IRF6基因多态性与黔北人群非综合征性唇腭裂的相关性研究
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摘要
目的探讨黔北地区人群IRF6基因rs2235371和rs2235373 SNP位点的多态性及其与非综合征性唇腭裂的相关性。方法采用PCR和测序方法对153个对照儿童和123个NSCL/P儿童的IRF6基因中2个SNP位点rs2235371和rs2235373进行扩增和测序;对样本群体进行Hardy-Weinberg平衡分析,比较2组人群的基因型频率、等位基因频率及OR分析;两位点连锁不平衡分析。结果对照组与病例组人群rs2235371基因型均含有GG、GA和AA型,rs2235373位点均含有CC、CT和TT型。对于2个位点,对照组和病例组均符合Hardy-Weinberg平衡法则(P>0.05)。2组人群中,rs2235371和rs2235373位点的等位基因和基因型差异均有统计学意义(P<0.05);rs2235371位点GGvs GA的OR值(95%CI)=1.725(1.025～2.902),GGvs AA的OR值(95%CI)=2.100(1.109～4.328);rs2235373位点CCvs TT的OR值(95%CI)=2.263(1.348～5.015),CTvs TT的OR值(95%CI)=2.061(1.108～2.169);(P<0.05)。rs2235371和rs2235373位点存在连锁不平衡,GC单倍型是主要的单倍体型,对NSCL/P均有致病风险,OR值(95%CI)=1.722(1.219～2.431),(P<0.05)。结论在黔北地区人群中,IRF6基因rs2235371和rs2235373位点均具有多态性;rs2235371位点的GG基因型和rs2235373位点的CC、CT基因型与NSCL/P的发生有相关性;rs2235371和rs2235373位点存在连锁不平衡,GC单倍型对NSCL/P有致病风险。
Objective To study the correlation between SNP sites rs2235371 and rs2235373 of IRF6 gene and nonsyndromic clepft lip with or without cleft in north of Guizhou. Methods PCR and DNA sequencing technology were used to detect the SNP sites in the IRF6 gene in 153 children without NSCL/P(control group) and 123 children with NSCL/P(case group). Two groups were performed Hardy-Weinberg test, Genotype frequencies analyses, allele frequencies analyses and odd ration analyses. Linkage disequilibrium analysis was performed on rs2235371 and rs2235373. Results SNP rs2235371 contained GG, GA and AA genetypes while SNP rs2235373 contained CC, CT and TT genetypes in both groups. The two groups were in line with the principles of Hardy-Weinberg equilibrium(P>0.05). The difference of frequencies of genotype and allele in two SNP sites between two groups were statistically significant(P<0.05). In rs2235371 site, OR(95%CI) of GGvsGA=1.725(1.025-2.902) and OR(95%CI) of GGvsAA=2.100(1.109-4.328). In rs2235373 site, OR(95%CI) of CCvsTT=2.263(1.348-5.015)and OR(95%CI) of CTvsTT=2.061(1.108-2.169). There was linkage disequilibrium between rs2235371 and rs2235373. GC haplotype was the main haplotype and be risk to NSCL/P, OR(95%CI)=1.722(1.219-2.431)(P<0.05). Conclusion Polymorphism exists in rs2235371 and rs2235373 in the people from north of Guizhou. GG genetype of rs2235371 is related to NSCL/P. CC and CT genetype of rs2235373 is related to NSCL/P. There is linkage disequilibrium between rs2235371 and rs2235373 of IRF6 gene. GC haplotype is risk to NSCL/P.
Objective To study the correlation between SNP sites rs2235371 and rs2235373 of IRF6 gene and nonsyndromic clepft lip with or without cleft in north of Guizhou. Methods PCR and DNA sequencing technology were used to detect the SNP sites in the IRF6 gene in 153 children without NSCL/P(control group) and 123 children with NSCL/P(case group). Two groups were performed Hardy-Weinberg test, Genotype frequencies analyses, allele frequencies analyses and odd ration analyses. Linkage disequilibrium analysis was performed on rs2235371 and rs2235373. Results SNP rs2235371 contained GG, GA and AA genetypes while SNP rs2235373 contained CC, CT and TT genetypes in both groups. The two groups were in line with the principles of Hardy-Weinberg equilibrium(P>0.05). The difference of frequencies of genotype and allele in two SNP sites between two groups were statistically significant(P<0.05). In rs2235371 site, OR(95%CI) of GGvsGA=1.725(1.025-2.902) and OR(95%CI) of GGvsAA=2.100(1.109-4.328). In rs2235373 site, OR(95%CI) of CCvsTT=2.263(1.348-5.015)and OR(95%CI) of CTvsTT=2.061(1.108-2.169). There was linkage disequilibrium between rs2235371 and rs2235373. GC haplotype was the main haplotype and be risk to NSCL/P, OR(95%CI)=1.722(1.219-2.431)(P<0.05). Conclusion Polymorphism exists in rs2235371 and rs2235373 in the people from north of Guizhou. GG genetype of rs2235371 is related to NSCL/P. CC and CT genetype of rs2235373 is related to NSCL/P. There is linkage disequilibrium between rs2235371 and rs2235373 of IRF6 gene. GC haplotype is risk to NSCL/P.
引文
[1] Mossey PA, Little J, Munger RG, et al. Cleft lip and palate[J]. Lancet,2009, 374(9703):1773-1785.
[2] Calzolari E, Pierini A, Astolfi G, et al. Associated anomalies in multi-malformed infants with cleft lip and palate:An epidemiologic study of nearly 6 million births in 23 EUROCAT registries[J]. American Journal of Medical Genetics Part A, 2007, 143A(6):528-537.
[3] Carinci F, Pezzetti F, Scapoli L, et al. Recent developments in orofacial cleft genetics[J]. The Journal of Craniofacial Surgery, 2003,14(2):130-143.
[4] Kondo S, Schutte BC, Richardson RJ, et al. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes[J]. Nature Genetics, 2002, 32(2):285-289.
[5] Lu Y, Liu Q, Xu W, et al. TGFA and IRF6 contribute to the risk of nonsyndromic cleft lip with or without cleft palate in Northeast China[J]. PLOS One, 2013, 8(8):e70754.
[6]黄永清.中国西部人群IRF6、MSX1基因SNPs与非综合症唇腭裂相关性的研究[D].成都：四川大学，2007.
[7]张健，古力巴哈·买买提力，洪玉.IRF6基因多态性位点与新疆维吾尔族、汉族非综合征性唇腭裂的相关性研究[J].中国医科大学学报，2013,42(5):388-393.
[8]沈亚，程璐，万伟东，等.非综合征性唇腭裂与干扰素调节因子6和转化生长因子α单核苷酸多态性的相关性[J].中华检验医学杂志，2007,30(12):1349-1353.
[9] Blanton SH, Burt A, Garcia E, et al. Ethnic heterogeneity of IRF6 AP-2αbinding site promoter SNP association with nonsyndromic cleft lip and palate[J]. Cleft Palate-Craniofacial Journal, 2010, 47(6):574-577.
[10] Ibarra-Arce A, García-álvarez M, Cortés-González D, et al.IRF6 polymorphisms in Mexican patients with non-syndromic cleft lip[J]. Meta Gene, 2015, 4:8-16.
[11] Letra A, Fakhouri W, Fonseca RF, et al. Interaction between IRF6and TGFA genes contribute to the risk of nonsyndromic cleft lip/palate[J]. PLOS One, 2012, 7(9):e45441.
[12]安玮，古丽，比力克孜·玉素甫，等.新疆维吾尔族干扰素调节因子6基因单核苷酸多态性与非综合征性唇腭裂相关性研究[J].新疆医科大学学报，2014,37(12):1600-1602, 1607.
[13] Wu WL, Hao JS, Wang HT, et al. Association of polymorphisms of IRF6 to non-syndromic cleft lip with or without palate in a Guangdong population[J]. International Journal of Clinical and Experimental Medicine, 2016, 9(6):11732-11739.
[14] Park JW, Mcintosh I, Hetmanski JB, et al. Association between IRF6and nonsyndromic cleft lip with or without cleft palate in four populations[J]. Genetics in Medicine, 2007, 9(4):219-227.
[15] Jugessur A, Rahimov F, Lie RT, et al. Genetic variants in IRF6 and the risk of facial clefts:single-marker and haplotype-based analyses in a population-based case-control study of facial clefts in Norway[J]. Genetic Epidemiology, 2008, 32(5):413-424.
[16] Rafighdoost H, Hashemi M, Danesh H, et al. Association of single nucleotide polymorphisms in AXIN2, BMP4, and IRF6 with NonSyndromic Cleft Lip with or without Cleft Palate in a sample of the southeast Iranian population[J]. Journal of Applied Oral Science,2017, 25(6):650-656.
[2] Calzolari E, Pierini A, Astolfi G, et al. Associated anomalies in multi-malformed infants with cleft lip and palate:An epidemiologic study of nearly 6 million births in 23 EUROCAT registries[J]. American Journal of Medical Genetics Part A, 2007, 143A(6):528-537.
[3] Carinci F, Pezzetti F, Scapoli L, et al. Recent developments in orofacial cleft genetics[J]. The Journal of Craniofacial Surgery, 2003,14(2):130-143.
[4] Kondo S, Schutte BC, Richardson RJ, et al. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes[J]. Nature Genetics, 2002, 32(2):285-289.
[5] Lu Y, Liu Q, Xu W, et al. TGFA and IRF6 contribute to the risk of nonsyndromic cleft lip with or without cleft palate in Northeast China[J]. PLOS One, 2013, 8(8):e70754.
[6]黄永清.中国西部人群IRF6、MSX1基因SNPs与非综合症唇腭裂相关性的研究[D].成都：四川大学，2007.
[7]张健，古力巴哈·买买提力，洪玉.IRF6基因多态性位点与新疆维吾尔族、汉族非综合征性唇腭裂的相关性研究[J].中国医科大学学报，2013,42(5):388-393.
[8]沈亚，程璐，万伟东，等.非综合征性唇腭裂与干扰素调节因子6和转化生长因子α单核苷酸多态性的相关性[J].中华检验医学杂志，2007,30(12):1349-1353.
[9] Blanton SH, Burt A, Garcia E, et al. Ethnic heterogeneity of IRF6 AP-2αbinding site promoter SNP association with nonsyndromic cleft lip and palate[J]. Cleft Palate-Craniofacial Journal, 2010, 47(6):574-577.
[10] Ibarra-Arce A, García-álvarez M, Cortés-González D, et al.IRF6 polymorphisms in Mexican patients with non-syndromic cleft lip[J]. Meta Gene, 2015, 4:8-16.
[11] Letra A, Fakhouri W, Fonseca RF, et al. Interaction between IRF6and TGFA genes contribute to the risk of nonsyndromic cleft lip/palate[J]. PLOS One, 2012, 7(9):e45441.
[12]安玮，古丽，比力克孜·玉素甫，等.新疆维吾尔族干扰素调节因子6基因单核苷酸多态性与非综合征性唇腭裂相关性研究[J].新疆医科大学学报，2014,37(12):1600-1602, 1607.
[13] Wu WL, Hao JS, Wang HT, et al. Association of polymorphisms of IRF6 to non-syndromic cleft lip with or without palate in a Guangdong population[J]. International Journal of Clinical and Experimental Medicine, 2016, 9(6):11732-11739.
[14] Park JW, Mcintosh I, Hetmanski JB, et al. Association between IRF6and nonsyndromic cleft lip with or without cleft palate in four populations[J]. Genetics in Medicine, 2007, 9(4):219-227.
[15] Jugessur A, Rahimov F, Lie RT, et al. Genetic variants in IRF6 and the risk of facial clefts:single-marker and haplotype-based analyses in a population-based case-control study of facial clefts in Norway[J]. Genetic Epidemiology, 2008, 32(5):413-424.
[16] Rafighdoost H, Hashemi M, Danesh H, et al. Association of single nucleotide polymorphisms in AXIN2, BMP4, and IRF6 with NonSyndromic Cleft Lip with or without Cleft Palate in a sample of the southeast Iranian population[J]. Journal of Applied Oral Science,2017, 25(6):650-656.