Replication of genome wide association identified candidate genes confirm the role of common and rare variants in PAX7 and VAX1 in the etiology of nonsyndromic CL(P).

Following recent genome wide association studies (GWAS), significant genetic associations have been identified for several genes with nonsyndromic cleft lip with or without cleft palate (CL(P)). To replicate two of these GWAS signals, we investigated the role of common and rare variants in the PAX7 and VAX1 genes. TaqMan genotyping was carried out for SNPs in VAX1 and PAX7 and transmission disequilibrium test (TDT) was performed to test for linkage and association in each population. Direct sequencing in and around the PAX7 and VAX1 genes in 1,326 individuals of European and Asian ancestry was done. The TDT analysis showed strong associations with markers in VAX1 (rs7078160, P = 2.7E-06 and rs475202, P = 0.0002) in a combined sample of Mongolian and Japanese CL(P) case-parent triads. Analyses using parent-of-origin effects showed significant excess transmission of the minor allele from both parents with the effect in the mothers (P = 6.5E-05, OR (transmission) = 1.91) more striking than in the fathers (P = 0.004, OR (transmission) = 1.67) for VAX1 marker rs7078160 in the combined Mongolian and Japanese samples when all cleft types were combined. The rs6659735 trinucleotide marker in PAX7 was significantly associated with all the US cleft groups combined (P = 0.007 in all clefts and P = 0.02 in CL(P)). Eight rare missense mutations found in PAX7 and two rare missense mutations in VAX1. Our study replicated previous GWAS findings for markers in VAX1 in the Asian population, and identified rare variants in PAX7 and VAX1 that may contribute to the etiology of CL(P). Determining the role of rare variants clearly warrants further investigation.

Tracking maternal mortality declines in Mongolia between 1992 and 2007: the importance of collaboration.

OBJECTIVE: To describe the declining trend in maternal mortality observed in Mongolia from 1992 to 2007 and its acceleration after 2001 following implementation of the Maternal Mortality Reduction Strategy by the Ministry of Health and other partners. METHODS: We performed a descriptive analysis of maternal mortality data collected through Mongolia's vital registration system and provided by the Mongolian Ministry of Health. The observed declining mortality trend was analysed for statistical significance using simple linear regression. We present the maternal mortality ratios from 1992 to 2007 by year and review the basic components of Mongolia's Maternal Mortality Reduction Strategy for 2001-2004 and 2005-2010. FINDINGS: Mongolia achieved a statistically significant annual decrease in its maternal mortality ratio of almost 10 deaths per 100 000 live births over the period 1992-2007. From 2001 to 2007, the maternal mortality ratio in Mongolia decreased approximately 47%, from 169 to 89.6 deaths per 100 000 live births. CONCLUSION: Disparities in maternal mortality represent one of the major persisting health inequities between low- and high-resource countries. Nonetheless, important reductions in low-resource settings are possible through collaborative strategies based on a horizontal approach and the coordinated involvement of key partners, including health ministries, national and international agencies and donors, health-care professionals, the media, nongovernmental organizations and the general public.

Mutations in BMP4 are associated with subepithelial, microform, and overt cleft lip.

Cleft lip with or without cleft palate (CL/P) is a complex trait with evidence that the clinical spectrum includes both microform and subepithelial lip defects. We identified missense and nonsense mutations in the BMP4 gene in 1 of 30 cases of microform clefts, 2 of 87 cases with subepithelial defects in the orbicularis oris muscle (OOM), 5 of 968 cases of overt CL/P, and 0 of 529 controls. These results provide confirmation that microforms and subepithelial OOM defects are part of the spectrum of CL/P and should be considered during clinical evaluation of families with clefts. Furthermore, we suggest a role for BMP4 in wound healing.