Neither single‐marker nor haplotype analyses support an association between the dopamine transporter gene and heroin dependence in Han Chinese

Much evidence suggests that dysfunction of dopamine transporter‐mediated dopamine transmission may be involved in the pathophysiology of substance abuse and dependence. The aim of this study was to examine whether the dopamine transporter gene (DAT1; SLC6A3) is associated with the development of heroin dependence (HD) and whether DAT1 influences personality traits in patients with HD. Polymorphisms of DAT1 were analyzed in a case–control study of 1046 Han Chinese (615 patients and 431 controls). All participants were screened using a Chinese version of the modified Schedule of Affective Disorder and Schizophrenia‐Lifetime and all patients met the criteria for HD. Furthermore, a Chinese version of the Tridimensional Personality Questionnaire (TPQ) was used to assess personality traits in the patient group and examine the association between their personality traits and DAT1 polymorphisms. Of the patient group, 271 completed the TPQ. No statistically significant differences in allele or genotype frequencies of all investigated variants between HD patients and controls were observed. In haplotype analyses, four haplotype blocks of DAT1 were not associated with the development of HD. These DAT1 polymorphisms did not influence novelty seeking and harm avoidance scores in HD patients. This study suggests that the DAT1 gene may not contribute to the risk of HD and specific personality traits in HD among the Han Chinese population.     

Minisatellite polymorphisms of the SLC6A19: susceptibility in hypertension

The SLC6A19 is a human homolog of B⁰AT1 that encodes a neutral amino acid transporter. We examined the distribution of VNTR (variable number of tandem repeats; minisatellites) and conducted polymorphic analysis of SCL6A19 isolated from the genomic DNA of controls and multi-generational families. The SLC6A19 was found to contain seven blocks of minisatellites, 3 of which (SLC6A19-MS1, -MS4, and -MS7) showed polymorphism and were found to be transmitted through meiosis following Mendelian inheritance in seven families. These minisatellite polymorphisms may be useful markers for paternity mapping and DNA fingerprinting. Furthermore, we conducted a case-control study in which genomic DNA from 400 controls and 205 cases with essential hypertension was compared. A statistically significant association was identified between rare SLC6A19-MS7 alleles and the occurrence of hypertension (odds ratio, 7.87; 95% confidence interval, 0.88-70.66; and p = 0.028). These findings suggest that the rare SLC6A19-MS7 allele may be a risk factor for hypertension.     

SLC6A4基因多态性与海洛因依赖的关联性研究

目的:探讨5-羟色胺转运体基因(solute carrier family 6 member 4,SLC6A4)基因4个单核苷酸多态性(single nucleotide polymorphism,SNP)位点与海洛因依赖之间的关系。方法:严格按照诊断标准,选取无亲缘关系的海洛因依赖个体397例(病例组)及健康对照个体402例(对照组)提取基因组DNA,采用SNaPshot SNP分型技术对SLC6A4基因4个SNP位点(rs1042173,rs3813034,rs6354,rs7224199)进行基因分型,比较病例-对照组间各位点等位基因、基因型频率的差异。结果:病例组和对照组SLC6A4基因rs1042173和rs3813034位点的基因型和等位基因频率比较存在显著性差异(P0.05),rs1042173的C等位基因(P=0.031,OR=1.317,95%CI=1.026-1.691)及rs3813034的C等位基因(P=0.013,OR=1.375,95%CI=1.069-1.768)是海洛因依赖的危险因素。病例组TCC单倍型(rs7224199、rs3813034和rs1042173)的比例较对照组显著增高(P0.05)。结论:SLC6A4基因rs1042173和rs3813034多态性可能与海洛因成瘾有关,携带有rs1042173的C等位基因和rs3813034的C等位基因的个体及携带TCC单倍型的个体可能更容易对海洛因产生依赖。     

Association of a serotonin transporter gene (SLC6A4) 5-HTTLPR polymorphism with body mass index categories but not type 2 diabetes mellitus in Mexicans

The serotonergic system has been hypothesized to contribute to the biological susceptibility to type 2 diabetes mellitus (T2DM) and body-mass index (BMI) categories. We investigate a possible association of 5-HTTLPR polymorphism (L and S alleles) in the promoter region of the serotonin transporter gene (SLC6A4) with the development of T2DM and/or higher BMI by analyzing a sample of 138 individuals diagnosed with T2DM and 172 unrelated controls from the Mexican general population. In the total sample genotypes were distributed according to Hardy-Weinberg equilibrium, and S allele frequency was 0.58. There was no statistical association between 5-HTTLPR polymorphism and the development of T2DM in this Mexican population sample (p = 0.12). Nevertheless, logistic regression analysis of the L allele and increased BMI disclosed an association, after adjusting for age, sex and T2DM (p = 0.02, OR 1.74, 95% CI: 1.079–2.808).     

Short allele of serotonin transporter gene promoter is a risk factor for obesity in adolescents

Obesity and hypertension are increasing medical problems in adolescents. Serotonin transporter (5-HTT) is involved in mood and eating disturbances. Encoded by the gene SLC6A4, the promoter shows functional insertion/deletion alleles: long (L) and short (S). Because individuals who are carriers for the short version are known to be at risk for higher levels of anxiety, we hypothesized that this variant may be associated with overweight. Data and blood samples were collected from 172 adolescents out of a cross-sectional, population-based study of 934 high school students. To replicate the findings, we also included 119 outpatients from the Nutrition and Diabetes Section of the Children's County Hospital. We found that the S allele was associated with overweight (BMI > 85th percentile), being a risk factor for overweight independently of sex, age, and hypertension [odds ratio (OR): 1.85; 95% confidence interval (CI): 1.13, 3.05; p < 0.02]. Additionally, in the outpatient study, compared with the homozygous LL subjects, S allele carriers showed a higher BMI z-score (1.47 +/- 1.09 vs. 0.51 +/- 1.4; p < 0.002) and were more frequent in overweight children. In conclusion, the S allele of the SLC6A4 promoter variant is associated with overweight being an independent genetic risk factor for obesity.     

SLC30A8基因rsl3266634多态性与内蒙古地区汉族人群2型糖尿病的相关性研究

目的：研究内蒙古地区汉族人群SLC30A8（solute carrier family 30,member 8）基因rsl3266634单核苷酸多态性（Single nucleotide polymorphism,SNP）的等位基因和基因型频率分布与2型糖尿病（Type 2 diabetes,T2DM）的相关性。方法：采用等位基因特异性聚合酶链式反应（AS-PCR）,对222例内蒙古地区汉族人（其中T2DM组125例,正常对照NC组97例）rsl3266634进行基因分型。结果：T2DM组中rsl3266634的C等位基因频率、CC基因型频率分别为61.2%和28.4%,均显著高于NC组的53.1%和24.7%（P值均〈0.05）;而T2DM组的TT基因型频率为6.4%,显著低于NC组的18.6%（P〈0.05）。C等位基因携带者患T2DM的风险是T等位基因的1.64倍（OR=1.64,95%CI=1.125-2.402）。结论：SLC30A8基因rsl3266634多态性位点的C等位基因可能是T2DM的风险等位基因,该位点C/T多态性与内蒙古地区汉族人群T2DM具有相关性,可能是内蒙古地区汉族人T2DM的易感基因之一。     

Genetic variability in sodium-glucose cotransporter 2 influences glycemic control and risk for diabetic retinopathy in type 2 diabetes patients

BackgroundGluconeogenesis and renal glucose excretion in kidneys both play an important role in glucose homeostasis. Sodium-glucose cotransporter (SGLT2), coded by the SLC5A2 gene is responsible for reabsorption up to 99% of the filtered glucose in proximal tubules. SLC5A2 genetic polymorphisms were suggested to influence glucose homeostasis. We investigated if common SLC5A2 rs9934336 polymorphism influences glycemic control and risk for macro or microvascular complications in Slovenian type 2 diabetes (T2D) patients.MethodsAll 181 clinically well characterized T2D patients were genotyped for SLC5A2 rs9934336 G>A polymorphism. Associations with glycemic control and T2D complications were assessed with nonparametric tests and logistic regression.ResultsSLC5A2 rs9934336 was significantly associated with increased fasting blood glucose levels (P<0.001) and HbA1c levels under the dominant genetic model (P=0.030). After adjustment for T2D duration, significantly higher risk for diabetic retinopathy was present in carriers of at least one polymorphic SLC5A2 rs9934336 A allele compared to non-carriers (OR=7.62; 95%CI=1.65-35.28; P=0.009).ConclusionsOur pilot study suggests an important role of SLC5A2 polymorphisms in the physiologic process of glucose reabsorption in kidneys in T2D patients. This is also the first report on the association between SLC5A2 polymorphism and diabetic retinopathy.     

Polymorphism of the serotonin 2A receptor gene (5HTR2A) and personality traits

The interindividual variation of temperament features (such as anxiety, neuroticism, harm avoidance) is determined, in particular, by allele polymorphism of genes involved in serotonin metabolism and has earlier been associated with the insertion/deletion polymorphism of the serotonin transporter gene. Polymorphic alleles of the serotonin 2A receptor gene (5HTR2A) were tested for association with personality traits assessed with several tests. The T102C and A1438G polymorphisms were associated with a variation in emotionality, activity, and sociability, which are integral characteristics of temperament. With each polymorphism, differences were significant only between heterozygotes and homozygotes. Carriers of T102C genotype A1/A2 displayed a lower level of anxiety-related traits, a higher score on scale Hypomania, and a lower score on scale Social Introversion and were assumed to have higher activity and sociability. Carriers of A1428G genotype A/G differed from homozygotes G/G in having a lower level of social introversion and a lower score on scale No close friends, which testified to higher sociability of heterozygotes. Thus, the polymorphic alleles of SHTR2A proved to be associated with personality traits in mentally healthy people.     

Mechanism and Putative Structure of B0-like Neutral Amino Acid Transporters

The Na⁺-dependent transport of neutral amino acids in epithelial cells and neurons is mediated by B⁰-type neutral amino acid transporters. Two B⁰-type amino acid transporters have been identified in the neurotransmitter transporter family SLC6, namely B⁰AT1 (SLC6A19) and B⁰AT2 (SLC6A15). In contrast to other members of this family, B⁰-like transporters are chloride-independent. B⁰AT1 and B⁰AT2 preferentially bind the substrate prior to the Na⁺-ion. The Na⁺-concentration affects the K _m of the substrate and vice versa. A kinetic scheme is proposed that is consistent with the experimental data. An overlapping binding site of substrate and cosubstrate has been demonstrated in the bacterial orthologue LeuT _Aa from Aquifex aeolicus, which elegantly explains the mutual effect of substrate and cosubstrate on each other’s K _m -value. LeuT _Aa is sequence-related to transporters of the SLC6 family, allowing homology modeling of B⁰-like transporters along its structure.     

Evidence for plasticity genotypes in a gene–gene–environment interaction: the TRAILS study

The purpose was to study how functional polymorphisms in the brain derived neurotrophic factor gene (BDNF val66met) and the serotonin transporter gene linked promotor region (5‐HTTLPR) interact with childhood adversities in predicting Effortful Control. Effortful Control refers to the ability to regulate behavior in a goal‐directed manner and is an interesting endophenotype for psychopathology because of its heritability and the association of low Effortful Control with both internalizing and externalizing problems. In a longitudinal population‐based study Effortful Control was assessed with the parent version of the Early Adolescent Temperament Questionnaire at age 11. Pregnancy and delivery adversities and childhood events were assessed in a parent interview at age 11. Long‐term difficulties until age 11 were assessed with a parent questionnaire at age 13.5. Blood or buccal cells were collected at age 16 for genotyping the rs6265 and rs25531 SNPs and the 5‐HTTLPR length polymorphism. The study included 1032 complete data sets. Effortful Control was significantly predicted by the interaction between BDNF val66met, 5‐HTTLPR and childhood events. The BDNF val66met val/val–5‐HTTLPR l′/l′ genotype was unaffected by childhood events, while having either at least one BDNF val66met met or 5‐HTTLPR s′ allele (l′/l′‐met‐carrier; l′/s′‐val/val; s′/s′‐val/val) made children sensitive to childhood events. Predictions of Effortful Control by pregnancy and delivery adversities and long‐term difficulties were largely independent of genotype. We concluded that the l′/l′‐met‐carrier, l′/s′‐val/val and the s′/s′‐val/val genotypes showed greatest plasticity while the l′/l′‐val/val genotype was unaffected by childhood events.     

GENE-GENE INTERACTION BETWEEN SEROTONIN TRANSPORTER (SLC6A4) AND CLOCK MODULATES THE RISK OF METABOLIC SYNDROME IN ROTATING SHIFTWORKERS

Serotonergic neurotransmission and the master circadian CLOCK gene are physiological modulators of the circadian system. In addition, both are involved in the physiopathology of metabolic syndrome (MS). The authors sought to examine the potential effect of the gene-gene interaction between the functional 44-bp insertion/deletion polymorphism in the promoter region (serotonin-transporter-linked promoter region polymorphism or 5-HTTLPR) of the serotonin transporter gene (SLC6A4) and common variants of the gene CLOCK on the genetic risk underlying MS of shift-workers. To test this hypothesis, 856 men were studied; 518 dayworkers were compared with 338 rotating shiftworkers. Medical history, health examination including anthropometric and arterial blood pressure measurements, a questionnaire on health-related behaviors, and biochemical determinations were obtained from every participant. 5-HTTLPR genotypes were determined using polymerase chain reaction followed by gel electrophoresis. Six tag single-nucleotide polymorphisms (SNPs) in the CLOCK gene with a minor allele frequency >10 % (rs1554483 C/G, rs11932595 A/G, rs4580704 C/G, rs6843722 A/C, rs6850524 C/G, and rs4864548 A/G), encompassing 117 kb of chromosome 4 and representing 115 polymorphic sites (r²?>?.8), were genotyped. A significant interaction between the 5-HTTLPR variant and the haplotype rs1554483–rs4864548 of the CLOCK gene was detected for diastolic (p?=?.0058) and systolic blood pressure (p?=?.0014), arterial hypertension (p?=?.033), plasma triglycerides levels (p?=?.033), and number of MS components (p?=?.01). In all these cases, the higher values were observed in rotating shiftworkers homozygous for the SLC6A4 S allele and carrying the haplotype composed by the CLOCK rs1554483 G and rs4864548 A variants. In conclusion, these data suggest a potential interaction (epistatic effect) of serotonin transporter and CLOCK gene variation on the genetic susceptibility to develop MS by rotating shiftworkers. (Author correspondence: cpirola@ciudad.com.ar or pirola.carlos@lanari.fmed.uba.ar)     

SLC2A9rs1014290位点基因多态性与北方汉族地区男性痛风发病的相关性研究

目的:探讨可溶性载体2家族成员9基因(SLC2A9)rs1014290位点的单核苷酸多态性与北方汉族地区男性原发性痛风的发病的相关性。方法:选取404例原发性痛风男性患者和412名健康体检者,分别检测其血清尿酸、血脂、肾功等生化指标,同时提取外周血DNA,应用连接酶检测反应(LDR)法分析其SLC2A9基因rs1014290位点基因型和等位基因频率。结果:痛风组空腹血糖、尿酸(UA)、甘油三酯(TG)、胆固醇(TC)、收缩压、BMI、肌酐(Cr)水平均显著高于对照组,差异有统计学意义(P0.05)。痛风组SLC2A9基因rs1014290位点各基因型频率(CC:12.8%;CT:53.5%;TT:38.7%)与对照组(CC:16.2%;CT:50.9%;TT:32.9%)相比差异有统计学意义(X2=3.978,P=0.041);两组的等位基因频率相比差异无统计学意义(X2=0.314,P=0.496)。结论:SLC2A9基因rs1014290位点多态性可能与我国北方汉族男性原发性痛风的易感性相关,携带TT基因型的个体更易患痛风。     

AVPR1A and SLC6A4 polymorphisms in choral singers and non-musicians: a gene association study

Amateur choral singing is a common pastime and worthy of study, possibly conferring benefits to health and social behaviour. Participants might be expected to possess musical ability and share some behavioural characteristics. Polymorphisms in genes concerned with serotonergic neurotransmission are associated with both behaviour and musical aptitude. Those investigated previously include the variable number tandem repeats RS1, RS3 and AVR in the AVPR1A (arginine vasopressin receptor 1a) gene and STin2 in the SLC6A4 (solute carrier family 6 [neurotransmitter transporter, serotonin], member 4) gene, as well as the SLC6A4 promoter region polymorphism, 5-HTTLPR. We conducted a genetic association study on 523 participants to establish whether alleles at these polymorphisms occur more commonly in choral singers than in those not regularly participating in organised musical activity (non-musicians). We also analysed tagging single nucleotide polymorphisms (SNPs) for AVPR1A and SLC6A4 to determine whether other variants in these genes were associated with singer/non-musician status. At the STin2 polymorphism, overall association with singer/non-musician status was evident at P = 0.006. The 9-repeat (P = 0.04) and 12-repeat (P = 0.04) alleles were more common in singers and the 10-repeat allele less so (P = 0.009). Odds ratios were 0.73 (95% CI 0.57-0.94) for the 10-repeat allele and 2.47 (95% CI 0.88-6.94) for the rarer 9-repeat allele. No overall association was detected at P<0.05 between any other polymorphism and singer/non-musician status. Our null findings with respect to RS3, RS1 and AVR, polymorphisms associated with musical ability by other authors, suggest that choir membership may depend partly on factors other than musical ability. In a related musical project involving one participating choir, a new 40-part unaccompanied choral work, "Allele", was composed and broadcast on national radio. In the piece, each singer's part incorporated their personal RS3 genotype.     

Genetic influences on behavioral inhibition and anxiety in juvenile rhesus macaques

In humans and other animals, behavioral responses to threatening stimuli are an important component of temperament. Among children, extreme behavioral inhibition elicited by novel situations or strangers predicts the subsequent development of anxiety disorders and depression. Genetic differences among children are known to affect risk of developing behavioral inhibition and anxiety, but a more detailed understanding of genetic influences on susceptibility is needed. Nonhuman primates provide valuable models for studying the mechanisms underlying human behavior. Individual differences in threat-induced behavioral inhibition (freezing behavior) in young rhesus monkeys are stable over time and reflect individual levels of anxiety. This study used the well-established human intruder paradigm to elicit threat-induced freezing behavior and other behavioral responses in 285 young pedigreed rhesus monkeys. We examined the overall influence of quantitative genetic variation and tested the specific effect of the serotonin transporter promoter repeat polymorphism. Quantitative genetic analyses indicated that the residual heritability of freezing duration (behavioral inhibition) is h ² = 0.384 ( P  = 0.012) and of 'orienting to the intruder' (vigilance) is h ² = 0.908 ( P  = 0.00001). Duration of locomotion and hostility and frequency of cooing were not significantly heritable. The serotonin transporter polymorphism showed no significant effect on either freezing or orienting to the intruder. Our results suggest that this species could be used for detailed studies of genetic mechanisms influencing extreme behavioral inhibition, including the identification of specific genes that are involved in predisposing individuals to such behavior.     

Insertion/Deletion Polymorphism of the Serotonin Transporter Gene and Neuroticism as a Temperament Trait in Affective Patients and Healthy Individuals

Some studies associate the insertion/deletion polymorphism of the serotonin transporter (5-HTT) gene with anxiety-related personality traits in mentally healthy people, the short (s) allele being associated with a higher neuroticism score. The 5-HTT genotype and neuroticism score were established for 114 affective patients, 87 healthy relatives of endogenous psychosis patients, and for 156 mentally healthy people without familial psychiatric history. The effects of sex and age on the association between the two parameters was studied. Neuroticism proved to be not associated with the 5-HTT genotype.     

Diagnostic Tests for Primary Renal Hypouricemia

Primary renal hypouricemia is a genetic disorder characterized by defective renal uric acid (UA) reabsorption with complications such as nephrolithiasis and exercise-induced acute renal failure. The known causes are: defects in the SLC22A12 gene, encoding the human urate transporter 1 (hURAT1), and also impairment of voltage urate transporter (URATv1), encoded by SLC2A9 (GLUT9) gene. Diagnosis is based on hypouricemia (<119 μmol/L) and increased fractional excretion of UA (>10%). To date, the cases with mutations in hURAT1 gene have been reported in East Asia only. More than 100 Japanese patients have been described. Hypouricemia is sometimes overlooked; therefore, we have set up the flowchart for this disorder. The patients were selected for molecular analysis from 620 Czech hypouricemic patients. Secondary causes of hyperuricosuric hypouricemia were excluded. The estimations of (1) serum UA, (2) excretion fraction of UA, and (3) analysis of hURAT1 and URATv1 genes follow. Three transitions and one deletion (four times) in SLC22A12 gene and one nucleotide insertion in SLC2A9 gene in seven Czech patients were found. Three patients had acute renal failure and urate nephrolithiasis. In addition, five nonsynonymous sequence variants and three nonsynonymous sequence variants in SLC2A9 gene were found in two UK patients suffering from acute renal failure. Our finding of the defects in SLC22A12 and SLC2A9 genes gives further evidence of the causative genes of primary renal hypouricemia and supports their important role in regulation of serum urate levels in humans.     

Polymorphism of the Serotonin 2A Receptor Gene (5HTR2A) and Personality Traits

The individual variation of temperament features (such as anxiety, neuroticism, harm avoidance) is determined, among other things, by allele polymorphism of genes involved in serotonin metabolism and has earlier been associated with the insertion/deletion polymorphism of the serotonin transporter gene. Polymorphic alleles of the serotonin 2A receptor gene (5HTR2A) were tested for association with personality traits assessed in several tests. The T102C and A1438G polymorphisms were associated with variation in emotionality, activity, and sociability, which are integral characteristics of temperament. With each polymorphism, differences were significant only between heterozygotes and homozygotes. Carriers of T102C genotype A1/A2 displayed a lower level of anxiety-related traits, a higher score on the Hypomania scale, and a lower score on the Social Introversion scale and were assumed to have higher activity and sociability. Carriers of A1438G genotype A/G differed from homozygotes G/G in having a lower level of social introversion and a lower score on the No Close Friends scale, which testified to higher sociability of heterozygotes. Thus, the polymorphic alleles of 5HTR2A proved to be associated with personality traits in mentally healthy people.     

The SLC19A1 80G>A polymorphism is not associated with male infertility

Previous studies have revealed that genetic factors may be involved in regulating folate turnover, e.g. methylenetetrahydrofolate reductase polymorphism in the development of male infertility. Folate transporter, encoded by the SLC19A1 gene, commonly referred to as reduced folate carrier (RFC) is a transmembrane protein, which transfers hydrophilic folates across the cell membrane. It was hypothesized that common polymorphism within the SLC19A1 gene (rs1051266:G>A, 80G>A) may alter RFC function. The aim of this study was to investigate a potential association between the SLC19A1 80G>A polymorphism and male infertility in a case–control study. The SLC19A1 80G>A polymorphism was determined by means of a polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assay in 213 infertile Caucasian men and 226 ethnically matched controls. The distribution of SLC19A1 genotypes in the infertile men was as follows: GG 26.8%, GA 51.2%, AA 22.1% and in fertile men: GG 24.8%, GA 50.4%, AA 24.8%, and was comparable in the both the evaluated groups. Odds ratios (95% confidence interval, CI): 0.90 (0.59–1.38) and 0.88 (0.56–1.36) for dominant and recessive models remained non-significant, also after adjustment for age: 0.89 (0.57–1.37) and 0.80 (0.51–1.25), respectively. Our study demonstrated that polymorphism 80G>A of the SLC19A1 gene is not associated with male infertility.