Abstract:

Background: Legg-Calve-Perthes disease (LCPD) is one of the most common causes of paediatric femoral head osteonecrosis. Besides the other known etiological aspects, till now genetic aspect has not been studied extensively. The present study was aimed to find the association of genetic polymorphism of CYR61 and MTHFR gene with the LCPD.

Materials and Methods: Single Nucleotide Polymorphisms (SNPs) analysis of the CYR61 and MTHFR genes in 41LCPDpatients and 110 healthy controls were genotyped in this hospital-based study by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP).

Results: The frequency of CYR61gene homozygous mutant GG polymorphism was not significant in LCPD patients when compared with controls.MTHFRC677T homozygous mutant TT polymorphism was significant in LCPD patients as compared to controls.

Conclusions: The present study showed a significant association of T allele of MTHFR C677T polymorphism with LCPD and may be regarded as a risk factor to develop the LCPD in North Indian patients.

References:

[1] Bahmanyar S, Montgomery SM, Weiss RJ, Ekbom A. Maternal smoking during pregnancy, other prenatal and perinatal factors, and the risk of Legg-Calve-Perthes disease. Pediatrics.2008;122:e459- 464.

[2] Boccia S, Hung R, Ricciardi G, Gianfagna F, Ebert MP, Fang JY, Gao CM, Gotze T, Graziano F, Lacasaña-Navarro M, Lin D, Lopez-Carrillo L, Qiao YL, Shen H, Stolzenberg-Solomon R, Takezaki T, Weng YR, Zhang FF, van Duijn CM, Boffetta P, Taioli E. Meta- and pooled analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer risk: a huge-GSEC review. Am J Epidemiol.2008; 167: 505- 516.

[3] Catterall A. Legg-calve Perthes syndrome. ClinorthopRelat Res 1981, 158:41-52

[4] Campbell I G. Methylenetetrahydrofolate reductase polymorphism and susceptibility to breast cancer. Breast Cancer Res. 2002; 14: 1-4.

[5] Chung SM. The arterial supply of the developing proximal end of the human femur. J Bone Joint Surg Am.1976;58:961- 970.

[6] Chu X, Dong C, Lei R, Sun L, Wang Z, Dong Y, Shen M, Wang Y, Wang B, Zhang K, Yang L, Li Y, Yuan W, Wang Y, Song H, Jin L, Xiong M, Huang W. Polymorphisms in the interleukin 3 gene show strong association with susceptibility to Graves' disease in Chinese population. Genes Immun.2009; 10: 260- 266.

[7] De Inocencio J. Epidemiology of musculoskeletal pain in primary care. Arch Dis Child.2004;89:431- 434.

[8] Hall AJ, Barker DJ, Dangerfield PH, Taylor JF. Perthes’ disease of the hip in Liverpool. Br Med J (Clin Res Ed).1983;287:1757- 1759.

[9] Kim HK. Legg-Calve-Perthes disease: etiology, pathogenesis, and biology. J PediatrOrthop.2011;31(2 suppl):S141- 146.

[10] Jandial S, Myers A, Wise E, Foster HE. Doctors likely to encounter children with musculoskeletal complaints have low confidence in their clinical skills. J Pediatr.2009;154:267-71.

[11] Jeong MC, Navani A, Oksenberg JR. Limited allelic polymorphismin the human interleukin-3 gene. Mol Cell Probes. 1998; 12: 49- 53.

[12] Joseph B, Varghese G, Mulpuri K, NarasimhaRao K, Nair NS. Natural evolution of Perthes disease: a study of 610 children under 12 years of age at disease onset. J PediatrOrthop.2003;23:590-600.

[13] Joseph B, Willoughby R. Perthes' disease: a review of contributions from the Asia-pacific region. Malays Orthop J. 2010;4: 1- 8.

[14] Kim HK. Legg-Calve-Perthes disease. J Am AcadOrthopSurg.2010;18: 676- 686.

[15] Kim HK, Morgan-Bagley S, Kostenuik P. RANKL inhibition: a novel strategy to decrease femoral head deformity after ischemicosteonecrosis. J Bone Miner Res.2006;21: 1946- 1954.

[16] Kim HK. Pathophysiology and new strategies for the treatment of Legg-Calve-Perthes disease. J Bone Joint Surg Am.2012;94: 659- 669.

[17] Lee ST, Vaidya SV, Song HR, Lee SH, Suh SW, Telang SS. Bone age delay patterns in Legg-Calve-Perthes disease: an analysis using the Tanner and Whitehouse 3 method. J PediatrOrthop.2007;27:198-203.

[18] Lechner A, Schutze N, Siggelkow H, Seufert J, Jakob F. The immediate early gene product hCYR61 localizes to the secretory pathway in human osteoblasts. Bone. 2000 Jul;27(1):53-60.

[19] Molloy MK, MacMahon B. Incidence of Legg-Perthes disease (osteochondritisde formans). N Engl J Med 1966;275:988-90.

[20] Nagase Y, Iwasawa M, Akiyama T, Kadono Y, Nakamura M, Oshima Y, Yasui T, Matsumoto T, Hirose J, Nakamura H, Miyamoto T, Bouillet P, Nakamura K, Tanaka S. Anti-apoptotic moleculeBcl-2 regulates the differentiation, activation, and survival of bothosteoblasts and osteoclasts. J Biol Chem.2009;284: 36659- 36669.

[21] Nelitz M, Lippacher S, Krauspe R, Reichel H.Perthes disease: current principles of diagnosis and treatment. Dtsch Arztebl Int.2009;106:517- 523.

[22] Park BL, Kim LH, Choi YH, Lee JH, Rhim T, Lee YM, Uh ST, Park HS, Choi BW, Hong SJ, Park CS, Shin HD. Interleukin 3 (IL3)polymorphisms associated with decreased risk of asthma and atopy. J Hum Genet. 2004; 49: 517- 527.

[23] Perry DC, Machin DM, Pope D, Bruce CE, Dangerfield P, Platt MJ, et al. Racial and geographic factors in the incidence of Legg-Calve-Perthes’ disease: a systematic review. Am J Epidemiol.2012;175:159-66.

[24] Sanja Srzentic, Gordana Nikcevic, Dusko Spasovski, Zoran Bascarevic, Zorica Zivkovic, Zorica Terzic-Supic, Dragana Matanovic, Valentina Djordjevic, Sonja Pavlovic, Vesna Spasovski. Predictive genetic markers of coagulation, inflammation and apoptosis in Perthes disease-Serbian experience. Eur J Pediatr.2015; 174: 1085-1092.

[25] Syed Rizwan Hussain ,Hena Naqvi , Syed Tasleem Raza, Faisal Ahmed, Sunil G. Babu, Ashutosh Kumar, Zeashan Haider Zaidi, Farzana Mahdi. Methylenetetrahydrofolate reductase C677T genetic polymorphisms and risk of leukaemia among the North Indian population. Cancer Epidemiology.2012; 36: 227-231.

[26] Tao L, Chen J, Zhou H, Qin C, Li P, Cao Q, Li J, Ju X, Zhu C, Wang M, Zhang Z, Shao P, Yin C. A functional polymorphism in the CYR61 (IGFBP10) gene is associated with prostate cancer risk. Prostate Cancer Prostatic Dis. 2013; 16: 95- 100.

[27] Yamada R, Tanaka T, Unoki M, Nagai T, Sawada T, Ohnishi Y, Tsunoda T, Yukioka M, Maeda A, Suzuki K, Tateishi H, Ochi T, Nakamura Y, Yamamoto K. Association between a singlenucleotidepolymorphism in the promoter of the human interleukin-3 gene and rheumatoid arthritis in Japanese patients, and maximumlikelihoodestimation of combinatorial effect that two genetic locihave on susceptibility to the disease. Am J Hum Genet.2001;68: 674- 685.