Influence Of Gene Variants Research Articles

Clinical and genetic characteristics of ALS patients with variants in genes regulating DNA methylation.

Aberrant DNA methylation alterations are implicated in amyotrophic lateral sclerosis (ALS). Nevertheless, the influence of genetic variants in genes regulating DNA methylation on ALS patients is not well understood. Therefore, we aim to provide a comprehensive variant profile of genes related to DNA methylation (DNMT1, DNMT3A, DNMT3B, DNMT3L) and demethylation (TET1, TET2, TET3, TDG) and to investigate the association of these variants with ALS. Variants were screened in a cohort of 2240 ALS patients from Southwest China, using controls from the Genome Aggregation Database (n = 9976) and the China Metabolic Analytics Project (n = 10,588). The over-representation of rare variants and their association with ALS risk were evaluated using Fisher's exact test with Bonferroni correction at both allele and gene levels. Kaplan-Meier analysis and Cox regression analysis were employed to explore the relationship between variants and survival. A total of 210 variants meeting the criteria were identified. Gene-based burden analysis identified a significant increase in ALS risk associated with rare variants in the TET2 gene (OR = 1.95, 95% CI = 1.29-2.88, P = 0.001). Survival analysis demonstrated that patients carrying variants in demethylation-related genes had a higher risk of death compared to those with methylation-related gene variants (HR = 1.29, 95% CI = 1.03-1.86, P = 0.039). This study provides a genetic variant profile of genes involved in DNA methylation and demethylation regulation, along with the clinical characteristics of ALS patients carrying these variants. The findings offer genetic evidence implicating disrupted DNA methylation dynamics in ALS.

Association of CYP27B1 gene polymorphisms with pulmonary tuberculosis and vitamin D levels

Background and ObjectivesGenetic factors are reported to be connected with tuberculosis (TB) infection. Studies have shown that genetic variations in genes involved in the vitamin D pathway influence the levels of vitamin D found in the bloodstream (serum). Cyp27b1 (1α-hydroxylase) is an enzyme that activates the synthesis of bioactive vitamin D3 by hydroxylation of 25(OH)D3.The in vitro studies reported rare gene variants of Cyp27b1 such as rs118204011 and rs118204012, associated with loss of Cyp27b1 function and lower serum vitamin D levels. Globally, a critical gap exists in understanding the link between these gene variants with TB and vitamin D levels. Hence, the study objective is to comprehend the association of Cyp27b1 rs118204009 (G/A), rs118204011 (C/T), and rs118204012 (A/G) with tuberculosis susceptibility/protection and to assess the influence of gene variants on vitamin D levels in both healthy controls (HCs) and those with pulmonary tuberculosis (PTB) in South India. MethodsGenomic DNA extraction was performed by salting-out procedure and subsequently genotyped through polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. Vitamin D level was measured by Enzyme-Linked Immunosorbent Assay (ELISA). ResultsIn rs118204012 (A/G), a substantial association was found with PTB susceptibility in allele ‘A’ [Odds Ratio (OR): 1.52 (1.02–2.26); p = 0.044] and ‘AA’ genotype [OR: 1.69 (1.02–2.81); p = 0.040] through the dominant model. Allele ‘G’ [OR: 0.66 (0.44–0.98); p = 0.044) was found to be associated with protection against TB. Males were associated with increased susceptibility towards TB compared to females in the rs118204011 “CC” [OR: 3.94 (1.94–7.98); p = 0.002] and rs118204012 ‘AA’ [OR: 4.57 (2.13–9.79); p = 0.0001] genotypes. Vitamin D insufficiency (<30 ng/ml) was more prevalent in PTB patients (66.67 %) with the rs118201012 ‘AA’ genotype compared with healthy controls (57.14 %). This genotype was associated with disease susceptible odds ratio of 1.5. ConclusionCyp27b1 rs118204012 ‘AA’ genotype was found to have association with vitamin D insufficiency and TB susceptibility. In terms of gender, our findings suggest that male individuals are correlated with a higher TB risk. This suggest that the gene variants may be involved in the downstream processing of serum Vitamin D levels and its association with the disease.

Profiling the Influence of Gene Variants Related to Folate-Mediated One-Carbon Metabolism on the Outcome of In Vitro Fertilization (IVF) with Donor Oocytes in Recipients Receiving Folic Acid Fortification.

Nutritional status and gene polymorphisms of one-carbon metabolism confer a well-known interaction that in pregnant women may affect embryo viability and the health of the newborn. Folate metabolism directly impacts nucleotide synthesis and methylation, which is of increasing interest in the reproductive medicine field. Studies assessing the genetic influence of folate metabolism on IVF treatments have currently been performed in women using their own oocytes. Most of these patients seeking to have a child or undergoing IVF treatments are advised to preventively intake folate supplies that restore known metabolic imbalances, but the treatments could lead to the promotion of specific enzymes in specific women, depending on their genetic variance. In the present study, we assess the influence of candidate gene variants related to folate metabolism, such as Serine Hydroxymethyltransferase 1 SHMT1 (rs1979276 and rs1979277), Betaine-Homocysteine S-Methyltransferase BHMT (rs3733890), Methionine synthase reductase MTRR (rs1801394), Methylenetetrahydrofolate reductase MTHFR (rs1801131 and rs1801133), methionine synthase MTR (rs12749581), ATP Binding Cassette Subfamily B Member 1 ABCB1 (rs1045642) and folate receptor alpha FOLR1 (rs2071010) on the success of IVF treatment performed in women being recipients of donated oocytes. The implication of such gene variants seems to have no direct impact on pregnancy consecution after IVF; however, several gene variants could influence pregnancy loss events or pregnancy maintenance, as consequence of folic acid fortification.

Association of CYP2R1 gene polymorphisms in pulmonary tuberculosis

The CYP2R1 gene express the enzyme 25-hydroxylase, involved in the synthesis of major circulating vitamin D metabolite 25-hydroxyvitaminD [25(OH)D]. CYP2R1 gene variants have been reported to be associated with altered 25(OH)D level and associated with the development of active disease including tuberculosis (TB). The aim of the present study was to understand the association of rs10741657 (G/A) and rs2060793(A/G) CYP2R1 gene polymorphisms with tuberculosis susceptibility/protection in 104 Healthy controls (HCs) and 105 pulmonary tuberculosis (PTB) patients and to understand the influence of gene variants on 25(OH)D levels in South Indian population. Genotyping was performed by polymerase chain reaction trailed by restriction fragment length polymorphism (PCR-RFLP) method. Plasma samples were used for 25(OH)D level estimation by ELISA method. In rs10741657, under a dominant model (GG vs AG + AA), “AG” and “AA” genotypes as well as in rs2060793 under an overdominant model (GA vs GG + AA), “GA” genotype were significantly associated with protection to pulmonary tuberculosis. Based on sex, rs10741657 “AG” was significantly associated with protection and “GG” was significantly associated with susceptibility to TB in males. A sufficient vitamin D level was found with rs10741657 “AA” and “AG” genotypes and “GG” genotype associated with 81.8% of vitamin D deficiency in PTB individuals. In conclusion, rs10741657 “AG” and “AA” genotypes were associated with higher 25(OH)D levels and protection to TB. The lower 25(OH)D levels associated with rs10741657 “GG” genotype individuals may be recommended for higher vitamin D supplementation for better outcome from the disease. Further studies with large sample size are needed to confirm this study finding.

Mutational profile of rare variants in inflammasome-related genes in Beh\xe7et disease: A Next Generation Sequencing approach

Behçet’s disease (BD) is an immune-mediated systemic disorder with a well-established association with HLA class I and other genes. BD has clinical overlap with many autoinflammatory diseases (AIDs). The aim of this study was to investigate the role of rare variants in seven genes involved in AIDs: CECR1, MEFV, MVK, NLRP3, NOD2, PSTPIP1 and TNFRSF1A using a next generation sequencing (NGS) approach in 355 BD patients. To check global association of each gene, 4 tests: SKAT, CollapseBt, C(α) and weighted KBAC were used. Databases: 1000 Genomes Project Phase 3, Infevers, HGMD and ClinVar and algorithms: PolyPhen2 and SIFT were consulted to collect information of the 62 variants found. All the genes resulted associated using SKAT but only 3 (MVK, NOD2 and PSTPIP1) with C(α) and weighted KBAC. When all the genes are considered, 40 variants were associated to AIDs in clinical databases and 25 were predicted as pathogenic at least by one of the algorithms. Including only MVK, NOD2 and PSTPIP1, the associated to AIDs variants found in BD were 20 and the predicted as pathogenic, 12. The maxima contribution corresponds to NOD2. This study supports influence of rare variants in genes involved in AIDs in the pathogenesis of BD.

Genetic variants influencing effectiveness of exercise training programmes in obesity - an overview of human studies.

Frequent and regular physical activity has significant benefits for health, including improvement of body composition and help in weight control. Consequently, promoting training programmes, particularly in those who are genetically predisposed, is a significant step towards controlling the presently increasing epidemic of obesity. Although the physiological responses of the human body to exercise are quite well described, the genetic background of these reactions still remains mostly unknown. This review not only summarizes the current evidence, through a literature review and the results of our studies on the influence of gene variants on the characteristics and range of the body's adaptive response to training, but also explores research organization problems, future trends, and possibilities. We describe the most reliable candidate genetic markers that are involved in energy balance pathways and body composition changes in response to training programmes, such as FTO, MC4R, ACE, PPARG, LEP, LEPR, ADRB2, and ADRB3. This knowledge can have an enormous impact not only on individualization of exercise programmes to make them more efficient and safer, but also on improved recovery, traumatology, medical care, diet, supplementation and many other areas. Nevertheless, the current studies still represent only the first steps towards a better understanding of the genetic factors that influence obesity-related traits, as well as gene variant x physical activity interactions, so further research is necessary.

A candidate gene approach of the calcineurin pathway to identify variants associated with clinical outcomes in renal transplantation.

To investigate the potential influence of variants in genes involved in the calcineurin pathway on the efficacy and toxicity of calcineurin inhibitors in renal transplantation. Twenty-three polymorphisms in thirteen genes were tested in 381 renal transplant recipients receiving ciclosporin (n = 221) or tacrolimus (n = 160) and mycophenolate mofetil. Data were collected prospectively over the first year post-transplantation. Multivariate survival analyses revealed no genetic associations with biopsy proven acute graft rejection and serious infections. Donor-recipient Cytomegalovirus mismatch was the only variable associated with serious infection. This large exploratory study casts doubts on the potential interest of genetic biomarkers related to CNI pharmacodynamics but associations with other phenotypes in transplantation deserve further studies.

Association of variants in genes related to the immune response and obesity with BPH in CLUE II.

BACKGROUNDChronic inflammation and obesity may contribute to the genesis or progression of benign prostatic hyperplasia (BPH) and BPH-associated lower urinary tract symptoms (LUTS). The influence of variants in genes related to these states on BPH has not been studied extensively. Thus, we evaluated the association of 17 single nucleotide polymorphisms (SNPs) in immune response genes (IL1B, IL6, IL8, IL10, TNF, CRP, TLR4, RNASEL) and genes involved in obesity, including insulin regulation (LEP, ADIPOQ, PPARG, TCF7L2), with BPH.METHODSBPH cases (N=568) and age-frequency matched controls (N=568) were selected from among adult male CLUE II cohort participants who responded in 2000 to a mailed questionnaire. BPH was defined as BPH surgery, use of BPH medications, or symptomatic BPH (American Urological Association Symptom Index Score ≥15). Controls were men who had not had BPH surgery, did not use BPH medications, and whose symptom score was ≤7. Age-adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression.RESULTSNone of the candidate SNPs was statistically significantly associated with BPH. However, we could not rule out possible weak associations for CRP rs1205 (1082C>T), ADIPOQ rs1501299 (276C>A), PPARG rs1801282 (-49C>G), and TCF7L2 rs7903146 (47833T>C). After summing risk alleles, men with ≥4 had an increased BPH risk compared with those with ≤1 (OR, 1.78; 95% CI, 1.10-2.89; Ptrend=0.006).CONCLUSIONSNPs in genes related to immune response and obesity, especially in combination, may be associated with BPH.

A constitutional variant in the transcription factor EP300 strongly influences the clinical outcome of patients submitted to allo-SCT

An adequate response of the innate immune system after allo-SCT is crucial for the clinical outcome of patients submitted to this procedure. EP300 is one of the key genes of the innate immune system (IIS). We evaluated the influence of gene variant A>G rs20551 in EP300 in donor and/or recipient on clinical results after HLA-identical sibling allo-SCT. Patients with AA gene variant had a lower relapse incidence (31 vs 48%, P=0.025; odds ratio (OR)=1.6, P=0.05), attained better disease-free survival (AA: 53% vs AG+GG: 24%, P=0.001; OR=1.8, P=0.01), and better OS (AA: 53% vs AG+GG: 34%, P=0.001; OR=1.9, P=0.007). This beneficial association was more evident when AA gene variant was present in both donor and patient. In healthy individuals, AA gene variant was associated with lower IL2 production after a mitogenic stimuli, higher CD4+ cell response after CMV infection, and higher expression of innate immune genes (IRF-3 and MIF), cell cycle genes (AURKB, CCNA2 and CCNB1), lymphocyte survival genes (NFAT5 and SLC38A2), and with a lower expression of P53 compared with recessive GG gene variant. These findings suggest a beneficial effect of the AA gene variant in rs20551 on clinical outcome after allo-SCT.

Results of Simultaneously Performed Analysis of 48 Gene Variants Reported to Have Influence on Transplant outcome

Abstract 3047Up to date, there are many conflicting reports existing in which different gene variants have been proposed to have influence on the outcome of allogeneic transplant. Hereby many of the published studies bare a distressing high weakness in the study set up as for example low number of study patients, large heterogeneity of donor types and/or GVHD prophlyaxis regimens and/or T cell depleting of grafts and/or type of conditioning regimens. In this study we aimed to evaluate in 285 patients and their HLA identical sibling donors the following in table 1 shown 48 different gene variants from which were reported to have influence on the outcome of transplants. Our study group consists of a homogenous group of patients who underwent all a non T cell-depleted transplantation after receiving a myeloablative conditioning regimen and a GVHD prophylaxis with MTX and CSA or CSA and MMF. Patients were transplanted from a HLA-identical sibling donor for various diseases like acute leukemia, CML, MDS, lymphoma and MM between January 2000 and June 2010 at our centerWe could confirm an influence of gene variants of NOD2 (80, 4% vs 61, 6%, p=0.0013), IL23R, MTHFR1298, and LCT 13910 on the occurrence of acute GVHD grade 1–4 on recipients side, whereas no influence was seen of any gene variant on the occurrence of grade 2–4 acute GVHD. But, NOD2 gene variants had a significant (p=0.041) influence on the occurrence of severe acute GVHD grade 3–4. The occurrence of acute GVHD grade 1–4 was significantly modified by the detection of following gene variants at donors side: CCL5 28 promotor (30, 8% vs 69, 2% p=0.033), GSTP 313 (74, 3% vs 62, 4%, p=0.043);IL23R (69, 9% vs 48%, p=0.049), MTHFR129 (86, 7 vs 37, 3% p=.0.06), MTHFR 677 (53, 8% vs 70%, p=0.05), NOD2 (65, 9% vs 84, 4%, p=0.01). Acute GVHD grade 2 –4 was significantly influenced only by GSTP (p<0.015) and MTHFR129 (p<0.025). Severe acute GVHD grade 3–4 was only influenced by GSTP gene variants (p<0.04).The 5-year TRM was influenced by MTHFR677 (30, 4% vs 19, 2%, p=0.05) at recipient side, and at donor side by the genes IL18 Rap (38, 5% vs 19%, p=0.046) and CYP1B1 (28, 8% vs 15, 6%, p=0.07).IL10 gene variants at recipients side influenced the 5-year OS significantly, at donor side the 5-year OS was influenced by CTLA4 (69, 4 vs 52, 2%, p=0.06) IL23R (53, 6% vs 71, 6%, p=0.044) and MBL2CD55 48, 9% vs 65, 2% p=0.02).In this study we could confirm that the above described gene variants might influence moderately the transplant outcome and may therefore be qualified for screening in patients and their respective donors prior to transplant.CCL5 28 promotor G/Crs1800825MBL2 Codon220rs7096206CCR5 2086 A/Grs1800023MBL2 Codon4rs7095891CCR5 2554 G/Trs2734648MBL2 Codon550rs11003125CP2C19*2rs4244285MBL2[G54D]rs1800450CP2C19*3rs4986893MBL2[G57E]rs1800451CTLA4 A/G pos.49rs231775MBL2[R55C]rs5030737CYP1B1 432rs1056836MCP1 1543 C/Trs13900CYP2C9*2rs1799853mdr1 C3435Trs1045642CYP2C9*3rs1057910MTHFR1298rs1801131CYP2D6*3rs4986774MTHFR677rs1801133CYP2D6*4,rs1800716NFKBIL1rs2857605CYP2D6*6rs5030655NOD2 G908Rrs2066847CYP3A4*1BNOD2 L1007F insCrs2066847CYP3A5*3NOD2 R702Wrs2066844FAS 670 G/Ars4934436TLR2 R753Qrs5743708GSTA1 A567T, 69C 52Grs3957356TLR3rs3775291GSTP1 313A/Grs1695TLR4 [D299G]rs4986790IL10 -1082rs1800896TLR4 [T399I]rs4987233IL10 592 C/Ars1800872TLR5rs764535IL23RTLR6 745C>Trs5743810IL18 137 G/Crs187238TLR9 C-1237Trs5743836IL18 RAPrs917997TLR9 T-1486Crs187084IL6 G174Crs1800795TNF alpha 238 A/Grs361525LTArs2844484VEGF 405G/Crs833061 Disclosures:No relevant conflicts of interest to declare.

Pharmacogenetics of Response to Antipsychotics in Patients with Schizophrenia

This review presents the findings of pharmacogenetic studies exploring the influence of gene variants on antipsychotic treatment response, in terms of both symptom improvement and adverse effects, in patients with schizophrenia. Despite numerous studies in the field, replicating findings across different cohorts that include subjects of different ethnic groups has been challenging. It is clear that non-genetic factors have an important contribution to antipsychotic treatment response. Differing clinical, demographic and environmental characteristics of the cohorts studied have added substantial complexity to the interpretation of the positive and negative findings of many studies. Pharmacogenomic genome-wide investigations are beginning to yield interesting data although they have failed to replicate the most robust findings of candidate gene studies, and are limited by the sample size, especially given the need for studying homogeneous cohorts. Most of the studies conducted on cohorts treated with single antipsychotics have investigated clozapine, olanzapine or risperidone response. These studies have provided some of the most replicated associations with treatment efficacy. Serotonergic system gene variants are significantly associated with the efficacy of clozapine and risperidone, but may have less influence on the efficacy of olanzapine. Dopamine D3 receptor polymorphisms have been more strongly associated with the efficacy of clozapine and olanzapine, and D2 genetic variants with the efficacy of risperidone. Serotonin influences the control of feeding behaviour and has been hypothesized to have a role in the development of antipsychotic-induced weight gain. Numerous studies have linked the serotonin receptor 2C (5-HT2C) -759-C/T polymorphism with weight gain. The leptin gene variant, -2548-G/A, has also been associated with weight gain in several studies. Pharmacogenetic studies support the role of cytochrome P450 enzymes and dopamine receptor variants in the development of antipsychotic-induced movement disorders, with a contribution of serotonergic receptors and other gene variants implicated in the mechanism of action of antipsychotics. Clozapine-induced agranulocytosis has been associated with polymorphisms in the major histocompatibility complex gene (HLA).

Additive effects of LPL, APOA5 and APOEvariant combinations on triglyceride levels and hypertriglyceridemia: results of the ICARIA genetic sub-study

BackgroundHypertriglyceridemia (HTG) is a well-established independent risk factor for cardiovascular disease and the influence of several genetic variants in genes related with triglyceride (TG) metabolism has been described, including LPL, APOA5 and APOE. The combined analysis of these polymorphisms could produce clinically meaningful complementary information.MethodsA subgroup of the ICARIA study comprising 1825 Spanish subjects (80% men, mean age 36 years) was genotyped for the LPL-HindIII (rs320), S447X (rs328), D9N (rs1801177) and N291S (rs268) polymorphisms, the APOA5-S19W (rs3135506) and -1131T/C (rs662799) variants, and the APOE polymorphism (rs429358; rs7412) using PCR and restriction analysis and TaqMan assays. We used regression analyses to examine their combined effects on TG levels (with the log-transformed variable) and the association of variant combinations with TG levels and hypertriglyceridemia (TG ≥ 1.69 mmol/L), including the covariates: gender, age, waist circumference, blood glucose, blood pressure, smoking and alcohol consumption.ResultsWe found a significant lowering effect of the LPL-HindIII and S447X polymorphisms (p < 0.0001). In addition, the D9N, N291S, S19W and -1131T/C variants and the APOE-ε4 allele were significantly associated with an independent additive TG-raising effect (p < 0.05, p < 0.01, p < 0.001, p < 0.0001 and p < 0.001, respectively). Grouping individuals according to the presence of TG-lowering or TG-raising polymorphisms showed significant differences in TG levels (p < 0.0001), with the lowest levels exhibited by carriers of two lowering variants (10.2% reduction in TG geometric mean with respect to individuals who were homozygous for the frequent alleles of all the variants), and the highest levels in carriers of raising combinations (25.1% mean TG increase). Thus, carrying two lowering variants was protective against HTG (OR = 0.62; 95% CI, 0.39-0.98; p = 0.042) and having one single raising polymorphism (OR = 1.20; 95% CI, 1.39-2.87; p < 0.001) or more (2 or 3 raising variants; OR = 2.90; 95% CI, 1.56-5.41; p < 0.001) were associated with HTG.ConclusionOur results showed a significant independent additive effect on TG levels of the LPL polymorphisms HindIII, S447X, D9N and N291S; the S19W and -1131T/C variants of APOA5, and the ε4 allele of APOE in our study population. Moreover, some of the variant combinations studied were significantly associated with the absence or the presence of hypertriglyceridemia.

Improved outcome of hematopoietic SCT in patients with homozygous gene variant of Toll-like receptor 9

Toll-like receptor 9 (TLR9) is part of the innate immune system, which is activated by CpG oligonucleotides (ODNs) and produces potent Th1-type innate and adaptive immune responses. It is reported that TLR9 gene variants, T1486C and T1237C, are associated with a reduced TLR9 expression compared with the wild-type gene. In two cohort analyses, we evaluated the influence of these gene variants on the outcome of transplant in 413 patients and donors. A retrospective analysis of the first cohort (n=293) showed that the homozygous CC gene variant of TLR9 (1486) compared with TC/TT gene variants was significantly associated with a markedly improved 5-year TRM (11.7 versus 36.4%, P<0.003), 5-year OS (86.1 vs 48.3%, P<0.001) and a lower relapse rate (13.2 vs 33.3%, P<0.007), whereas the occurrence of acute GVHD was not different. A prospectively performed analysis of the second cohort (n=120) and multivariate analyses confirmed the influence of the CC gene variant on these end points. Compared with patients with TC/TT gene at position 1486 of TLR9, patients with the homozygous CC gene variant had a lower TLR9 mRNA expression and a delayed T-cell immune reconstitution after transplant, which might prevent them from overwhelming immune responses as sepsis or systemic inflammatory response syndrome (SIRS) associated with an increased TRM. In vitro studies using CpG-rich ODNs showed an upregulation of TLR9 expression in cell lines with CC gene variant, but not in cell lines with wild-type gene.

Inflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults

Interleukin-6 (IL-6) is an inflammatory cytokine that influences the development of inflammatory and aging-related disorders and ultimately longevity. In order to study the influence of variants in genes that regulate inflammatory response on IL-6 levels and longevity, we screened a panel of 477 tag SNPs across 87 candidate genes in >5000 older participants from the population-based Cardiovascular Health Study (CHS). Baseline plasma IL-6 concentration was first confirmed as a strong predictor of all-cause mortality. Functional alleles of the IL6R and PARP1 genes were significantly associated with 15%–20% higher baseline IL-6 concentration per copy among CHS European–American (EA) participants (all p<10−4). In a case/control analysis nested within this EA cohort, the minor allele of PARP1 rs1805415 was nominally associated with decreased longevity (p=0.001), but there was no evidence of association between IL6R genotype and longevity. The PARP1 rs1805415 – longevity association was subsequently replicated in one of two independent case/control studies. In a pooled analysis of all three studies, the “risk” of longevity associated with the minor allele of PARP1 rs1805415 was 0.79 (95%CI 0.62–1.02; p=0.07). These findings warrant further study of the potential role of PARP1 genotype in inflammatory and aging-related phenotypes.

Association study of the INPP1, 5HTT, BDNF, AP-2β and GSK-3β GENE variants and restrospectively scored response to lithium prophylaxis in bipolar disorder

In the present study we investigated the influence of a series variants in genes (the serotonin transporter, glycogen synthase kinase-3β, inositol polyphosphatase 1-phosphate, brain-derived neurotrophic factor and activator protein 2β) related to the action of lithium carbonate, a drug used for prophylaxis in mood disorders. We used a sample of unrelated patients with bipolar disorder type I on lithium therapy for at least 2 years who met the proposed response criteria for prophylactic response. Of the 134 patients, 61 patients were considered full responders, 49 non-responders and 24 partial responders. No significant differences were observed for the genotype or allele frequencies for good, partial and poor responders for the five gene variants: for BDNF G196A (genotype: χ 2 = 3.67, 4 d.f., p = 0.45; allele: χ 2 = 2.31, 2 d.f., p = 0.31); for INPP1 C973A (genotype: χ 2 = 1.35, 4 d.f., p = 0.85; allele: χ 2 = 0.04, 2 d.f., p = 0.98); for AP-2β [CAAA] 4/5 (genotype: χ 2 = 3.18; 4 d.f., p = 0.52; allele: χ 2 = 0.92, 2 d.f., p = 0.063); for 5HTTLPR (genotype: χ 2 = 0.67, 4 d.f., p = 0.96; allele: χ 2 = 0.27, 2 d.f., p = 0.87); for GSK-3β A-1727T (genotype: χ 2 = 3.55, 4 d.f., p = 0.47; allele: χ 2 = 0.48, 2 d.f., p = 0.78). These investigated variants are not predictive factors for lithium prophylactic response in our sample of bipolar disorder type I patients. However, it is still possible that a subgroup of a diverse ethnic ancestry may be predisposing to some of those variants for lithium response.