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.

Common and Rare Sequence Variants Influencing Tumor Biomarkers in Blood.

BACKGROUND: Alpha-fetoprotein (AFP), cancer antigens 15.3, 19.9, and 125, carcinoembryonic antigen, and alkaline phosphatase (ALP) are widely measured in attempts to detect cancer and to monitor treatment response. However, due to lack of sensitivity and specificity, their utility is debated. The serum levels of these markers are affected by a number of nonmalignant factors, including genotype. Thus, it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. METHODS: We performed genome-wide association studies of serum levels of AFP (N = 22,686), carcinoembryonic antigen (N = 22,309), cancer antigens 15.3 (N = 7,107), 19.9 (N = 9,945), and 125 (N = 9,824), and ALP (N = 162,774). We also examined the correlations between levels of these biomarkers and the presence of cancer, using data from a nationwide cancer registry. RESULTS: We report a total of 84 associations of 79 sequence variants with levels of the six biomarkers, explaining between 2.3% and 42.3% of the phenotypic variance. Among the 79 variants, 22 are cis (in- or near the gene encoding the biomarker), 18 have minor allele frequency less than 1%, 31 are coding variants, and 7 are associated with gene expression in whole blood. We also find multiple conditions associated with higher biomarker levels. CONCLUSIONS: Our results provide insights into the genetic contribution to diversity in concentration of tumor biomarkers in blood. IMPACT: Genetic correction of biomarker values could improve prediction algorithms and decision-making based on these biomarkers.

A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease.

Mutations in genes encoding subunits of the phagocyte NADPH oxidase complex are recognized to cause chronic granulomatous disease (CGD), a severe primary immunodeficiency. Here we describe how deficiency of CYBC1, a previously uncharacterized protein in humans (C17orf62), leads to reduced expression of NADPH oxidase's main subunit (gp91phox) and results in CGD. Analyzing two brothers diagnosed with CGD we identify a homozygous loss-of-function mutation, p.Tyr2Ter, in CYBC1. Imputation of p.Tyr2Ter into 155K chip-genotyped Icelanders reveals six additional homozygotes, all with signs of CGD, manifesting as colitis, rare infections, or a severely impaired PMA-induced neutrophil oxidative burst. Homozygosity for p.Tyr2Ter consequently associates with inflammatory bowel disease (IBD) in Iceland (P = 8.3 × 10-8; OR = 67.6), as well as reduced height (P = 3.3 × 10-4; -8.5 cm). Overall, we find that CYBC1 deficiency results in CGD characterized by colitis and a distinct profile of infections indicative of macrophage dysfunction.

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.

Clinical features of microscopic colitis in a nation-wide follow-up study in Iceland.

OBJECTIVE: The long-term natural history of collagenous colitis (CC) and lymphocytic colitis (LC) is not well known. The few reports available that address these issues have a limited follow-up. The aims of this study were to evaluate the natural history of microscopic colitis (MC), to describe the treatment medications prescribed and to assess the use of non-steroidal anti-inflammatory drugs (NSAIDs) in MC. MATERIAL AND METHODS: This study is based on an earlier epidemiological study conducted in Iceland where 125 patients with MC (71 with CC and 54 with LC) were diagnosed in the period 1995-99. All patients still alive and available were questioned about symptoms, treatment and NSAID use in the 3 months preceding the interview. RESULTS: In a mean follow-up time of 6.4 years from diagnosis, 15% of the patients had diarrhoeal symptoms more than once a week, 30% less than once a week and 55% had no diarrhoea. Abdominal pain was reported in 18% of the patients. There was no statistically significant difference in symptoms of CC and LC patients. Forty-eight patients (50%) were receiving medication for MC, 16% used aminosalicylates and 14% corticosteroids. Patients using medication for MC had significantly more diarrhoeal symptoms compared with those who did not (p = 0.002). Patients using NSAIDs regularly or as required, statistically did not have more symptoms related to MC than non-NSAID users. CONCLUSIONS: Only a minority of patients with MC had diarrhoea more than once a week in a long-term follow-up and the symptom pattern was similar between CC and LC patients. The use of NSAIDs was not associated with more diarrhoeal symptoms.

[Microscopic colitis - review]. / Smásae ristilbólga - yfirlit.

Microscopic colitis (MC) is an encompassing term for two diseases; collagenous colitis and lymphocytic colitis. The colon appears normal by colonoscopy and a diagnosis is only obtained with a biopsy. The histopathology of collagenous colitis is mainly characterized by a thickening of the subepithelial basement membrane of the colonic mucosa with a band of collagen. Lymphocytic colitis is mainly characterized by an intraepithelial lymphocytosis without the collagen thickening. Even though the two diseases have a distinctive pathology their clinical symptoms are characterized by chronic watery diarrhea without bleeding. Microscopic colitis is thought to cause about 4-13% of all chronic diarrhea but their relative frequency is much higher among older people. The mean annual incidence for collagenous and lymphocytic colitis has been increasing. Steroids are the most effective treatment for microscopic colitis and budesonide is the most studied and effective therapy for MC. The aim of this paper is to give a review of two relatively new diseases which are among the most common cause of chronic diarrhea, especially among older people.

[The relationship of gastrointestinal symptoms and menstrual cycle phase in young healthy women]. / Tengsl meltingarfaeraeinkenna vid hluta tídahrings hjá ungum, hraustum konum.

BACKGROUND: Abdominal discomfort is a common complaint by women and may vary with the menstrual cycle. The aim of this study was to investigate abdominal symptoms and general well being of women in relation to different phases of the menstrual cycle as well as gastrointestinal transit time. METHODS: Fourteen young women who were not using any contraceptive medications were recruited. Questionnaire was used to exclude functional gastrointestinal problems. Questionnaires on abdominal symptoms and general well being were used. Gastric emptying time, small intestinal transit time and colonic transit time were measured and serum sex hormone concentrations were measured at three points in the menstrual cycle. RESULTS: Abdominal symptoms were significantly more pronounced at the beginning of the follicular phase. Gastric emptying and colonic transit times were not significantly different between the follicular and the luteal phase of the menstrual cycle. Small bowel transit was faster in the luteal phase (75,7 min) compared with the follicular phase (99,3 min). There was no correlation between the transit times, symptoms or hormone concentrations. CONCLUSIONS: Results indicate that women experience more abdominal symptoms at the beginning of the follicular phase compared to the early luteal phase. Small bowel transit appears to be faster in the luteal phase than in the follicular phase. Further studies on the relationship of gastrointestinal symptoms and the menstrual cycle are needed.

Collagenous and lymphocytic colitis in Iceland.

The aim of this study was to determine the nationwide incidence of collagenous and lymphocytic colitis in Iceland and the location of histopathological changes in the large bowel. All pathology reports of patients diagnosed with or suspected of having collagenous colitis or lymphocytic colitis in the period 1995-1999 were identified. All pathology samples were reevaluated using strict diagnostic criteria. After reevaluation 125 patients fulfilled our diagnostic criteria, 71 as collagenous colitis and 54 as lymphocytic colitis. The mean annual incidence for collagenous colitis was 5.2/100,000 inhabitants, and the mean age at diagnosis was 66.1 years. The mean annual incidence for lymphocytic colitis was 4.0/100,000 inhabitants, the mean age at diagnosis was 68.7 years. Both diseases more commonly involved the colon than the rectum. The incidence of collagenous colitis and lymphocytic colitis is high in Iceland. The mean annual incidence of collagenous colitis is much higher in Iceland than hitherto reported elsewhere.