Genome-wide Interaction Study Implicates VGLL2 and Alcohol Exposure and PRL and Smoking in Orofacial Cleft Risk.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect, affecting approximately 1 in 700 births. NSCL/P has complex etiology including several known genes and environmental factors; however, known genetic risk variants only account for a small fraction of the heritability of NSCL/P. It is commonly suggested that gene-by-environment (G×E) interactions may help explain some of the "missing" heritability of NSCL/P. We conducted a genome-wide G×E interaction study in cases and controls of European ancestry with three common maternal exposures during pregnancy: alcohol, smoking, and vitamin use using a two-stage design. After selecting 127 loci with suggestive 2df tests for gene and G x E effects, 40 loci showed significant G x E effects after correcting for multiple tests. Notable interactions included SNPs of 6q22 near VGLL2 with alcohol and 6p22.3 near PRL with smoking. These interactions could provide new insights into the etiology of CL/P and new opportunities to modify risk through behavioral changes.

Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate.

Nonsyndromic orofacial clefts (OFCs) are a heterogeneous group of common craniofacial birth defects with complex etiologies that include genetic and environmental risk factors. OFCs are commonly categorized as cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which have historically been analyzed as distinct entities. Genes for both CL/P and CP have been identified via multiple genome-wide linkage and association studies (GWAS); however, altogether, known variants account for a minority of the estimated heritability in risk to these craniofacial birth defects. We performed genome-wide meta-analyses of CL/P, CP, and all OFCs across two large, multiethnic studies. We then performed population-specific meta-analyses in sub-samples of Asian and European ancestry. In addition to observing associations with known variants, we identified a novel genome-wide significant association between SNPs located in an intronic TP63 enhancer and CL/P (p = 1.16 × 10-8). Several novel loci with compelling candidate genes approached genome-wide significance on 4q21.1 (SHROOM3), 12q13.13 (KRT18), and 8p21 (NRG1). In the analysis of all OFCs combined, SNPs near FOXE1 reached genome-wide significance (p = 1.33 × 10-9). Our results support the highly heterogeneous nature of OFCs and illustrate the utility of meta-analysis for discovering new genetic risk factors.

Minimally invasive treatment of the nasal inverted papilloma.

BACKGROUND: The purpose of this work is to evaluate our results in the treatment of the nasal inverted papillomas with an endoscopic approach using a retrospective case series. METHODS: Between 1993 and 2000 we treated 27 patients with nasal inverted papillomas. All patients underwent endoscopic nasal surgery under general anesthesia. None of the inverted papillomas extended outside of the paranasal sinuses. All tissue samples underwent polymerase chain reaction and hybridization in situ to detect genetic sequences of the human papilloma virus and Epstein Barr virus. RESULTS: The study population consisted of 16 men and 11 women with a median age of 52 years (range, 22-77 years). Ten patients (37%) had undergone a previous nasal surgery. The median follow-up was 5 years (range, 2-8 years). None of the patients presented with bilateral nasal involvement or a synchronous carcinoma. Seven patients underwent an additional surgical approach (two endoscopic approaches via a Caldwel-Luc approach, four sublabial approaches via a Caldwel-Luc approach, and one external ethmoidectomy). There were no surgical complications. Two patients (7%) had recurrent papilloma 4 and 6 years after surgery and again underwent endoscopic resection. The amplification both by polymerase chain reaction and hybridization in situ for human papilloma virus and Epstein Barr virus were negative in the specimens from all patients. CONCLUSIONS: According to the literature and our own experience, we believe that the initial surgical management of primary and recurrent inverted papillomas limited to the nasal cavity and paranasal sinuses should be endoscopic sinus surgery.