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Articles by E Andersson
Total Records ( 2 ) for E Andersson
  T Sparso , A Bonnefond , E Andersson , N Bouatia Naji , J Holmkvist , L Wegner , N Grarup , A. P Gjesing , K Banasik , C Cavalcanti Proenca , M Marchand , M Vaxillaire , G Charpentier , M. R Jarvelin , J Tichet , B Balkau , M Marre , C Levy Marchal , K Faerch , K Borch Johnsen , T Jorgensen , S Madsbad , P Poulsen , A Vaag , C Dina , T Hansen , O Pedersen and P. Froguel
  OBJECTIVE

Genome-wide association studies have identified several variants within the MTNR1B locus that are associated with fasting plasma glucose (FPG) and type 2 diabetes. We refined the association signal by direct genotyping and examined for associations of the variant displaying the most independent effect on FPG with isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), type 2 diabetes, and measures of insulin release and peripheral and hepatic insulin sensitivity.

RESEARCH DESIGN AND METHODS

We examined European-descent participants in the Inter99 study (n = 5,553), in a sample of young healthy Danes (n = 372), in Danish twins (n = 77 elderly and n = 97 young), in additional Danish type 2 diabetic patients (n = 1,626) and control subjects (n = 505), in the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study (n = 4,656), in the North Finland Birth Cohort 86 (n = 5,258), and in the Haguenau study (n = 1,461).

RESULTS

The MTNR1B intronic variant, rs10830963, carried most of the effect on FPG and showed the strongest association with FPG (combined P = 5.3 x 10–31) and type 2 diabetes. The rs10830963 G-allele increased the risk of i-IFG (odds ratio [OR] 1.64, P = 5.5 x 10–11) but not i-IGT. The G-allele was associated with a decreased insulin release after oral and intravenous glucose challenges (P < 0.01) but not after injection of tolbutamide. In elderly twins, the G-allele associated with hepatic insulin resistance (P = 0.017).

CONCLUSIONS

The G-allele of MTNR1B rs10830963 increases risk of type 2 diabetes through a state of i-IFG and not through i-IGT. The same allele associates with estimates of β-cell dysfunction and hepatic insulin resistance.

  J. E Walter , F Rucci , L Patrizi , M Recher , S Regenass , T Paganini , M Keszei , I Pessach , P. A Lang , P. L Poliani , S Giliani , W Al Herz , M. J Cowan , J. M Puck , J Bleesing , T Niehues , C Schuetz , H Malech , S. S DeRavin , F Facchetti , A. R Gennery , E Andersson , N. R Kamani , J Sekiguchi , H. M Alenezi , J Chinen , G Dbaibo , G ElGhazali , A Fontana , S Pasic , C Detre , C Terhorst , F. W Alt and L. D. Notarangelo
 

The contribution of B cells to the pathology of Omenn syndrome and leaky severe combined immunodeficiency (SCID) has not been previously investigated. We have studied a mut/mut mouse model of leaky SCID with a homozygous Rag1 S723C mutation that impairs, but does not abrogate, V(D)J recombination activity. In spite of a severe block at the pro–B cell stage and profound B cell lymphopenia, significant serum levels of immunoglobulin (Ig) G, IgM, IgA, and IgE and a high proportion of Ig-secreting cells were detected in mut/mut mice. Antibody responses to trinitrophenyl (TNP)-Ficoll and production of high-affinity antibodies to TNP–keyhole limpet hemocyanin were severely impaired, even after adoptive transfer of wild-type CD4+ T cells. Mut/mut mice produced high amounts of low-affinity self-reactive antibodies and showed significant lymphocytic infiltrates in peripheral tissues. Autoantibody production was associated with impaired receptor editing and increased serum B cell–activating factor (BAFF) concentrations. Autoantibodies and elevated BAFF levels were also identified in patients with Omenn syndrome and leaky SCID as a result of hypomorphic RAG mutations. These data indicate that the stochastic generation of an autoreactive B cell repertoire, which is associated with defects in central and peripheral checkpoints of B cell tolerance, is an important, previously unrecognized, aspect of immunodeficiencies associated with hypomorphic RAG mutations.

 
 
 
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