somatic mutations in FLT3 are associated with acute myeloid leukaemia8 with a poor prognosis and rs76428106-C also predisposes individuals to acute myeloid leukaemia (OR = 1.90, P = 5.40 × 10-3). Thus, a predicted loss-of-function germline mutation in FLT3 causes a reduction in full-length FLT3, with a compensatory increase in the levels of its ligand and an increased disease risk, similar to that of a gain-of-function mutation.

[Iodine intake of two-year-olds and adults in Iceland and estimation of the effect of using iodized salt in breads].

INTRODUCTION: Insufficient iodine status was recently identified in pregnant women in Iceland. Iodine fortification of salt is widely used to decrease the risk of iodine deficiency disorders, but the use of iodized salt has not been recommended in Iceland. The aim was to describe iodine intake among Icelandic adults and two-year-olds and estimate the effect of using iodized salt in bread. MATERIAL AND METHODS: Iodine intake was assessed using data from the Icelandic National Dietary Survey 2019-2021 (18-80 years, n=822) and a study of two-year-old children (n=124). Data on bread intake was used to estimate expected iodine intake if iodized salt was used in bread. The results are compared with recommended iodine intake (90 µg/day for two-year-olds and 150 µg/day for adults) and upper intake level (200 µg/day and 600 µg/day, respectively). RESULTS: Average iodine intake was 88 µg/day for children and 134 µg/day for adults. If all types of bread consumed would contain 20 µg of iodine in 100 grams, the average iodine intake would increase to 99 and 153 µg/day, respectively. With higher bread iodine content, >5% of two-year-olds would exceed the upper intake level, while concentration up to 70 µg/100 grams of bread would result in iodine intake below the upper intake level for adults. CONCLUSION: Use of iodized salt in bread corresponding to 20µg of iodine in 100 grams of bread seems safe for young children in Iceland. However, based on the current dietary habits, adding this amount of iodine to bread would not be sufficient to secure optimal intake of iodine in all adults.

Can physician laboratory-test requests be influenced by interventions?

BACKGROUND: Laboratory tests affect healthcare costs and unnecessary test requests can thus be a concern. We studied whether it was possible to influence physician laboratory-test requests using four structured interventions: introduction of clinical guidelines, education, feedback, and reminder letters. The interventions occurred at different times at Landspítali University Hospital, Reykjavik, Iceland. Akureyri Hospital, northern Iceland, was used as a control, since no formal interventions were introduced there. MATERIALS AND METHODS: Six types of laboratory tests were analyzed. The relative risk of a laboratory test being conducted at Landspítali University Hospital compared to Akureyri Hospital was calculated for various points in time, as well as the associated 95% confidence intervals. The primary estimates compare the pre- and post-intervention periods (2007-2009 vs. 2010-2013), but also on a monthly basis in order to observe the trends in greater detail. RESULTS: Interventions at Landspítali University Hospital led to a significant reduction in the average number of laboratory tests (12-52%, p < 0.001) compared with Akureyri Hospital. Relative risk coefficients of laboratory tests at Landspítali University Hospital (LUH) compared to Akureyri Hospital (AH) were calculated pre- and post-guidelines, the relative risk for ASAT, CRP and GGT fell markedly, while ALAT and ALP tests did not show a significant decrease. Relative risk for a blood culture test in the period after the guidelines was statistically significantly increased. CONCLUSION: It is possible to influence physician laboratory-test requests using multifaceted interventions that include continuous monitoring and follow-up.

Iodine status of pregnant women in a population changing from high to lower fish and milk consumption.

OBJECTIVES: Pregnancy is one of the most critical periods for iodine deficiency. The aim of the present study was to assess the iodine status and dietary intake of pregnant women in a population changing from high to lower consumption of milk and fish. DESIGN: Cross-sectional observational study. Urine samples were collected for measuring urinary iodine concentration (UIC) and creatinine, and blood samples for measuring serum thyroid-stimulating hormone (TSH). Frequency of consumption of selected food and beverages was obtained through a semi-quantitative validated FFQ. The difference in the distribution of UIC, ratio of iodine to creatinine (I:Cr) and TSH between groups following recommendations on fish and dairy product intake or not (fish ≥2 times/week as a main meal, diary products ≥2 portions/d) was assessed. SETTING: Primary Health Care of the Capital Area, Reykjavik, Iceland. SUBJECTS: Randomly selected pregnant women (19-43 years old, n 162). RESULTS: The median UIC was 180 µg/l, I:Cr 173 µg/g and TSH 1·5 mmol/l. Women who did not consume fish ≥2 times/week and also did not consume dairy products in line with the recommended intake level of ≥2 portions/d had median UIC of 160 µg/l (I:Cr 149 µg/g) compared with 220 µg/l (I:Cr 190 µg/g) in the group following both the recommendations for fish and those for dairy products. Use of dietary supplements in the two groups was similar. CONCLUSIONS: Iodine status in the population studied was within the optimal range (150-249 µg/d) defined by the WHO.

Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations.

A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 × 10-7, 4.3 × 10-9) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.

Association of immunoglobulin A deficiency and elevated thyrotropin-receptor autoantibodies in two Nordic countries.

Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency, with suggested association with various types of autoimmunity, including Graves' disease. This study investigated the association of IgAD with elevated thyrotropin-receptor autoantibodies (TRAb). IgA was measured in TRAb-seropositive individuals from both Iceland (N = 299] and Sweden (N = 841]. In addition, TRAb levels were evaluated in 43 Icelandic and 50 Swedish IgAD individuals using Medizym TRA immunoassay, and positive samples were re-evaluated using BRAHMS TRAK human RIA. The IgAD individuals were HLA-genotyped to determine the HLA-B, DR, and DQ alleles. None of the 299 Icelandic TRAb-seropositive individuals had IgAD, whereas, a high prevalence of IgAD (14/841 (1:60)) was observed in the Swedish cohort (p = 0.027). The prevalence of TRAb-seropositivity in IgAD individuals was, however, increased in both cohorts. The HLA-DQ6 allele was associated with TRAb-seronegativity within the Icelandic IgAD cohort (p = 0.037). The prevalence of IgAD in TRAb-seropositive individuals in Sweden is 10 times higher than expected in the general population. Furthermore, TRAb seropositivity is common among IgAD individuals, both in Iceland and Sweden, suggesting a predisposition toward Graves' disease. These findings underline the significant association of IgAD with autoimmunity and its possible association with certain HLA-DQ alleles.