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Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma.Multiple myeloma (MM) is characterized by an uninhibited, clonal growth of plasma cells. While first-degree relatives of patients with MM show an increased risk of MM, the genetic basis of inherited MM susceptibility is incompletely understood. Here we report a genome-wide association study in the Nordic region identifying a novel MM risk locus at ELL2 (rs56219066T; odds ratio (OR)=1.25; P=9.6 × 10(-10)). This gene encodes a stoichiometrically limiting component of the super-elongation complex that drives secretory-specific immunoglobulin mRNA production and transcriptional regulation in plasma cells. We find that the MM risk allele harbours a Thr298Ala missense variant in an ELL2 domain required for transcription elongation. Consistent with a hypomorphic effect, we find that the MM risk allele also associates with reduced levels of immunoglobulin A (IgA) and G (IgG) in healthy subjects (P=8.6 × 10(-9) and P=6.4 × 10(-3), respectively) and, potentially, with an increased risk of bacterial meningitis (OR=1.30; P=0.0024).
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Primary sclerosing cholangitis associated with elevated immunoglobulin G4: clinical characteristics and response to therapy.Steroid responsive biliary strictures in patients fulfilling criteria for primary sclerosing cholangitis (PSC) have been reported. The clinical course and response to therapy in patients with PSC with elevated immunoglobulin G4 (IgG4) levels has not been investigated previously. Patients with PSC were screened for IgG4-related biliary disease during 2006 to 2008 and data were collected prospectively. A total of 33 out of 285 (12%) patients with PSC (18 males) had elevated IgG4 (>140mg/dL) with a median age of 46 years (interquartile range 29-60); 24 could be evaluated. All patients had both intrahepatic and extrahepatic biliary strictures. Pancreatic disorders were found in 4 (17%), and 11 of 24 (46%) presented with jaundice; 8 of 24 (33%) received biliary stenting for a median time of 4 months (0-6). Liver cirrhosis was diagnosed in 12 of the 24 (50%). Overall, 18 patients were treated with corticosteroids and 6 patients managed conservatively. Nine of 10 patients with elevated bilirubin had improvement. Alkaline phosphatase decreased significantly at 2 months and at last follow-up. IgG4 levels at baseline were 242 (216-357) mg/dL and decreased to 109 (80-236) at 2 months (P < 0.05) and 174 (115-269) at last follow-up (P < 0.05). A total of 39% had adverse effects of steroids, mostly hyperglycemia. Relapses occurred in 7 of the 14 (50%), but biliary stents could be removed in all. Elevated IgG4 levels were observed in 12% of typical patients with PSC. Prevalence of cirrhosis was high, suggesting a severe liver disease course. Most patients had a good biochemical response to steroids, but adverse effects were common. Future work should be directed at finding therapy that is more effective, better tolerated, and of more lasting benefit.
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Serum immunoglobulinD in infants and childrenSerum immunoglobulinD (IgD) concentration is usually low in healthy individuals as compared to other immunoglobulin classes. Most studies on serum IgD are concerned with serum levels in healthy adults but reference values for young children and infants are not easily available. In order to establish age specific reference values we measured IgD levels in serum of 184 healthy Icelandic children, age 0-14 years and 60 healthy blood donors age 18-63, using the ELISA technique. Special attention was paid to the youngest age groups. Results showed low IgD values in infants and young children, gradually increasing until the age of 10 but then decreasing with age. We conclude that IgD gradually increases with age in childhood as other immunoglobulin classes but later declines. These findings can be of importance in revealing the function of IgD in the immune system as well as in the diagnosis of the hyper-IgD syndrome.
