A Functional Polymorphism of the Stromelysin Gene (MMP-3) Influences Susceptibility to Primary Sclerosing Cholangitis

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 121; no. 1; pp. 124 - 130
• Main Authors: Satsangi, Jack, Chapman, Roger W.G., Haldar, Neil, Donaldson, Peter, Mitchell, Stephen, Simmons, Jon, Norris, Suzanne, Marshall, Sara E., Bell, John I., Jewell, Derek P., Welsh, Ken I.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-07-2001; Elsevier
• Subjects: Adult; Alleles; Biological and medical sciences; Case-Control Studies; Cholangitis, Sclerosing - diagnosis; Cholangitis, Sclerosing - genetics; Female; Gastroenterology. Liver. Pancreas. Abdomen; Genetic Carrier Screening; Genetic Predisposition to Disease; Genotype; Humans; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Matrix Metalloproteinase 3 - genetics; Medical sciences; Other diseases. Semiology; Polymorphism, Genetic; Human; Stromelysin 1; Enzyme; Metalloendopeptidases; Biliary tract disease; Structure gene; Genetic determinism; Peptidases; Predisposition; Digestive diseases; Genetics; Hydrolases; Sclerosing cholangitis; Polymorphism
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/gast.2001.25527

Background & Aims:
We have investigated the influence of a biallelic polymorphism of the promoter region of stromelysin (matrix metalloproteinase 3) on susceptibility to primary sclerosing cholangitis (PSC). The 5A allele is associated with increased transcription, compared with wild-type (6A).
Methods:
An allelic association study was performed: in stage 1, 52 PSC patients (43 with inflammatory bowel disease [IBD]) and 99 healthy subjects (HS) were genotyped. In stage 2, 59 PSC patients (49 IBD), 84 patients with uncomplicated ulcerative colitis, and 72 HS were genotyped.
Results:
In stage 1, 5A carriage rate (90.4% vs. 72.7%;
P = 0.012) and 5A allelic frequency (65.4% vs. 48.5%;
P = 0.005) were increased, and 6A homozygosity was reduced in PSC (9.6% vs. 27.3%;
P = 0.012). In stage 2, 5A allelic carriage was increased in PSC (93.2% vs. 76.4% in HS;
P = 0.0092) and 6A homozygosity was reduced (6.8% vs. 23.8% in HS;
P = 0.0092). Portal hypertension was associated with 5A homozygosity in PSC (
P = 0.035; odds ratio [OR], 3.88). In the combined data set, 5A allelic frequencies (63.5% vs. 49.4%;
P = 0.001; OR, 1.78) and 5A carriage rates (91.9% vs. 74.2%;
P = 0.0002; OR, 3.92) were increased, and 6A homozygosity was reduced in PSC (8.1% vs. 25.7%;
P = 0.0002; OR, 0.25). Overall, portal hypertension was associated with 5A homozygosity (
P = 0.0192; OR, 3.12).
Conclusions:
Stromelysin polymorphism may influence susceptibility and disease progression in PSC.