Details

Autor(en) / Beteiligte

• LEI SUN
• ROMMENS, Johanna M
• ZELENIKA, Diana
• BLACKMAN, Scott M
• COREY, Mary
• DOSHI, Vishal K
• HENDERSON, Lindsay
• NAUGHTON, Kathleen M
• O'NEAL, Wanda K
• PACE, Rhonda G
• STONEBRAKER, Jaclyn R
• WOOD, Sally D
• CORVOL, Harriet
• WRIGHT, Fred A
• ZIELENSKI, Julian
• CLEMENT, Annick
• DRUMM, Mitchell L
• BOËLLE, Pierre-Yves
• CUTTING, Garry R
• KNOWLES, Michael R
• DURIE, Peter R
• STRUNG, Lisa J
• WEILI LI
• XIN LI
• CHIANG, Theodore A
• FAN LIN
• DORFMAN, Ruslan
• BUSSON, Pierre-François
• PAREKH, Rashmi V

Titel

Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis

Ist Teil von

• Nature genetics, 2012-05, Vol.44 (5), p.562-569

Ort / Verlag

New York, NY: Nature Publishing Group

Erscheinungsjahr

2012

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.