| BackgroundNonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most commonhuman congenital malformations. Multiple genetic and environmental factors contribute to thesusceptibility to NSCL/P. However, the complex pathogenesis of NSCL/P remains to beelucidated. In the current study we investigated the association of single nucleotidepolymorphisms (SNPs) in v-maf musculoaponeurotic fibrosarcoma oncogene homolog B(MAFB) and interferon regulatory factor-6 (IRF6) genes, as well as those at 8q24 and 10q25with NSCL/P in a Southern Chinese Han cohort.Methods431 NSCL/P patients and 451 controls were recruited in the current study. 6 SNPs includingrs17820943, rs6102085 and rs6072081 in MAFB, rs10863790 in IRF6, rs987525 at 8q24 andrs7078160 at 10q25 were genotyped using TaqMan SNPs genotyping assays. Associationanalysis was performed by comparing allele and genotype frequencies between NSCL/Ppatients and the controls using Chi-Square test.ResultsMAFB SNPs rs6072081, rs17820943, rs6102085 and IRF6 SNP rs10863790 were found to beassociated with NSCL/P in Southern Chinese population.1. Significantly higher frequencies in NSCL/P patients compared with the controls werefound in the A allele and AA genotype of MAFB rs6072081 (P = 0.001 and 0.004 respectively),the C allele and CC genotype of rs17820943 (P = 0.001 and 0.002 respectively), and the Aallele and AA genotype of rs6102085 (P = 1.22×10-6 and 1.27×10-5 respectively). The AAgenotype of IRF6 rs10863790 was also significantly more prevalent in NSCL/P patients (P =0.007). No significant association with NSCL/P was found in 10q25 rs7078160 and 8q24 rs987525.2. Comparison between subtypes of NSCL/P and the controls revealed increasedfrequencies of the A allele and AA genotype of MAFB rs6072081 (P = 4.52×10-4 and 0.002respectively), the C allele and CC genotype of rs17820943 (P = 6.69×10-5 and 2.43×10-4respectively), and the A allele and AA genotype of rs6102085 (P = 0.009 and 8.37×10-7respectively) in patients with cleft lip with palate (CLP). There were significant increases in thefrequency of AA genotype of IRF6 rs10863790 in CLP patients and in patients with cleft liponly (CLO) (P = 0.006 and 0.017 respectively) compared to the controls. The A allele of IRF6rs10863790 was more prevalent in CLO compared to the controls (P = 0.024). No significantassociation was found between CLO and cleft palate only (CPO) and the 3 MAFB SNPs, orbetween CPO and IRF6 rs10863790.3. Comparison between gender of NSCL/P and the controls revealed increased frequenciesof the A allele and AA genotype of MAFB rs6072081 (P = 0.016 and 0.041 respectively), the Callele and CC genotype of rs17820943 (P = 0.018 and 0.045 respectively), and the A allele andAA genotype of rs6102085 (P = 0.032 and 0.046 respectively) in female. Comparison betweengender of NSCL/P and the controls revealed increased frequencies of the C allele of MAFBrs17820943 (P = 0.048), the A allele and AA genotype of rs6102085 (P = 5.64×10-5 and1.15×10-4 respectively) in male, while no significant was found between male and MAFBrs6072081 (P = 0.069). No significant was found between male patients and female patients andthe MAFB rs6072081, rs17820943 and rs610208 (P = 0.626, 0.859 and 0.211 respectively). Thefrequency of the AA genotype of IRF6 rs10863790 was significant higher in NSCL/P malepatients compared with male controls (P = 0.023). There was no significant increase in thefrequencies of the AA genotype of IRF6 rs10863790 in female (P = 0.185).4. Haplotype analysis of the SNPs rs6072081-rs17820943-rs6102085 further supported theassociation between MAFB and NSCL/P. The ACA haplotype frequency was significantlyincreased in the NSCL/P patients (P = 1.623×10-6), while GTG and ACG haplotype frequencieswere increased in the controls (P =0.0015 and 0.0215 respectively).ConclusionsOur results showed that MAFB and IRF6 SNPs conferred risk of NSCL/P in Southern Han Chinese population, and were also involved with different subtypes and sex.1. The A allele of rs6072081, C allele of rs17820943 and G allele of the rs6102085 in theMAFB and the A allele of rs10863790 in the IRF6 were associated with NSCL/P.2. The MAFB SNPs were associated with CLP, but not associated with CLP and CPOsubtypes of NSCL/P, while IRF6 rs10863790 was associated with CLO and possibly CLP.3. The MAFB rs17820943 and rs6102085 were associated with NSCL/P in both male andfemale patients. MAFB rs6072081 was associated with NSCL/P in female patients and wasprobable associated with NSCL/P in male patients. IRF6 rs10863790 was associated withNSCL/P in male patients, but not in female patients.4. No significant association with NSCL/P was found in either 10q25 rs7078160 or 8q24rs987525.5. The ACA haplotype of MAFB SNPs (rs6072081-rs17820943-rs6102085) was associatedwith NSCL/P.
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