Lysyl oxidase polymorphisms and susceptibility to osteosarcoma.
Despite the knowledge of many genetic alterations present in osteosarcoma, the complexity of this disease precludes placing its biology into a simple conceptual framework. Lysyl oxidase (LOX) catalyzes the cross-linking of elastin and collagen, which is essential for the structural integrity and function of bone tissue. In the current study, we performed genomic sequencing on all seven exons--including the intron-exon splice sites, and the putative promoter region of LOX gene--followed by luciferase reporter assay to analyze the function of newly identified polymorphisms. Associations between LOX polymorphisms and osteosarcoma were then evaluated. Our sequencing data revealed three polymorphisms (-22G/C, 225C/G, and 473G/A) in the exons and promoter region of LOX. The -22G/C polymorphism lies in the downstream core promoter element (DPE) region and caused a decrease in promoter activity of LOX. The prevalence of the -22C allele and 473A allele were significantly increased in osteosarcoma patients compared to controls (odds ratio [OR] = 3.88, 95% confidence interval [CI]= 1.94-7.78, p = 4.18×10(-5), and OR = 1.38, 95%CI = 1.07-1.78, p = 0.013; p 0.0167 was considered significant after Bonferroni correction). Analyzing haplotype showed that the frequency of CCG haplotype (-22, 225, 473) was significantly higher in osteosarcoma cases than in healthy controls after Bonferroni correction (p = 4.46×10(-4)). These results indicate that the -22G/C polymorphism may affect the expression of LOX, and that -22G/C and 473G/A polymorphisms may be new risk factors for osteosarcoma. These findings reveal a potential new pathway by which genetic polymorphisms may affect human diseases.
Department of Spine Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Yang
Y
Liu
Bitao
B
Lv
Zhimin
Z
He
Yujia
Y
Zhou
Carrie
C
Han
Guodong
G
Shi
Rui
R
Gao
Ce
C
Wang
Lili
L
Yang
Haihan
H
Song
Wen
W
Yuan
D000293:Adolescent; D000328:Adult; D000368:Aged; D000594:Amino Acid Oxidoreductases / Q000235:genetics*; D020029:Base Pairing / Q000235:genetics; D001483:Base Sequence; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016366:Open Reading Frames / Q000235:genetics; D012516:Osteosarcoma / Q000201:enzymology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D055815:Young Adult
D000594:Amino Acid Oxidoreductases; C445313:LOXL1 protein, human