期刊
DIABETES
卷 62, 期 10, 页码 3627-3635出版社
AMER DIABETES ASSOC
DOI: 10.2337/db13-0510
关键词
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资金
- National Institutes of Health [K23 DK076446, R01 HL068927, R01 HL068890, R01 DK066368, R01 HL095396, HG0004314]
- United States Cystic Fibrosis Foundation [CUTTIN06P0, R025-CR07, KNOWLE00A0, R026-CR07, KNOWLE11P0, STONEB12I0, DRUMM0A00]
- Pediatric Endocrine Society
- Genome Canada through the Ontario Genomics Institute [2004-OGI-3-05]
- Ontario Research Fund
- Research Excellence Program, the Ontario Ministry of Research and Innovation Early Researcher
- Cystic Fibrosis Canada
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Canadian Institutes of Health Research (CIHR) [119556]
- NSERC [250053-2008]
- CIHR [MOP 84287]
- United States Cystic Fibrosis Foundation
Diabetes is a common age-dependent complication of cystic fibrosis (CF) that is strongly influenced by modifier genes. We conducted a genome-wide association study in 3,059 individuals with CF (644 with CF-related diabetes [CFRD]) and identified single nucleotide polymorphisms (SNPs) within and 5 to the SLC26A9 gene that associated with CFRD (hazard ratio [HR] 1.38; P = 3.6 x 10(-8)). Replication was demonstrated in 694 individuals (124 with CFRD) (HR, 1.47; P = 0.007), with combined analysis significant at P = 9.8 x 10(-10). SLC26A9 is an epithelial chloride/bicarbonate channel that can interact with the CF transmembrane regulator (CFTR), the protein mutated in CF. We also hypothesized that common SNPs associated with type 2 diabetes also might affect risk for CFRD. A previous association of CFRD with SNPs in TCF7L2 was replicated in this study (P = 0.004; combined analysis P = 3.8 x 10(-6)), and type 2 diabetes SNPs at or near CDKAL1, CDKN2A/B, and IGF2BP2 were associated with CFRD (P < 0.004). These five loci accounted for 8.3% of the phenotypic variance in CFRD onset and had a combined population-attributable risk of 68%. Diabetes is a highly prevalent complication of CF, for which susceptibility is determined in part by variants at SLC26A9 (which mediates processes proximate to the CF disease-causing gene) and at four susceptibility loci for type 2 diabetes in the general population.
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