Lack of Association Between the Aggrecan Gene and Familial Idiopathic Scoliosis

Marosy, Beth; Justice, Cristina M.; Nzegwu, Nneka; Kumar, Gunjan; Wilson, Alexander F.; Miller, Nancy H.

doi:10.1097/01.brs.0000219944.18223.52

Cited by 27 publications

(12 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…2 As scoliosis is a phenotypic characteristic of many ECM disorders, such as Marfan syndrome and Ehlers -Danlos syndrome, the hypothesis that a defect within the ECM is the causative factor of idiopathic scoliosis is plausible. Preliminary studies have focused on the genes responsible for the structural components of the ECM system, including COL1A1, 19 COL1A2, 19,20 COL2A1, 19 FBN1, 20 elastin 20 and aggrecan genes; 21,22 however, all the genes were excluded as potential causative factors for idiopathic scoliosis within the study populations. Matrilin-1, a non-collagenous protein, is secreted primarily by chondrocytes and has a role in the assembly of cartilage ECM.…”

Section: Introductionmentioning

confidence: 99%

Promoter polymorphism of matrilin-1 gene predisposes to adolescent idiopathic scoliosis in a Chinese population

et al. 2008

View full text Add to dashboard Cite

Adolescent idiopathic scoliosis (AIS) is widely recognized as a complex disorder with a strong genetic predisposition. In previous studies, a number of extracellular matrixes (ECMs) related genes have been duplicated as candidate genes for AIS. Matrilin-1 plays an important role in the organization of the ECM, and matrilin-1 gene (MATN1) mutant mice showed similar phenotypes to scoliosis. We hypothesized that MATN1 was a candidate predisposition gene for AIS. A gene-based association study was conducted using seven tagging SNPs identified from the HapMap data. For initial screening, the seven tagSNPs were genotyped in 197 cases and 172 controls. Next, we validated any significant association in an additional sample of 222 cases and 288 controls. In addition, another 290 controls were genotyped to confirm the results. We found that allele G of rs1149048 was a significant predisposition allele of AIS (P ¼ 0.0007, odds ratio (OR) ¼ 1.35 within 95% confidence interval (CI) ¼ 1.14 -1.61), and individuals with genotype GG had a higher risk for AIS compared with AA þ AG (P ¼ 0.0001, OR ¼ 1.61 within 95% CI ¼ 1.25-2.08). Polymorphism of rs1149048 was also associated with curve severity in AIS patients. Also, a significantly higher maximum Cobb angle was found in patients with GG genotype (P ¼ 0.002). We concluded that the tagSNP rs1149048 polymorphism in the MATN1 promoter region was associated with both susceptibility and disease progression in AIS.

show abstract

Section: Introductionmentioning

confidence: 99%

Promoter polymorphism of matrilin-1 gene predisposes to adolescent idiopathic scoliosis in a Chinese population

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Studies that tested associations using microsatellite markers are not listed: Aggrecan, tested in American [18] and Russian [16] cohorts; COL1A1, COL1A2, and COL2A1, tested in 4 Caucasian families with autosomal dominant inheritance [15]; COL1A2, ELN, and FBN1, tested in 11 Caucasian families with autosomal dominant inheritance [14]; and MTNR1A, tested in an American cohort [17] SNP single nucleotide polymorphism* Female cohort…”

Section: Candidate Gene Studiesmentioning

confidence: 99%

“…The genes encoding fibrillin ( FBN1 ), elastin ( ELN ), collagen I A1 and A2 ( COL1A1 , COL1A2 ), collagen II A1 ( COL2A1 ), and aggrecan ( ACAN ), showed no association with IS on linkage analysis and/or transmission disequilibrium testing [14–16, 18]. Interestingly, using 50 informative Italian trios, Montanaro and colleagues [19] showed that an intragenic microsatellite (short tandem repeat) polymorphism in the 3′ untranslated region of the matrilin 1 gene ( MATN1 ) was associated with adolescent IS.…”

Section: Candidate Gene Studiesmentioning

confidence: 99%

The genetic epidemiology of idiopathic scoliosis

2012

View full text Add to dashboard Cite

PurposeIdiopathic scoliosis is a complex developmental syndrome defined by an abnormal structural curvature of the spine. High treatment costs, chronic pain/discomfort, and the need for monitoring at-risk individuals contribute to the global healthcare burden of this musculoskeletal disease. Although many studies have endeavored to identify underlying genes, little progress has been made in understanding the etiopathogenesis. The objective of this comprehensive review was to summarize genetic associations/linkages with idiopathic scoliosis, as well as explore the strengths and weaknesses of each study, such that it may serve as a guide for the design and interpretation of future genetic studies in scoliosis.MethodsWe searched PubMed and Human Genome Epidemiology (HuGE) Navigator using the search terms “gene and scoliosis”. Linkage or association studies published in English and available full-text were further analyzed as regards results, experimental design, and statistical approach.ResultsWe identified and analyzed 50 studies matching our criteria. These consisted of 34 candidate gene studies (6 linkage, 28 association) and 16 genome-wide studies [14 pedigree-based linkage, 2 genome-wide association studies (GWAS)]. Findings involved genes related to connective tissue structure, bone formation/metabolism, melatonin signaling pathways, puberty and growth, and axon guidance pathways. Variability in results between studies suggested ethnic and/or genetic heterogeneity.ConclusionsThe major difficulty in idiopathic scoliosis research is phenotypic and genetic heterogeneity. Genetic research was overrepresented by underpowered studies. The use of biological endophenotypes, as well as restricted clinical definitions, may help to partition variation and increase the power of studies to detect or confirm an effect.

show abstract

“…IS-related susceptible genes currently being researched include melatonin receptor 1A [14], melatonin receptor 1B [15], Matrilin-1 (MATN1) [16], γ-1-syntrophin (SNTG1) [17], COL1A1 [18], COL1A2, COL2A1, elastic fibre [19] and aggrecan [20] genes. Studies showed that these genes are related with IS but cannot explain all IS patients.…”

Section: Introductionmentioning

confidence: 99%

“…Studies showed that these genes are related with IS but cannot explain all IS patients. Chromosomal regions involved in IS susceptibility include 6p, 10q, 18q [21], 6p, 6q, 17p11.2 [5], 8q [22], 9q, 16q [23], 19p13 [3], 19p13.3 [9], 15q25-26 [20], 9q31.2, 9q34.2, 17q25.3-qtel [24], 12p [25] and Xq23-26 [26]. There are considerable numbers of genes in these foci.…”

Section: Introductionmentioning

confidence: 99%

Epidemiological survey of idiopathic scoliosis and sequence alignment analysis of multiple candidate genes

Yang

QuanZhang

Guo

et al. 2011

International Orthopaedics (SICOT)

View full text Add to dashboard Cite

Purpose To investigate the effects of genetic factors on idiopathic scoliosis (IS) and genetic modes through genetic epidemiological survey on IS in Chongqing City, China, and to determine whether SH3GL1, GADD45B, and FGF22 in the chromosome 19p13.3 are the pathogenic genes of IS through genetic sequence analysis. Methods 214 nuclear families were investigated to analyse the age incidence, familial aggregation, and heritability. SH3GL1, GADD45B, and FGF22 were chosen as candidate genes for mutation screening in 56 IS patients of 214 families. The sequence alignment analysis was performed to determine mutations and predict the protein structure. Results The average age of onset of 10.8 years suggests that IS is a early onset disease. Incidences of IS in first-, second-, third-degree relatives and the overall incidence in families (5.68%) were also significantly higher than that of the general population (1.04%). The U test indicated a significant difference, suggesting that IS has a familial aggregation. The heritability of first-degree relatives (77.68 ±10.39%), seconddegree relatives (69.89 ±3.14%), and third-degree relatives (62.14 ±11.92%) illustrated that genetic factors play an important role in IS pathogenesis. The incidence of firstdegree relatives (10.01%), second-degree relatives (2.55%) and third-degree relatives (1.76%) illustrated that IS is not in simple accord with monogenic Mendel's law but manifests as traits of multifactorial hereditary diseases. Sequence alignment of exons of SH3GL1, GADD45B, and FGF22 showed 17 base mutations, of which 16 mutations do not induce open reading frame (ORF) shift or amino acid changes whereas one mutation (C→T)occurred in SH3GL1 results in formation of the termination codon, which induces variation of protein reading frame. Prediction analysis of protein sequence showed that the SH3GL1 mutant encoded a truncated protein, thus affecting the protein structure. Conclusion IS is a multifactorial genetic disease and SH3GL1 may be one of the pathogenic genes for IS.

show abstract

Lack of Association Between the Aggrecan Gene and Familial Idiopathic Scoliosis

Abstract: Despite the negative association reported here, further investigation of the gene and its potential association to FIS is required.

Cited by 27 publications

References 30 publications

Promoter polymorphism of matrilin-1 gene predisposes to adolescent idiopathic scoliosis in a Chinese population

Promoter polymorphism of matrilin-1 gene predisposes to adolescent idiopathic scoliosis in a Chinese population

The genetic epidemiology of idiopathic scoliosis

Epidemiological survey of idiopathic scoliosis and sequence alignment analysis of multiple candidate genes

Contact Info

Product

Resources

About