Verônica Contini

Further evidence for the association between a polymorphism in the promoter region of SLC6A3/DAT1 and ADHD: findings from a sample of adults.

The dopamine transporter (SLC6A3/DAT1) plays a key role in the regulation of dopaminergic neurotransmission and is the major site of action for methylphenidate, a first-line medication for attention deficit hyperactivity disorder (ADHD). Most genetic association studies with ADHD have investigated a 40-bp variable number of tandem repeats (VNTR) polymorphism in the 3′-untranslated region (UTR) of the DAT1, but these investigations have reported heterogeneous findings. The few studies focused on the 5′ region have reported promising results. Despite rs2652511 not being included, nor having any proxy SNP available in GWAS, the few candidate gene studies that analyzed it suggested an association with ADHD and schizophrenia. Here, we analyzed the −839 C/T (rs2652511) promoter variant and the 3′-UTR and intron 8xa0(Int8) VNTR polymorphisms in 522 adults with ADHD and 628 blood donor controls. The diagnostic procedures followed the DSM-IV criteria. A significant association was detected (Pxa0=xa00.002) between the rs2652511 C-allele with ADHD. In addition, the 6-repeat allele of Int8 VNTR was associated with higher inattention scores (Pxa0=xa00.034). The haplotype analysis including DAT1 3′-UTR and Int8 VNTR polymorphisms did not reveal associations with ADHD susceptibility or severity dimensions. These findings extend to adult samples previous findings from children samples on the role of the rs2652511 polymorphism in the promoter region of DAT1 as a risk factor for ADHD susceptibility.

MR and GR functional SNPs may modulate tobacco smoking susceptibility

A number of studies have demonstrated that stress is involved in all aspects of smoking behavior, including initiation, maintenance and relapse. The mineralocorticoid (MR) and glucocorticoid (GR) receptors are expressed in several brain areas and play a key role in negative feedback of the hypothalamic–pituitary–adrenal (HPA) axis. As nicotine increases the activation of the HPA axis, we wondered if functional SNPs (single nucleotide polymorphisms) in MR and GR coding genes (NR3C2 rs5522 and NR3C1 rs6198, respectively) may be involved in smoking susceptibility. The sample included 627 volunteers, of which 514 were never-smokers and 113 lifetime smokers. We report an interaction effect between rs5522 and rs6198 SNPs. The odds ratio (OR) for the presence of the NR3C2 rs5522 Val allele in NR3C1 rs6198 G carriers was 0.18 (Pxa0=xa00.007), while in rs6198 G noncarriers the OR was 1.83 (Pxa0=xa00.027). We also found main effects of the NR3C1 rs6198 G allele on number of cigarettes smoked per day (Pxa0=xa00.027) and in total score of the Fagerström Test for Nicotine Dependence (Pxa0=xa00.007). These findings are consistent with a possible link between NR3C2 and NR3C1 polymorphisms and smoking behavior and provide a first partial replication for a nominally significant GWAS finding between NR3C2 and tobacco smoking.

Waist-to-height ratio (WHtR) and triglyceride to HDL-c ratio (TG/HDL-c) as predictors of cardiometabolic risk

INTRODUCTIONnThe excessive concentration of fat in the abdominal region is related to a higher risk of developing cardiovascular disease (CVD). Studies have been performed to identify simple and effective indicators of abdominal obesity and associated cardiometabolic risk through the use of simple parameters such as anthropometric and biochemical measures. The Triglyceride / High-density Lipoprotein Cholesterol (TG/HDL-c) has been proposed as a more practical and easy to use atherogenic marker, along with the Waist-to-Height Ratio (WHtR), which makes a superior tool for separating cardiometabolic risk related to overweight/obesity when comparing to Body Mass Index (BMI).nnnOBJECTIVEnTo verify the applicability of the WHtR and the TG/HDL-c ratio as predictors of cardiometabolic risk.nnnMETHODSnThis cross-sectional study was performed at the Department of Nutrition of the UNIVATES University Center, where the participants anthropometric and biochemical data were collected. Statistical analysis was performed by the Statistical Package for the Social Sciences software (SPSS) 20.0, with a significance level of 5% (p < 0.05).nnnRESULTSnA total of 498 individuals took part on this research, 77.5% female and with a mean age of 25.5 ± 6.5. A high percentage of fat was found in both men and women (19.9 ± 5.80% and 29.24 ± 5.43%, respectively). The prevalence of overweight/obesity (BMI ≥ 25Kg/m(2)) was 35.05%. The WHtR marker was significantly correlated to Low-density Lipoprotein Cholesterol (LDL-c), Triglyceride (TG) and Anthropometric BMI values, waist circumference (WC) and body fat percentage (BF%). For the TG/HDL-c ratio, there was a positive and significant correlation to the same markers, beyond TC. There was also a correlation between WHtR and TG/HDL-c, and both presented a negative and significant correlation with HDL-c.nnnCONCLUSIONnWHtR and TG/HDL-c values were found to be good markers for the cardiometabolic risk ratio in the studied sample. Several studies, original articles and academic reviews confirm the use of the WHtR or TG/HDL-c markers for that purpose in adults.

Could comorbid bipolar disorder account for a significant share of executive function deficits in adults with attention-deficit hyperactivity disorder?

The frequent comorbidity between attention‐deficit hyperactivity disorder (ADHD) and bipolar disorder (BD) represents a challenge for disentangling specific impairments of each disorder in adulthood. Their functional impairments seem to be mediated by executive function deficits. However, little is known about the extent to which each executive function deficit might be disorder specific or explained by the comorbidity. The aim of the present study was to determine if comorbid BD could account for a significant share of executive function deficits when measured by the Wisconsin Card Sorting Test (WCST) in adults with ADHD.

Exocytosis-related genes and response to methylphenidate treatment in adults with ADHD

Experimental studies have demonstrated that methylphenidate (MPH) modulates the synaptic vesicle trafficking and synaptotagmin-1 (SytI) mRNA levels. SytI is a regulatory protein of the SNARE complex, a neurotransmitter exocytosis mediator. Despite this evidence, most SNARE complex-related genes have never been evaluated in attention-deficit/hyperactivity disorder (ADHD) pharmacogenetics. This study evaluates, for we believe the first time, polymorphisms on the SNARE complex-related genes STX1A (rs2228607), VAMP2 (26bp Ins/Del) and SYT1 (rs1880867 and rs2251214) on the response to immediate-release methylphenidate (IR-MPH) in a naturalistic sample of adults with ADHD. The sample comprised 433 subjects, of which 272 (62.8%) have completed the short-term IR-MPH treatment (at least 30 days). The main outcome measure was the categorical variable of short-term response to IR-MPH based on the Swanson, Nolan and Pelham Rating Scale version 4 (SNAP-IV), and on the clinical global impression-improvement scale. Additional analyses evaluated the percentage of SNAP-IV symptom reduction for each dimension as well as short- and long- (7 years) term treatment persistence. SYT1-rs2251214 was associated with the categorical short-term response to IR-MPH (P=0.006, PFDR=0.028), and with the percentage of inattention and oppositional defiant disorder symptoms reduction (P=0.007, PFDR=0.028 and P=0.017, PFDR=0.048, respectively). SYT1-rs2251214 was also associated with short-term treatment persistence (P=0.018, PFDR=0.048), and with months of treatment (P=0.002, PFDR=0.016) in the long-term protocol. Our findings suggest that SYT1-rs2251214 presents a broad influence in IR-MPH response variability in adults with ADHD, being involved with both symptom response and treatment persistence. If such findings are replicated, SytI could represent a key element in MPH pharmacodynamics in adults with ADHD.

Evidence of sexual dimorphism of HTR1B gene on major adult ADHD comorbidities

Attention-deficit/hyperactivity disorder (ADHD) is a very common psychiatric disorder across the life cycle and frequently presents comorbidities. Since ADHD is highly heritable, several studies have focused in the underlying genetic factors involved in its etiology. One of the major challenges in this search is the phenotypic heterogeneity, which could be partly attributable to the sexual dimorphism frequently seen in psychiatric disorders. Taking into account the well-known sexual dimorphic effect observed in serotonergic system characteristics, we differentially tested the influence of HTR1B SNPs (rs11568817, rs130058, rs6296 and rs13212041) on ADHD susceptibility and on its major comorbidities according to sex. The sample comprised 564 adults with ADHD diagnosed according to DSM-IV criteria and 635 controls. There was no association of any HTR1B SNPs tested in relation to ADHD susceptibility. As for the comorbidities evaluated, after correction for multiple tests, significant associations were observed for both rs11568817 and rs130058 with substance use disorders (Pcorrxa0=xa00.009 and Pcorrxa0=xa00.018, respectively) and for rs11568817 with nicotine dependence (Pcorrxa0=xa00.025) in men with ADHD. In women with ADHD, the same rs11568817 was associated with generalized anxiety disorder (Pcorrxa0=xa00.031). The observed effects of rs11568817xa0G allele presence conferring risk to either substance use disorders or generalized anxiety disorder according to sex, suggest an overall scenario where a higher transcriptional activity of HTR1B, resulting from the presence of this allele, is related to externalizing behaviors in men and internalizing behaviors in women. These results are consistent with and expand previous evidence of sexual dimorphism of the serotoninergic system.

Replicated association of Synaptotagmin (SYT1) with ADHD and its broader influence in externalizing behaviors

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder, affecting both children and adults. The Soluble N-ethylmaleimide sensitive factor Attachment REceptors (SNARE) complex has been implicated in ADHD pathophysiology since it is a key component of neurotransmitter release events and neurodevelopment processes, and SNPs in this complex have been associated with ADHD. Here we aim to analyze the effects of SNARE complex variants on ADHD susceptibility and its clinical heterogeneity in affected adults. We tested the association between ADHD and polymorphisms on the SNARE genes STX1A (rs2228607), SYT1 (rs1880867 and rs2251214), VAMP2 (26bp Ins/Del) and SNAP25 (rs6108461 and rs8636) on a sample comprised of 548 adults with ADHD and 644 non-affected controls. Regarding clinical heterogeneity, we further investigated the effects of associated SNPs on age at onset of impairment due to ADHD and on relevant externalizing behaviors (i.e. school suspensions/expulsions and problems with law/authority) and comorbidities (i.e. Substance Use Disorder, Oppositional Defiant Disorder, Conduct Disorder and Antisocial Personality Disorder). We replicated a previously reported association between SYT1-rs2251214 and ADHD in adulthood. This SNP was also associated with age at onset of impairment due to ADHD symptoms and with a range of externalizing phenotypes. These findings involving SYT1 suggest that variation in neurotransmitter exocytosis mechanisms may represent an underlying genetic factor shared by a spectrum of externalizing behaviors and disorders, including - but not restricted to - ADHD.

A vitamin D pathway gene–gene interaction affects low-density lipoprotein cholesterol levels

Much evidence suggests an association between vitamin D deficiency and chronic diseases such as obesity and dyslipidemia. Although genetic factors play an important role in the etiology of these diseases, only a few studies have investigated the relationship between vitamin D-related genes and anthropometric and lipid profiles. The aim of this study was to investigate the association of three vitamin D-related genes with anthropometric and lipid parameters in 542 adult individuals. We analyzed the rs2228570 polymorphism in the vitamin D receptor gene (VDR), rs2134095 in the retinoid X receptor gamma gene (RXRG) and rs7041 in the vitamin D-binding protein gene (GC). Polymorphisms were genotyped by TaqMan allelic discrimination. Gene-gene interactions were evaluated by the general linear model. The functionality of the polymorphisms was investigated using the following predictors and databases: SIFT (Sorting Intolerant from Tolerant), PolyPhen-2 (Polymorphism Phenotyping v2) and Human Splicing Finder 3. We identified a significant effect of the interaction between RXRG (rs2134095) and GC (rs7041) on low-density lipoprotein cholesterol (LDL-c) levels (P=.005). Furthermore, our in silico analysis suggested a functional role for both variants in the regulation of the gene products. Our results suggest that the vitamin D-related genes RXRG and GC affect LDL-c levels. These findings are in agreement with other studies that consistently associate vitamin D and lipid profile. Together, our results corroborate the idea that analyzing gene-gene interaction would be helpful to clarify the genetic component of lipid profile.

Investigation of polymorphisms rs7903146 and rs12255372 in the TCF7L2 gene in biochemical markers of severity of type 2 diabetes mellitus (T2DM) in a sample of adults with T2DM

Diabetes mellitus type 2 (DM2) is a metabolic disease that involves complex multifactorial genetic and environmental factors [1]. Studies on the molecular genetics has suggested that many genes may be important in susceptibility to DM26. Recently, large-scale studies such as genome-wide associations studies (GWAS) have shown several important genes associated with T2DM. Among these genes, one of the most strongly associated with the disease is TCF7L2. This gene has many polymorphisms described, however the majority of studies indicate variants rs7903146 and rs12255372 as the most important within this gene.