Phenotype variations affect genetic association studies of degenerative disc disease: conclusions of analysis of genetic association of 58 single nucleotide polymorphisms with highly specific phenotypes for disc degeneration in 332 subjects

• Published in: The spine journal 2013-10, Vol.13 (10), p.1309-1320
• Main Authors: Rajasekaran, S., MS, MCh, FRCS(Ed), FRCS(London), FACS, PhD, Kanna, Rishi Mugesh, MS Ortho, MRCS (UK), FNB Spine, Senthil, Natesan, PhD, Raveendran, Muthuraja, PhD, Cheung, Kenneth M.C., PhD, Chan, Danny, PhD, Subramaniam, Sakthikanal, MS, DNB, Shetty, Ajoy Prasad, MS, DNB
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Asian Continental Ancestry Group - genetics; Case-Control Studies; Cross-Sectional Studies; Disc degeneration; Female; Genetic association; Genetic Association Studies - methods; Genetic Predisposition to Disease - ethnology; Genetic Predisposition to Disease - genetics; Genotype; Humans; India; Intervertebral Disc Degeneration - diagnostic imaging; Intervertebral Disc Degeneration - genetics; Male; Middle Aged; Orthopedics; Phenotype; Polymorphism, Single Nucleotide; Radiography; Single nucleotide Polymorphism; Young Adult
• ISSN: 1529-9430; 1878-1632
• DOI: 10.1016/j.spinee.2013.05.019

Abstract Background context Although the influence of genetics on the process of disc degeneration is well recognized, in recently published studies, there is a wide variation in the race and selection criteria for such study populations. More importantly, the radiographic features of disc degeneration that are selected to represent the disc degeneration phenotype are variable in these studies. The study presented here evaluates the association between single nucleotide polymorphisms (SNPs) of candidate genes and three distinct radiographic features that can be defined as the degenerative disc disease (DDD) phenotype. Purpose The study objectives were to examine the allelic diversity of 58 SNPs related to 35 candidate genes related to lumbar DDD, to evaluate the association in a hitherto unevaluated ethnic Indian population that represents more than one-sixth of the world population, and to analyze how genetic associations can vary in the same study subjects with the choice of phenotype. Study design A cross-sectional, case-control study of an ethnic Indian population was carried out. Methods Fifty-eight SNPs in 35 potential candidate genes were evaluated in 342 subjects and the associations were analyzed against three highly specific markers for DDD, namely disc degeneration by Pfirrmann grading, end-plate damage evaluated by total end-plate damage score, and annular tears evaluated by disc herniations and hyperintense zones. Genotyping of cases and controls was performed on a genome-wide SNP array to identify potential associated disease loci. The results from the genome-wide SNP array were then used to facilitate SNP selection and genotype validation was conducted using Sequenom-based genotyping. Results Eleven of the 58 SNPs provided evidence of association with one of the phenotypes. For annular tears, rs1042631 SNP of AGC1 and rs467691 SNP of ADAMTS5 were highly significantly associated (p