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Wright FA Strug LJ Doshi VK Commander CW Blackman SM Sun L Berthiaume Y Cutler D Cojocaru A Collaco JM Corey M Dorfman R Goddard K Green D Kent JW Lange EM Lee S Li W Luo J Mayhew GM Naughton KM Pace RG Paré P Rommens JM Sandford A Stonebraker JR Sun W Taylor C Vanscoy LL Zou F Blangero J Zielenski J O'Neal WK Drumm ML Durie PR Knowles MR Cutting GR 《Nature genetics》2011,43(6):539-546
A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 × 10(-8)) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del homozygotes (P = 0.006) from a separate family based study (n = 557), with P = 1.49 × 10(-9) for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family based study identified a significant quantitative trait locus on chromosome 20q13.2 (log(10) odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder. 相似文献
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Sun L Rommens JM Corvol H Li W Li X Chiang TA Lin F Dorfman R Busson PF Parekh RV Zelenika D Blackman SM Corey M Doshi VK Henderson L Naughton KM O'Neal WK Pace RG Stonebraker JR Wood SD Wright FA Zielenski J Clement A Drumm ML Boëlle PY Cutting GR Knowles MR Durie PR Strug LJ 《Nature genetics》2012,44(5):562-569
Variants associated with meconium ileus in cystic fibrosis were identified in 3,763 affected individuals by genome-wide association study (GWAS). Five SNPs at two loci near SLC6A14 at Xq23-24 (minimum P = 1.28 × 10(-12) at rs3788766) and SLC26A9 at 1q32.1 (minimum P = 9.88 × 10(-9) at rs4077468) accounted for ~5% of phenotypic variability and were replicated in an independent sample of affected individuals (n = 2,372; P = 0.001 and 0.0001, respectively). By incorporating the knowledge that disease-causing mutations in CFTR alter electrolyte and fluid flux across surface epithelium into a hypothesis-driven GWAS (GWAS-HD), we identified associations with the same SNPs in SLC6A14 and SLC26A9 and established evidence for the involvement of SNPs in a third solute carrier gene, SLC9A3. In addition, GWAS-HD provided evidence of association between meconium ileus and multiple genes encoding constituents of the apical plasma membrane where CFTR resides (P = 0.0002; testing of 155 apical membrane genes jointly and in replication, P = 0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis. 相似文献
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Pan SH O'Neal JP Badzey RL Chamon C Ding H Engelbrecht JR Wang Z Eisaki H Uchida S Gupta AK Ng KW Hudson EW Lang KM Davis JC 《Nature》2001,413(6853):282-285
The parent compounds of the copper oxide high-transition-temperature (high-Tc) superconductors are unusual insulators (so-called Mott insulators). Superconductivity arises when they are 'doped' away from stoichiometry. For the compound Bi2Sr2CaCu2O8+x, doping is achieved by adding extra oxygen atoms, which introduce positive charge carriers ('holes') into the CuO2 planes where the superconductivity is believed to originate. Aside from providing the charge carriers, the role of the oxygen dopants is not well understood, nor is it clear how the charge carriers are distributed on the planes. Many models of high-Tc superconductivity accordingly assume that the introduced carriers are distributed uniformly, leading to an electronically homogeneous system as in ordinary metals. Here we report the presence of an electronic inhomogeneity in Bi2Sr2CaCu2O8+x, on the basis of observations using scanning tunnelling microscopy and spectroscopy. The inhomogeneity is manifested as spatial variations in both the local density of states spectrum and the superconducting energy gap. These variations are correlated spatially and vary on the surprisingly short length scale of approximately 14 A. Our analysis suggests that this inhomogeneity is a consequence of proximity to a Mott insulator resulting in poor screening of the charge potentials associated with the oxygen ions left in the BiO plane after doping, and is indicative of the local nature of the superconducting state. 相似文献
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