ABSTRACT
A valuable approach to understand how individual and population genetic differences can predispose to disease is to assess the impact of genetic variants on cellular functions (e.g., gene expression) of cell and tissue types related to pathological states. To understand the genetic basis of nonsyndromic cleft lip with or without cleft palate (NSCL/P) susceptibility, a complex and highly prevalent congenital malformation, we searched for genetic variants with a regulatory role in a disease-related tissue, the lip muscle (orbicularis oris muscle [OOM]), of affected individuals. From 46 OOM samples, which are frequently discarded during routine corrective surgeries on patients with orofacial clefts, we derived mesenchymal stem cells and correlated the individual genetic variants with gene expression from these cultured cells. Through this strategy, we detected significant cis-eQTLs (i.e., DNA variants affecting gene expression) and selected a few candidates to conduct an association study in a large Brazilian cohort (624 patients and 668 controls). This resulted in the discovery of a novel susceptibility locus for NSCL/P, rs1063588, the best eQTL for the MRPL53 gene, where evidence for association was mostly driven by the Native American ancestry component of our Brazilian sample. MRPL53 (2p13.1) encodes a 39S protein subunit of mitochondrial ribosomes and interacts with MYC, a transcription factor required for normal facial morphogenesis. Our study illustrates not only the importance of sampling admixed populations but also the relevance of measuring the functional effects of genetic variants over gene expression to dissect the complexity of disease phenotypes.
Subject(s)
Cleft Lip/genetics , Cleft Palate/genetics , Ribosomal Proteins/genetics , Adolescent , Child , Child, Preschool , Female , Genes/genetics , Genome-Wide Association Study , Humans , Infant , Infant, Newborn , Male , Mitochondrial Ribosomes/metabolism , Oligonucleotide Array Sequence Analysis , Polymorphism, Single Nucleotide/genetics , Quantitative Trait Loci/genetics , Young AdultABSTRACT
Oral manifestations in HIV positive children were observed in thirty-eight HIV infected children that have received care at the Special Care Dentistry Center (SCDC) of the School of Dentistry, University of Sao Paulo. Results have shown that 52.63% of the children presented at least one oral manifestation related with HIV/AIDS. Angular cheilitis occurred in 28.94%, parotid gland bilateral enlargement, pseudomembranous candidiasis and erythematous candidiasis in 18.42%, conventional gingivitis in 13.15%, herpes simplex in 5.26%, hairy leukoplakia, recurrent aphthous ulcer and condyloma acuminatum in 2.63%. Although enamel hypoplasia occurred in 23.68%, this could not be attributed specifically to HIV infection.