Non-syndromic cleft lip with palate (NSCLP) is the most serious sub-phenotype of non-syndromic orofacial clefts (NSOFC), which are the most common craniofacial birth defects in humans. Here we conduct a GWAS of NSCLP with multiple independent replications, totalling 7,404 NSOFC cases and 16,059 controls from several ethnicities, to identify new NSCLP risk loci, and explore the genetic heterogeneity between sub-phenotypes of NSOFC. We identify 41 SNPs within 26 loci that achieve genome-wide significance, 14 of which are novel (RAD54B, TMEM19, KRT18, WNT9B, GSC/DICER1, PTCH1, RPS26, OFCC1/TFAP2A, TAF1B, FGF10, MSX1, LINC00640, FGFR1 and SPRY1). These 26 loci collectively account for 10.94% of the heritability for NSCLP in Chinese population. We find evidence of genetic heterogeneity between the sub-phenotypes of NSOFC and among different populations. This study substantially increases the number of genetic susceptibility loci for NSCLP and provides important insights into the genetic aetiology of this common craniofacial malformation.

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Objective. To investigate the association between bone morphogenetic protein 4 (BMP4) rs17563 polymorphism and nonsyndromic cleft lip with or without palate (NSCL/P) risk. Methods. Four online databases were researched and the related publications were collected. Odds ratio (OR) with 95% confidence interval (CI) was applied to assess the relationship; publication bias, metaregression, and sensitivity analysis were conducted to guarantee the strength of results. Results. Six published case-control studies were collected. Overall, no significant association between BMP4 rs17563 polymorphism and NSCL/P risk was found. It was notable that significant susceptibility on different ethnicity was observed in the stratified analysis. For Chinese population, the BMP4 rs17563 polymorphism was a significantly increased risk for NSCL/P (C versus T: OR = 1.52, 95% CI = 1.28–1.82, P < 0.01, I 2 = 0%; CC versus TT: OR = 2.58, 95% CI = 1.74–3.82, P < 0.01, I 2 = 0%; TC + CC versus TT: OR = 1.45, 95% CI = 1.14–1.84, P < 0.01, I 2 = 0%; CC versus TT + TC: OR=2.46, 95% CI = 1.46–4.14, P < 0.01, I 2 = 47.0%). On the contrary, significantly protective effects were found in Brazilian population (C versus T: OR = 0.69, 95% CI = 0.50–0.96, P = 0.03, I 2 = 68.5%; TC versus TT: OR = 0.52, 95% CI = 0.40–0.68, P < 0.01, I 2 = 0%; TC + CC versus TT: OR = 0.52, 95% CI = 0.35–0.78, P < 0.010, I 2 = 54.4%). Conclusion. This meta-analysis indicated that BMP4 rs17563 polymorphism could play a different role during the development of NSCL/P based on ethnicity diversity.

The 3 major subphenotypes observed in patients with nonsyndromic orofacial clefts (NSOFCs) are nonsyndromic cleft lip only (NSCLO), nonsyndromic cleft lip with palate (NSCLP), and nonsyndromic cleft palate only (NSCPO). However, the genetic architecture underlying NSCPO is largely unknown. Here we performed a 2-stage genome-wide association study (GWAS) on NSCPO and replication analyses of selected variants in other NSOFCs from the Chinese Han population. We identified a novel locus (15q24.3) and a known locus (1q32.2) where variants in or near the gene reached genome-wide significance (2.80 × 10−13 < P < 1.72 × 10−08) in a test for association with NSCPO in a case-control design. Although a variant from 15q24.3 was found to be significantly associated with both NSCPO and NSCLP, the direction of estimated effects on risk were opposite. Our functional annotation of the risk alleles within 15q24.3 coupled with previously established roles of the candidate genes within identified risk loci in periderm development, embryonic patterning, and/or regulation of cellular processes supports their involvement in palate development and the pathogenesis of cleft palate. Our study advances the understanding of the genetic basis of NSOFCs and provides novel insights into the pathogenesis of NSCPO.

Oral cancer is one of the most common malignancies in the world. The present study aimed to investigate the effects of dexmedetomidine on immune response in patients undergoing radical and reconstructive surgery for oral cancer. Patients were randomly divided into the dexmedetomidine and control groups. Within 15 min before anesthesia induction, dexmedetomidine was infused with a 0.5 µg·kg −1 loading dose followed by a maintenance dose of 0.4 µg·kg −1 ·h −1 to the end of operation in the dexmedetomidine group, whereas the same volume of saline was administered in the control group. Blood samples were obtained at five time-points: 30 min Before induction (T 0 ), 1 h after induction (T 1 ), end of the operation (T 2 ) and 24 (T 3 ) and 48 h (T 4 ) after the operation. The T lymphocyte subsets (including CD3 + , CD4 + and CD8 + cells) and CD4 + /CD8 + ratio, B lymphocytes, dendritic cells and myeloid-derived suppressor cells (MDSCs) were analyzed by flow cytometry. All immunological indicators, except CD8 + cells, significantly decreased between the two groups at T 1–3 compared with T 0 (P<0.05). The percentages of CD3 + , CD4 + , dendritic cells and the CD4 + /CD8 + ratios were significantly higher at T 2–4 and the percentages of MDSCs were significantly lower at T 2–4 in the dexmedetomidine group compared with the control group (all P<0.05). These findings suggested that dexmedetomidine can attenuate immunosuppression in patients undergoing radical and reconstructive surgery for oral cancer.