Gut microbiota dysbiosis in a cohort of patients with psoriasis.

BACKGROUND: There is increasing evidence of the key role that the gut microbiota plays in inflammatory diseases. OBJECTIVES: To identify differences in the faecal microbial composition of patients with psoriasis compared with healthy individuals in order to unravel the microbiota profiling in this autoimmune disease. METHODS: 16S rRNA gene sequencing and bioinformatic analyses were performed with the total DNA extracted from the faecal microbiota of 19 patients with psoriasis and 20 healthy individuals from the same geographic location. RESULTS: Gut microbiota composition of patients with psoriasis displayed a lower diversity and different relative abundance of certain bacterial taxa compared with healthy individuals. CONCLUSIONS: The gut microbiota profile of patients with psoriasis displayed a clear dysbiosis that can be targeted for microbiome-based therapeutic approaches. What's already known about this topic? Psoriasis is a chronic inflammatory immune-mediated skin disease, the aetiology of which remains unclear. The human microbiota is a complex microbial community that inhabits our body and has been related with the maintenance of a healthy status. Several studies have focused on the skin microbiome and its connection with psoriasis although less attention has been focused on the potential role of the gut microbiota in psoriatic disease. What does this study add? This study unravels the gut microbiome dysbiosis present in a cohort of patients with psoriasis, compared with a healthy control group from the same geographical location. This study shows a lower bacterial diversity and different relative abundance of certain bacterial taxa in patients with psoriasis. We gain knowledge and insight into the microbiome alterations in psoriatic disease, opening new avenues for therapeutic approaches to reshape the human microbiome towards a healthy status.

IL17RA gene variants and anti-TNF response among psoriasis patients.

Polymorphisms at genes encoding proteins involved in the pathogenesis of psoriasis (Psor) or in the mechanism of action of biological drugs could influence the treatment response. Because the interleukin (IL)-17 family has a central role in the pathogenesis of Psor, we hypothesized that IL17RA variants could influence the response to anti-TNF drugs among Psor patients. To address this issue we performed a cross-sectional study of Psor patients who received the biological treatments for the first time, with a follow-up of at least 6 months. All of the patients were Caucasian, older than 18 years old, with chronic plaque Psor, and had completed at least 24 weeks of anti-TNF therapy (adalimumab, etanercept or infliximab). The treatment response to anti-TNF agents was evaluated according to the achievement of PASI50 and PASI75 at weeks 12 and 24. Those who achieved PASI75 at week 24 were considered good responders. All patients were genotyped for the selected single-nucleotide polymorphisms (SNPs) at IL17RA gene. A total of 238 patients were included (57% male, mean age 46 years). One hundred and five patients received adalimumab, 91 patients etanercept and 42 infliximab. The rs4819554 promoter SNP allele A was significantly more common among responders at weeks 12 (P=0.01) and 24 (P=0.04). We found a higher frequency of AA versus AG+GG among responders, but the difference was only significant at week 12 (P=0.03, odd ratio=1.86, 95% confidence of interval=1.05-3.27). Thus, in the study population, the SNP rs4819554 in the promoter region of IL17RA significantly influences the response to anti-TNF drugs at week 12.

Common and rare CARD14 gene variants affect the antitumour necrosis factor response among patients with psoriasis.

BACKGROUND: The CARD14 gene encodes a protein that enhances nuclear factor (NF)-κB activation and the upregulation of proinflammatory pathway genes. CARD14 is upregulated in psoriatic vs. normal skin, and rare and common CARD14 variants have been associated with the risk of developing psoriasis. Our hypothesis was that CARD14 variants could also influence the response to antitumour necrosis factor (anti-TNF) therapies among patients with psoriasis. OBJECTIVES: To determine whether CARD14 gene variants were linked to a significant positive anti-TNF response in patients with psoriasis. METHODS: DNA from 116 patients with psoriasis was subjected to next-generation sequencing of the CARD14 gene. All of the patients were nonresponders or had contraindications to conventional systemic treatments. RESULTS: A reduction of at least 75% in Psoriasis Area and Severity Index (PASI 75) at week 24 was considered a positive response to treatment. In total 116 patients (79 responders and 37 nonresponders) were next-generation sequenced, and we identified five nucleotide variants that would result in missense amino acid changes. These variants were determined in all of the patients, and allele and genotype frequencies were compared between the two groups. We found a significantly higher frequency of rs11652075 CC (p.Arg820Trp) among the group with a positive response (P = 0.01, odds ratio 3.71, 95% confidence interval 1.30-10.51). Furthermore, among responders, six patients were heterozygous carriers of the rare p.Glu422Lys variant, and two patients were heterozygous for p.Arg682Trp (P = 0.04). CONCLUSIONS: The common CARD14 p.Arg820Trp variant might have a significant effect on the response to anti-TNF therapies among patients with psoriasis. In addition, rare CARD14 missense variants could also predispose to a better response.

Estimated glomerular filtration rate (eGFR), 25(OH) D3, chronic kidney disease (CKD), the MYH9 (myosin heavy chain 9) gene in old and very elderly people.

It is known that the common physiological denominator of the ageing process is an attenuation of functional performance with respect to the situation of young people and adults. However, since the first cohort-based longitudinal studies, it has not been possible to establish a "linear" relationship between age and glomerular filtration in all cases. This does not mean that there is no physiological ageing process at all; in addition to those already elucidated, its mechanisms include cell senescence, podocyte dysfunction, a vitamin D deficiency, and homozygotic forms of the MYH9 gene. The aim of the present work was to analyse the prevalence of chronic kidney disease (CKD) and, where possible, the correlation between CKD, defined by an eGFR < 60 ml/min/1.73 m(2), plasma 25(OH)D3 levels and the MYH9 gene in a population of elderly and very elderly persons. These parameters have not been evaluated previously in populations of elderly and very elderly patients. It is concluded that a moderate decrease in the eGFR occurs with age. This does not imply the presence of CKD in elderly people, since in most individuals the reduced eGFR is not accompanied by anaemia, and no individuals show hypocalcaemia, hyperphosphataemia or a high Alb/Cr ratio. Here we observed a lower Hb level and an elevated Alb/Cr ratio in subjects heterozygotic for the MYH9 gene. This could be interpreted in the sense that the gene could exert some protective effect on renal function, whereas the heterozygotic form (allele A) of the MYH9 gene could be considered a very early marker, a new risk factor for the appearance of CKD, or a sign of renal frailty in elderly people.

Association of matrix Gla protein gene functional polymorphisms with loss of bone mineral density and progression of aortic calcification.

UNLABELLED: Two matrix Gla protein (MGP) polymorphisms were associated with progression of aortic calcification and femoral neck bone loss in men. All these findings were also functionally corroborated in two vascular and bone in vitro systems indicating that MGP genetic variations can be partly responsible of higher risk of bone loss and vascular calcification. INTRODUCTION: MGP plays an important role in bone and vascular mineralization as confirmed by MGP-deficient murine model. We therefore aimed to find a genetic association among -138T>C, -7G>A, and Thr83Ala MGP single-nucleotide polymorphisms (SNPs), bone loss, and progression of aortic calcification in a randomly selected general population of 296 individuals who participated in the European Vertebral Osteoporosis Study. METHODS: To evaluate the rate of change in bone mineral density (BMD) and the progression of aortic calcification, dual X-ray absorptiometry and lateral spine X-rays were performed at baseline and after 4 years of follow-up. Genotyping for the three polymorphisms was carried out using polymerase chain reaction and restriction fragment length analysis. In addition, functional studies of MGP-7G>A and Thr83Ala SNPs were performed on transiently transfected osteoblast-like UMR-106 and vascular smooth muscle A7r5 cells. RESULTS: The proportion of men who had lost BMD in the femoral neck was higher among homozygous -7AA and 83Ala-Ala (p = 0.039 and p = 0.009, respectively), and also featured a higher risk of progression of aortic calcifications (OR = 5.6, 95% CI = 1.2-27.8 and OR = 6.8, 95% CI = 1.4-32.3, respectively). No effect was observed in women. The MGP-7A allele produced a reduction in luciferase activity compared to MGP-7G: 47% less in vascular cells and 34% less in bone cells (p = 0.001 and 0.012, respectively). In vascular cells under calcifying conditions, the MGP 83Thr allele showed a slightly higher, although not significant, inhibition than the MGP 83 Ala allele in calcium content suggesting functional differences between both variants. CONCLUSION: These results suggest that MGP genetic variations could predict a higher risk of bone loss and progression of vascular calcification in men.

Psoriasis, psoriatic arthritis and type 2 diabetes mellitus: a systematic review and meta-analysis.

Several observational studies have assessed the association between psoriasis, psoriatic arthritis (PsA) and type 2 diabetes mellitus, with inconclusive results. We set out to investigate the association between psoriasis, PsA and type 2 diabetes mellitus. Observational studies assessing the relationship between psoriasis or PsA and type 2 diabetes mellitus up to December 2012 were identified by electronic and hand searches in Medline, Embase, PubMed, the Cochrane Database of Systematic Reviews and Google Scholar. For each study we collected the first author's last name, publication year, country of origin, study design, characteristics of participants (sample size, age and sex), the variables incorporated into the multivariable analyses, and the odds ratios (ORs) of psoriasis associated with diabetes along with the corresponding 95% confidence intervals (CIs). From the data provided in each article, the crude OR was also calculated. Forty-four observational studies (in 37 articles) were identified for the final analysis. The pooled OR from random-effects analysis was determined to be 1·76 (95% CI 1·59-1·96). The highest risk was for patients suffering from PsA (OR 2·18, 95% CI 1·36-3·50). We also observed a dose effect in the risk of suffering from type 2 diabetes mellitus, as patients considered as having severe psoriasis had higher risk (OR 2·10, 95% CI 1·73-2·55) than the pooled OR. We perform meta-regression and sensitivity analyses to explore sources of heterogeneity among the studies and to determine how they would influence the estimates, and found no significant influence in the results of the meta-analyses. The findings support the association between psoriasis, PsA and type 2 diabetes mellitus. Some caution must be taken in the interpretation of these results because there may be heterogeneity between studies.

SPG7 mutational screening in spastic paraplegia patients supports a dominant effect for some mutations and a pathogenic role for p.A510V.

Mutations in the SPG7 gene were initially reported in patients with autosomal recessive hereditary spastic paraplegia (HSP). Recent works suggested a dominant effect for some SPG7 mutations. To characterize the SPG7 mutational spectrum in a large cohort of Spanish HSP patients, we sequenced the whole SPG7 gene in a total of 285 Spastic Paraplegia patients. Large gene rearrangements were also ascertained in some patients. We found a total of 14 SPG7 mutations (12 new) in 14 patients; 2 were large deletions. All the mutation carriers had an adult onset age but only five (35%) had a complicated phenotype. We identified a single mutation in 13 patients. Familial analysis suggested a dominant inheritance for one (p.Leu78*) of these mutations. Carriers of the rare p.A510V variant were significantly more frequent in patients vs healthy controls (3% vs 1%), suggesting a pathogenic role for this SPG7 variant. We reported a high frequency of patients with only one SPG7 mutation, and a putative pathogenic role for the p.A510V variant.

Effect of CYP3A5, CYP3A4, and ABCB1 genotypes as determinants of tacrolimus dose and clinical outcomes after heart transplantation.

BACKGROUND: Tacrolimus (Tac) is mainly metabolized by cytochrome P450 3A isoenzymes. In a cohort of heart transplant recipients, we investigated the effect of CYP3A5, CYP3A4, and ABCB1/MDR1 polymorphisms on Tac dose requirements and the risk of developing new-onset diabetes after transplantation (NODAT). METHODS: A total of 65 heart transplant recipients were genotyped for 3 single nucleotide polymorphisms (SNPs) in the CYP3A5 (SNP rs776746), CYP3A4 (SNP rs2740574), and ABCB1 (SNP rs104564). The mean Tac dose values were compared between the genotypes. RESULTS: CYP3A5 3 homozygotes (nonexpressers; n = 55, 85%) received significantly higher Tac dose compared with CYP3A5 1 carriers (expressers). No different NODAT frequencies were found between the genotypes. CONCLUSIONS: The CYP3A5 polymorphism was the main determinant of Tac dose requirements among heart transplant recipients. This common functional polymorphism had no influence on the risk of developing NODAT.

APOE and Alzheimer disease: a major gene with semi-dominant inheritance.

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.

Bases clínicas y genéticas de la nefroesclerosis hipertensiva. Estudio NEFROSEN / Clinical and genetic bases of hypertensive nephrosclerosis. NEFROSEN Study

Justificación: Se conoce como nefroesclerosis la enfermedad renal crónica (ERC) que complica la hipertensión arterial (HTA) esencial. La ausencia de correlación entre el control de la HTA y la progresión a ERC terminal sugiere la existencia de una enfermedad intrínseca y primitiva. Recientemente se ha asociado con polimorfismos del gen MYH9 en individuos afroamericanos. El objetivo del trabajo que presentamos es determinar si algún polimorfismo de dicho gen se relaciona en raza caucásica con la asociación de HTA esencial y nefroesclerosis y, además, conocer los marcadores de progresión a ERC terminal. Será un estudio retrospectivo que comparará a pacientes con nefroesclerosis frente a pacientes con HTA esencial sin enfermedad renal y, además, se incluirán pacientes con nefroesclerosis y progresión de la enfermedad renal frente a los que se mantienen estables. Métodos: Entre octubre de 2009 y octubre de 2010 se incluirán 500 pacientes con ERC (estadios 3-5) atribuida a nefroesclerosis según criterios clínicos habituales, y 300 pacientes afectados de HTA esencial (FGe >60ml/min/1,73 m2; microalbuminuria <300 mg/g). Para el estudio genético también se incluirán 200 controles sanos de población general. Habrá dos cortes del estudio, la primera visita en el hospital y la visita final (en estadio 5 el inicio del tratamiento sustitutivo constituirá el final del seguimiento). Se registrarán datos clínicos y analíticos, y se recogerán muestras de sangre para el estudio genético. Discusión: Nuestro estudio, con la doble vertiente genética y clínica, tratará de determinar si en la raza caucásica existe relación entre el diagnóstico de nefroesclerosis y el gen MYH9, y estudiará, además, los posibles marcadores de progresión (AU)

Background: Hypertensive nephrosclerosis is a chronic kidney disease (CKD) associated to essential hypertension. The lack of correlation between strict control of hypertension and progression of CKD suggests an intrinsic and primary disease. New evidence suggests that MYH9 gene alterations are associated with nephrosclerosis in African Americans. The aim of this study is to investigate whether a polymorphism of MYH9 in Caucasians is linked to the association of essential hypertension and nephrosclerosis. The secondary objective is to identify the clinical risk factors of progression to end-stage renal disease (ESRD). This is a retrospective study that will compare patients with nephrosclerosis versus essential hypertensives without renal disease, and also patients with nephrosclerosis and impaired rena l function versu s those that are stable .Methods: Between October 2009 and October 2010, 500patients stages 3-5 CKD attributed to nephrosclerosis according to usual clinical criteria, and 300 essential hypertensives (eGFR > 60 mL/min/1.73m2; mi c roalbuminur ia<300 mg/g) will be recruited. 200 healthy controls from general population will also be included for the genetic study. There will be two sections of the study, first and final visit to the clinic (stage 5, the start of replacement therapy will be the end of follow-up). Clinical and laboratory data will be recorded, and blood samples will be collected. Discussion: Our study will seek to determine if there exists a relationship between the diagnosis of nephrosclerosis and MYH9 gene in the Caucasian race, and to study possible risk factors for progression to ESRD, on both clinical and genetic basis (AU)

[Clinical and genetic basis of hypertensive nephrosclerosis. NEFROSEN Study]. / Bases clínicas y genéticas de la nefroesclerosis hipertensiva. Estudio NEFROSEN.

BACKGROUND: Hypertensive nephrosclerosis is a chronic kidney disease (CKD) associated with essential hypertension. The lack of correlation between hypertension control and progression to end-stage CKD suggests an intrinsic and primitive disease. New evidence suggests that MYH9 gene alterations are associated with polymorphisms in African Americans. The aim of this study is to investigate whether a polymorphism of MYH9 in Caucasians is linked to essential hypertension and nephrosclerosis. The secondary objective is to identify the clinical risk factors of progression to end-stage CKD. This is a retrospective study that will compare patients with nephrosclerosis and essential hypertensives without renal disease, and also patients with nephrosclerosis and impaired renal function with those that are stable. METHOD: Between October 2009 and October 2010, 500 patients with stages 3-5 CKD attributed to nephrosclerosis according to usual clinical criteria, and 300 essential hypertensives (eGFR>60 mL/min/1.73 m2; microalbuminuria <300 mg/g) are to be recruited. A total of 200 healthy controls from the general population are also to be included for the genetic study. There are two study sections, being the first and final visits to the clinic (for stage 5 cases, the start of replacement therapy will be the end of follow-up). Clinical and laboratory data will be recorded, and blood samples will be collected. DISCUSSION: Our study will aim to determine if there is a relationship between the diagnosis of nephrosclerosis and the MYH9 gene in Caucasians, and to study possible risk factors for progression to end-stage CKD, on both clinical and genetic bases.

[Magnesium homeostasis. Etiopathogeny, clinical diagnosis and treatment of hypomagnesaemia. A case study]. / Homeostasis del magnesio. Etiopatogenia, clínica y tratamiento de la hipomagnesemia. A propósito de un caso.

Magnesium is the fourth-most abundant cation in the human body and the second-most abundant intracellular cation after potassium. Magnesium is pivotal in the transfer, storage, and utilization of energy as it regulates and catalyzes more than 300 enzyme systems. Hypomagnesemia may thus result in a variety of metabolic abnormalities and clinical consequences. It results from an imbalance between gastrointestinal absorption and renal excretion of magnesium. The main consequence related directly to hypomagnesemia is cardiovascular arrhythmias secondary to hipokaliemia and if this is not recognized and treated it may be fatal. In this article we review the hypomagnesemic disorders in children with emphasis on the molecular mechanisms responsible for abnormalities in magnesium homeostasis, differential diagnosis and appropriate therapy, and we describe the clinical and biochemical manifestations as well as the genetic defect in a family with Gitelman syndrome.

TWEAK, el facilitador del daño renal agudo / No disponible

No disponible

Heterocigosis compuesta para las mutaciones intrón 9 + 1 g > T y Leu 850pro en el gen SLC12A3 en el Síndrome de Gitelman / No disponible

No disponible

Asociación entre el polimorfismo A-1438G del gen del receptor de serotonina 2A (5-HT2A) e impulsividad del comportamiento suicida / Association of serotonin 2A (5HT2A) receptor gene A-1438G polymorphism and impulsivity within the context of suicidal behaviour

Objetivos: Investigar la posible asociación entre cuatro polimorfismos serotoninérgicos (A-1438G (rs6311) y T102C (rs6313) del gen del receptor 5-HT2A y STin2 VNTR y 5-HTTLPR del gen SLC6A4) e impulsividad de la tentativa suicida (TS).Método: 180 pacientes (Asturias – Norte de España) que habían realizado una tentativa suicida fueron evaluados utilizando la Suicidal Intent Scale (SIS) y, posteriormente, genotipados utilizando métodos estándar. Las TS fueron divididas en dos subgrupos: impulsivas (puntuaciones inferiores a 6 puntos) o no impulsivas (6 o más puntos), utilizándola subescala de planificación suicida de la SIS. Resultados: Edad media (SD) de la muestra total = 35,6 (12,5) años; mujeres: 63,3%.La mayoría de los pacientes (95,6%) tenían al menos un diagnóstico psiquiátrico. Los diagnósticos más prevalentes fueron: trastornos afectivos (36,7%), esquizofrenia y otras psicosis (18,3%), trastornos de ansiedad (12,2%) y trastornos de la personalidad(11,1%). En un 49,4% se constató la existencia de TS previas. Un 64,4% de las TS fueron de tipo impulsivo. Los polimorfismos A-1438G y T102C estaban en completo desequilibrio de ligamiento en nuestra población. El genotipo –1438GG y el alelo –1438Gfueron más prevalentes entre los pacientes que realizaron TS impulsivas [34,5% vs14,1%, X2 (2) = 11,5, p corregida = 0,012; 0,59 vs 0,41; X2 (1) = 11,2, p corregida =0,004, OR = 2,11 (1,36-3,27), respectivamente]. No se encontraron diferencias en las distribuciones genotípicas o alélicas de los polimorfismos del gen SLC6A4.Conclusiones: Variaciones polimórficas del gen 5-HT2A podrían predisponer hacia la realización de TS de tipo impulsivo (AU)

Objective: To determine the association between four serotonergic polymorphisms (A-1438G (rs6311) and T102C(rs6313) of the 5-HT2A receptor gene, and STin2 VNTR and 5-HTTLPR of the SLC6A4 gene) and impulsivity in suicide attempts (SA).Methods: 180 suicide attempters from Asturias (Northern Spain) were assessed using the Suicidal Intent Scale (SIS)and genotyped by standard methods. According to the SIS definition SA were divided into two subgroups (impulsive and non-impulsive). A score of 6 on the planning subscale was used to classify attempts as impulsive or non-impulsive. Results: Mean age (SD) was 35.6 (12.5) years and about 63.3% of cases were female. Most of patients (95.6%) had at least one psychiatric diagnosis. More prevalent diagnoses were affective disorders (36.7%), schizophrenia and other psychosis (18.3%), anxiety disorders (12.2%), and personality disorders (11.1%). Previous SA was found in 49.4% of cases. About 64.4% of SA patients were classified as impulsive SA. A-1438G and T102C polymorphisms were in complete linkage disequilibrium in our population. We found and excess of –1438GG genotype and –1438G allele when compared impulsive SA with the non-impulsive group (34.5% vs 14.1%, X2 (2) = 11.5, corrected P = 0.012; 0.59% vs0.41%, X2 (1) = 11.2, corrected P = 0.004, OR = 2.11 (1.36-3.27), respectively). No differences in genotypic or allele frequencies of the SLC6A4 gene polymorphisms were found. Conclusions: Our findings suggest that polymorphic variants on the 5-HT2A gene may predispose for impulsive suicidal behaviour (AU)

A search for cyclophilin-A gene (PPIA) variation and its contribution to the risk of atherosclerosis and myocardial infarction.

Cyclophilin A is secreted by vascular smooth muscle cells in response to inflammatory stimuli, and could thus contribute to atherosclerosis. We hypothesized that the genetic variation at the cyclophilin A gene (PPIA) could affect the risk for developing atherosclerosis and myocardial infarction. This study included 250 myocardial infarction patients (all male and < 60 years; 95% are smokers). All these cases had at least one atherosclerotic diseased coronary vessel. DNA was obtained from patients and from 250 healthy controls. The variation at the PPIA gene was determined in the patients through single-strand conformation analysis and direct sequencing of seven polymerase chain reaction fragments. Allele and genotype frequencies were compared between patients and controls. The effect of a promoter polymorphism (-11 G/C) on gene expression was in vitro analysed with luciferase-reporter assays. We found two common polymorphisms in the PPIA promoter (-11 G/C) and the 5' non-translated (+36 G/A) regions. Cells transfected with luciferase-plasmids containing the -11 G had significantly higher luciferase activity. Genotype frequencies for these polymorphisms did not differ between patients and controls. In conclusion, we reported a functional variant in the PPIA promoter. However, the PPIA variation did not significantly contribute to the risk of suffering from myocardial infarction among patients with atherosclerotic diseased vessels.

Association between heroin dependence and 5-HT2A receptor gene polymorphisms.

OBJECTIVE: To investigate the association between four polymorphisms of the 5-HT(2A) receptor and 5-HT transporter genes and heroin dependence. METHODS: 113 heroin- dependent patients (DSM-IV criteria) and 420 unrelated healthy controls from Asturias (Northern Spain) were genotyped using standard methods. RESULTS: There was an apparent difference in the distribution of genotypes for A-1438G polymorphisms (p = 0.024, not significant after Bonferroni correction). The 5-HT(2A) -1438A allele was significantly more common in patients than controls [0.55 and 0.45, respectively; corrected p = 0.042, OR = 1.51 (95% CI = 1.13-2.03)]. An interaction was observed between A-1438G of 5-HT(2A) and 5-HTT polymorphisms. The association between the -1438AA vs. AG/GG genotypes and heroin dependence was enhanced in the presence of 12-repeat 5-HTT VNTR and short 5-HTTLPR alleles [24.8% in heroin-dependent patients vs. 12.6% in controls; corrected p = 0.045, OR = 2.28 (95% CI = 1.36-3.82)]. CONCLUSIONS: Our findings support a contribution of the 5-HT(2A) gene to susceptibility to heroin dependence, as well as a possible synergistic effect of 5-HT(2A) and 5-HTT genes on susceptibility to heroin dependence.