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

Abstract

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.

Lack of association between adolescent idiopathic scoliosis and previously reported single nucleotide polymorphisms in MATN1, MTNR1B, TPH1, and IGF1 in a Japanese population

“…The previously reported association of rs1149048, rs10488682, and rs4753426 with AIS predisposition found in Chinese [19][20][21] was not replicated in our study (Table 1). This lack of replication is not unusual in genetic-association studies of common diseases.…”

“…Chen et al 19 reported an association between rs1149048 and curve severity in a study of 267 AIS cases, and Yeung et al 22 reported an association between rs5742612 and curve severity in a study of 340 AIS cases. However, these associations were not replicated in our analysis of 538 cases (Table 2).…”

“…Alternatively, it might result from a lack of statistical power. According to the data of the previous studies, [19][20][21] the odds ratios for the association between the SNPs rs1149048, rs10488682, and rs4753426 with AIS predisposition were 1.61, 1.29, and 3.54, respectively. The present study has a power of 100%, 80%, and 100% to detect associations with these effect sizes, and therefore has sufficient power to detect any possible associations.…”

“…Recent genome-wide linkage analyses have identified many predisposing loci of AIS, [7][8][9][10][11][12][13][14][15][16] further supporting a role of genetic factor(s) in AIS. Single nucleotide polymorphisms (SNPs) in the genes for estrogen receptor 1 (ESR1), 17 estrogen receptor 2 (ESR2), 18 matrilin 1 (MATN1), 19 melatonin receptor 1B (MTNR1B), 20 and tryptophan hydroxylase 1 (TPH1) 21 are reported to be associated with AIS predisposition. In addition, SNPs in ESR1, 17,22 ESR2, 18 MATN1, 19 and insulin-like growth factor 1 (IGF1) 23 are reported to be associated with curve severity.…”

“…25 An association of rs1149048 in MATN1 with AIS predisposition and curve severity was reported in a study of Chinese using 419 cases and 750 controls. 19 Melatonin is a hormone primarily synthesized by pinealocytes in the pineal gland. 26 Machida et al 27 found that pinealectomy in chickens consistently produces scoliosis, and intramuscular implantation of the pineal gland into pinealectomized chickens prevents the development of experimentally induced scoliosis.…”