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Variants in mannose-binding lectin and tumor necrosis factor α affect survival in cystic fibrosis
  1. Kitti Buranawuti (kburana{at}msn.com)
  1. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, United States
    1. Michael P Boyle
    1. Department of Medicine, Johns Hopkins University School of Medicine, United States
      1. Suzanne Cheng
      1. Department of Human Genetics, Roche Molecular Systems Inc., United States
        1. Lori L Steiner
        1. Johns Hopkins University School of Medicine, United States
          1. Kathryn McDougal
          1. McKusick-Nathans Institute of Geneic Medicine, Johns Hopkins University School of Medicine, United States
            1. M Daniele Fallin
            1. Department of Epidemiology Johns Hopkins /Bloomberg School of Public Health, United States
              1. Christian Merlo
              1. Department of Medicine, Johns Hopkins University School of Medicine, United States
                1. Pamela L Zeitlin
                1. Department of Pediatrics, Johns Hopkins University School of Medicine, United States
                  1. Beryl J Rosenstein
                  1. Department of Pediatrics, Johns Hopkins University School of Medicine, United States
                    1. Peter J Mogayzel, Jr
                    1. Department of Pediatrics, Johns Hopkins University School of Medicine, United States
                      1. Xinjing Wang
                      1. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, United States
                        1. Garry R Cutting (gcutting{at}jhmi.edu)
                        1. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, United States

                          Abstract

                          Background: Cystic Fibrosis (CF) patients with the same mutations in the CF Transmembrane Conductance Regulator (CFTR) gene differ widely in survival suggesting other factors play a substantial role in mortality.

                          Objective: To determine if the genotype distribution of variants in 3 putative CF modifier genes (tumor necrosis factor α (TNF α), transforming growth factor β1 (TGFβ1) or mannose binding lectin (MBL2) differed among CF patients grouped according to age and survival status.

                          Methods: Genotypes of four variants (TNFα-238, TNFα-308, TGFβ1-509, and MBL2 O) were determined in 3 groups of 254 CF Caucasians from a single medical center: 101 CF children (<17 y.o.; mean age 9.4), 115 CF adults (≥17 y.o.; mean age 30.8), and 38 non-surviving CF adults (21 deceased and 17 lung transplant after 17 years of age). Genotypes of 127 healthy Caucasians in the same geographic region were used as controls. Kaplan-Meier and Cox hazard regression were used to evaluate genotype effect upon cumulative survival.

                          Results: Genotype frequencies among CF adults and CF children, differed for TNFα-238 (G/G vs G/A; p=0.022) and MBL2 (A/A vs O/O; p=0.016). When CF adults were compared to non-surviving CF adults, genotype frequencies of both genes differed (TNFα-238 G/G vs G/A; p= 0.0015 and MBL2: A/A vs O/O; p= 0.009). The hazard ratio for TNFα-238 G/G vs G/A was 0.25 (95% C.I. 0.06-1.0 p=0.04) and for MBL2 O/O vs A/A or A/O was 2.5 (95% C.I. 1.3-4.9; p=0.007).

                          Conclusions: TNFα-238 G/A and MBL2 O/O genotypes appear to be genetic modifiers of CF survival.

                          • cystic fibrosis
                          • inflammatory mediator
                          • innate immunity
                          • modifier gene
                          • mortality

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