A Whole Exome Study Identifies Novel Candidate Genes for Vertebral Bone Marrow Signal Changes (Modic Changes)

Abstract

Study Design. Family-based study Objective. To identify rare genetic factors predisposing to Modic changes (MC).Summary of Background Data. Lumbar disc degeneration (LDD) is one of the contributing factors behind low back pain (LBP). Lumbar MC visualized as bone marrow signal intensity changes on magnetic resonance imaging (MRI) represent a specific phenotype of LDD, which has stronger association with LBP than LDD without MC.Methods. The study set consisted of two Finnish families: Family I included seven affected and four unaffected individuals and Family II eight affected and seven unaffected individuals. MC were evaluated in 26 individuals using MRI. Whole exome sequencing was used to identify alleles co-segregating with MC. ANNOVAR was used to carry out functional annotation of alleles and their frequencies were evaluated using 1000Genomes, Sequencing Initiative Suomi (SISu) and the Exome Aggregation Consortium (ExAC) databases.Results. We identified predisposing genetic alleles for MC in two Finnish families. In each family only single allele co-segregated with MC. In Family I the observed allele was an insertion and deletion in the HSPG2 gene, resulting in a premature termination codon. In Family II a single nucleotide polymorphism (rs61753465) in the MAML1 gene was identified in all affected family members.Conclusions. We have identified two novel candidate genes, MAML1 and HSPG2, associating with MC. These genes are important in cartilage structure and joint cartilage maintenance. Our findings are novel among lumbar spine degenerative phenotypes.3

Intelligence-Based Spine Care Model: A New Era of Research and Clinical Decision-Making

“…For the past 20 years, the spine field has seen a surge in studies addressing human genetics and the ability to identify millions of individual single nucleotide polymorphisms in relation to various imaging and/or clinical phenotypes. [36][37][38][39][40][41][42][43][44][45][46][47][48][49] In fact, we have been witnesses to the rise of transcriptomics, proteomics, microbiome, metabolomics and a plethora of other big data "omics" platforms along with their applications toward spine disease. Even the phenotyping of disc cells and other spinal structures, the exponential rise of molecular and biomarker epidemiology, and motion kinematic and analyses further lend to multidimensional big data considerations and integration between different disciplines.…”

Whole exome sequencing in Finnish families identifies new candidate genes for osteoarthritis

“…This is not unexpected in the light of the Finnish population history of local isolates and enrichment of rare, functional alleles [ 16 – 18 ]. We have previously shown that specific variants associate with vertebral endplate signal changes (modic changes) in two Finnish families [ 45 ]. Functional evidence is needed, however, to understand the biological effect of the identified variants.…”

Does bone scintigraphy show Modic changes associated with increased bone turnover?

“…Some researchers believe that these processes are closely interrelated with each other and that each might play a role in the chain of events leading to MC [13,14]. Recently, novel candidate genes have also been identified as a predisposing factor [15].…”