Genes in the pathway of tooth mineral tissues and dental caries risk: a systematic review and meta-analysis

Objectives

To perform a systematic review of the literature, investigating the influence of tooth mineral tissues genes on dental caries.

Materials and methods

Five databases were searched. Only human studies with cross-sectional, longitudinal, and case-control design were included. Meta-analysis was performed for each polymorphism, providing allele and genotype estimates. A meta-analysis was performed, pooling several polymorphisms for each gene. A Funnel Plot and Egger’s test were also performed.

Results

A total of 1124 records were found. Of these, 25 papers were included in the systematic review and 18 in the meta-analysis. Most of the studies (52%) were of medium quality. With regard to the allele analysis, the T allele of rs134136 (TFIP11) (OR 1.51; 95%CI 1.02–2.22) showed an association with high experience of caries and the summarization of polymorphisms investigated in the TFIP11 gene, after exclusion of SNP linkage disequilibrium, showed an association with caries experience (OR 1.64; 95%CI 1.08–2.50). An analysis of the homozygous genotype did not show any significant association. The pooled SNPs of AMBN showed associations with caries (OR 0.45; 95%CI 0.29–0.72). The pooled polymorphisms of AMELX were associated with caries experience (OR 1.78; 95%CI 1.23–2.56). In the analysis of the homozygous genotype, no SNP showed a significant association. Egger’s test showed no significant publication bias for all models (p > 0.05).

Conclusion

The present findings showed that the genes TFIP11, AMBN, and AMELX play an important role in dental caries.

Clinical relevance

Several single nucleotide polymorphisms related to the genes in the formation of tooth mineral are linked to the occurrence of dental caries, and these genes have proved to be important for an explanation of differences in the risk of dental caries.

     

Evolutionary pattern in the OXT-OXTR system in primates: Coevolution and positive selection footprints

Oxytocin is a nonapeptide involved in a wide range of physiologic and behavioral functions. Until recently, it was believed that an unmodified oxytocin sequence was present in all placental mammals. This study analyzed oxytocin (OXT) in 29 primate species and the oxytocin receptor (OXTR) in 21 of these species. We report here three novel OXT forms in the New World monkeys, as well as a more extensive distribution of a previously described variant (Leu8Pro). In structural terms, these OXTs share the same three low-energy conformations in solution during molecular dynamic simulations, with subtle differences in their side chains. A consistent signal of positive selection was detected in the Cebidae family, and OXT position 8 showed a statistically significant (P = 0.013) correlation with litter size. Several OXTR changes were identified, some of them promoting gain or loss of putative phosphorylation sites, with possible consequences for receptor internalization and desensitization. OXTR amino acid sites are under positive selection, and intramolecular and intermolecular coevolutionary processes with OXT were also detected. We suggest that some New World monkey OXT-OXTR forms can be correlated to male parental care through the increase of cross-reactivity with its correlated vasopressin system.Oxytocin has crucial functions related to physiological processes and social behaviors in primates and other placental mammals. A nonapeptide (Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly) (1), oxytocin (OXT-8Leu) is both a neurotransmitter released by neuronal cells in synapses and a hormone, activating receptors distant from the site of its synthesis through the circulatory system (2). In mammals, OXT acts as a hormone in uterine contraction during parturition and in milk ejection while lactating. It is also a key central nervous system neurotransmitter, regulating/modulating complex social and reproductive behaviors (i.e., pair bonding and parental care) (3–7).Until recently, it was believed that the OXT amino acid chain was the same in all placental mammals. However, Lee and colleagues (8) reported a T > C change in four New World monkeys (NWms), Saimiri sciureus, Cebus apella, Callithrix jacchus, and Aotus nancimae, substituting leucine to proline at position 8 (OXT-8Pro). This form was also found in Tupaia belangeri, a tree shrew species of Southeast Asia (8). OXT differs from its paralog vasopressin (AVP; Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly) at positions 3 and 8. Variation at position 8 also identifies nonplacental OXT/AVP-like nonapeptides, such as mesotocin, present in some marsupials (7, 9). These findings dispel the notion of a universal OXT amino acid sequence for placental mammals. They also suggest that residue variability at position 8, in some cases associated with variations at positions 2–5, may be connected with the recognition, binding, and activation of receptors, potentially leading to species-specific functional changes (7, 10).OXT activity depends on adequate interaction with its unique receptor, OXTR, although it can also bind to the vasopressin receptors (AVPR1a, AVPR1b, and AVPR2) with lower affinity (11–13). Similar to other receptors that use G proteins as transducer signals across the cell membranes, OXTR is composed of seven transmembrane (TM1–TM7), four extracellular (N-terminal tail-ECL3), and four intracellular (ICL1-C-terminal tail) domains. ECL and ICL are important for the interaction with OXT and G proteins, respectively, whereas TMs are connected with both functions (7, 11).In contrast to what is observed for placental mammal OXT, OXTR presents hundreds of variants in regulatory and coding regions, including at the intraspecific level. In humans, OXTR single-nucleotide polymorphisms have been associated with several social behavioral phenotypes (14).The presence of OXT-OXTR-related systems throughout the animal kingdom indicates that their typical roles in placental mammals are likely exaptations of ancient functions, such as regulation of fluid balance and egg-laying (15, 16). Studies have attempted to investigate both the interaction of OXT-OXTR-like systems and their coevolution (11, 17). However, our knowledge about this nonapeptide-receptor system, including the extent of its variability in the primate order, remains limited.NWm emerged ∼30 million years ago. They are classified into 16 genera and ∼75 species and present a wide range of reproductive and social behaviors (18, 19), but little is known about their genetic variability and concurrent phenotypic variation (20).The present study reports results about OXT and OXTR diversity in 29 primate species, including 20 NWm species. These analyses include original OXT and OXTR sequences for 16 and 12 NWm species, respectively. We discuss details about the coevolution of these systems, as well as possible connections among reported genetic variability, positive selection, and some key species-specific biologic traits.     

Is there a role for rare variants in DRD4 gene in the susceptibility for ADHD? Searching for an effect of allelic heterogeneity

Although several studies have demonstrated an association between the 7-repeat (7R) allele in the 48-bp variable number of tandem repeats (VNTRs) in the exon 3 at dopamine receptor D4 (DRD4) gene and attention-deficit/hyperactivity disorder (ADHD), others failed to replicate this finding. In this study, a total of 786 individuals with ADHD were genotyped for DRD4 exon 3 VNTR. All 7R homozygous subjects were selected for VNTR re-sequencing. Subjects homozygous for the 4R allele were selected paired by age, ancestry and disorder subtypes in order to have a sample as homogeneous as possible with 7R/7R individuals. Using these criteria, 103 individuals (66 with ADHD and 37 control individuals) were further investigated. An excess of rare variants were observed in the 7R alleles of ADHD patient when compared with controls (P=0.031). This difference was not observed in 4R allele. Furthermore, nucleotide changes that predict synonymous and non-synonymous substitutions were more common in the 7R sample (P=0.008 for total substitutions and P=0.043 for non-synonymous substitutions). In silico prediction of structural/functional alterations caused by these variants have also been observed. Our findings suggest that not only repeat length but also DNA sequence should be assessed to better understand the role of DRD4 exon 3 VNTR in ADHD genetic susceptibility.     

Temperament traits mediate the relationship between CACNA1C polymorphisms and bipolar disorder in cisgender women

European Archives of Psychiatry and Clinical Neuroscience - The influence of temperament traits on bipolar disorder (BD) has been investigated. Both temperament traits and BD are partially...