Polymorphisms in COL15 Gene Are Not Associated with Systemic Sclerosis

SUDEEP P. PUSHPAKOM, ARIANE L. HERRICK, SHANT KUMAR, and JANE WORTHINGTON

ABSTRACT.

Objective. Systemic sclerosis (SSc) is marked by microvascular abnormalities leading to ischemic features such as Raynaud's phenomenon and fingertip ulcers. Digital ischemia in turn results in hypoxia, which is expected to drive compensatory angiogenesis; however, this phenomenon is deregulated in SSc. Vascular basement membrane (VBM) that consists of type IV, XV, and XVIII collagens supports the growth and survival of vascular endothelial cells and plays a key role in regulating angiogenesis. Recent gene expression analyses of skin tissue and dermal fibroblasts from patients with SSc revealed COL15 to be one of the significantly differentially regulated genes. We undertook an association study to explore the role of COL15 single-nucleotide polymorphisms (SNP) in SSc disease development.

Methods. Eleven SNP across COL15 were genotyped in a cohort of 175 UK Caucasian patients with SSc and 190 population-matched unrelated healthy subjects using 2 methods: TaqMan and SNaPshot. Statistical analysis was performed by Pearson's chi-square test and HelixTree software was utilized for haplotype analysis.

Results. No difference in genotype or allele frequencies were detected between patients with SSc and controls. None of the haplotype frequencies were found to differ between patients and controls.

Conclusion. Failure to detect an association may reflect a true lack of association or could be a false-negative result arising as a result of low power of the study. Our study had sufficient power to detect an effect size of 2.1 (p = 0.05); however, larger patient cohorts may be needed for exclusion of COL15 from a possible candidacy in SSc. (J Rheumatol First Release Jan 15 2008)

Key Indexing Terms:

SYSTEMIC SCLEROSIS
SCLERODERMA
GENE POLYMORPHISMS
COL15
VASCULAR BASEMENT MEMBRANE
ANGIOGENESIS

---

From the Department of Pathology and ARC Epidemiology Unit, University of Manchester, Manchester; and Rheumatic Diseases Centre, Hope Hospital, Salford, UK.

Supported by a grant from the Arthritis Research Campaign (ARC).

S.P Pushpakom, MPharm, PhD, Clinical Scientist, National Genetics Reference Laboratory, Department of Medical Genetics, St. Mary's Hospital, Manchester; A.L. Herrick ,MD, FRCP, Consultant Rheumatologist, Rheumatic Diseases Centre, Hope Hospital; S. Kumar, PhD, FRCPath, Professor, Department of Pathology; J. Worthington, PhD, Professor of Chronic Disease Genetics, ARC Epidemiology Unit, University of Manchester.

Address reprint requests to Dr. S.P. Pushpakom, National Genetics Reference Laboratory, Department of Medical Genetics, St. Mary's Hospital, Hathersage Road, Manchester M13 0JH, UK. E-mail: sudeep.parameshwar@cmmc.nhs.uk

Accepted for publication September 7, 2007.