Fatty Acid desaturase gene polymorphisms and metabolic measures in schizophrenia and bipolar patients taking antipsychotics.
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ABSTRACT:
SUBMITTER: Burghardt KJ
PROVIDER: S-EPMC3880735 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPolyunsaturated fatty acids (PUFAs) are associated with a lower risk of multiple diseases. Fatty acid desaturase 1 gene (FADS1) polymorphisms and dietary PUFA intake are both established determinants of circulating PUFA proportions.ObjectiveWe explored the joint effects of FADS1 polymorphisms and dietary PUFA intake on circulating PUFA proportions.DesignWe studied 2288 participants from a nested case-control study of coronary artery disease among participants who provided blood samples in the Nurses' Health Study and the Health Professionals Follow-Up Study. Dietary PUFA intake was obtained from semiquantitative food-frequency questionnaires. FADS1 rs174546 was genotyped by using the Affymetrix 6.0 platform, and circulating PUFA proportions were measured with gas-liquid chromatography. Linear regression models were used to examine the associations between rs174546 and circulating proportions of each fatty acid. Gene-diet interactions were tested by including a cross-product term of dietary intake of each PUFA by rs174546 genotype in the linear regression models.ResultsAfter adjustment for sex and ancestry, each copy of the C allele of rs174546 was associated with higher circulating proportions of arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) and lower proportions of linoleic acid and α-linolenic acid. The magnitude of positive association between higher consumption of dietary EPA or DHA and circulating proportions of EPA increased with each copy of the rs174546_T allele (P-interaction = 0.01 and 0.007, respectively). Each 1-SD increment in EPA intake was associated with an average 3.7% increase in circulating EPA proportions among participants with the rs174546_CC genotype and an average 7.8% increase among participants with the TT genotype.ConclusionsCarriers of the T allele at FADS1 rs174546 may need higher doses of dietary EPA and DHA to achieve the same circulating proportions of EPA as carriers of the C allele. The implications of these findings on disease risk and dietary guidelines require further study.
| S-EPMC6692647 | biostudies-literature
Project description:Fatty acid desaturase (FADS) genes and their variants have been associated with multiple metabolic phenotypes, including liver enzymes and hepatic fat accumulation, but the detailed mechanism remains unclear. We aimed to delineate the role of FADSs in modulating lipid composition in human liver. We performed a targeted lipidomic analysis of a variety of phospholipids, sphingolipids, and ceramides among 154 human liver tissue samples. The associations between previously genome-wide association studies (GWASs)-identified six FADS single-nucleotide polymorphisms (SNPs), and these lipid levels as well as total hepatic fat content (HFC) were tested. The potential function of these SNPs in regulating transcription of three FADS genes (FADS1, FADS2, and FADS3) in the locus was also investigated. We found that though these SNPs were in high linkage disequilibrium (r(2)?>?0.8), the rare alleles of these SNPs were consistently and significantly associated with the accumulation of multiple long-chain fatty acids (LCFAs), with C47H85O13P (C36:4), a phosphatidylinositol (PI), and C43H80O8PN (C38:3), a phosphatidylethanolamine (PE), reached the Bonferroni corrected significance (P?<?3 × 10(-4)). Meanwhile, these SNPs were significantly associated with increased ratios between the more saturated and relatively less saturated forms of LCFAs, especially between PEs, PIs, and phosphatidylcholines (PCs; P???3.5 × 10(-6)). These alleles were also associated with increased total HFC (P?<?0.05). Further analyses revealed that these alleles were associated with decreased hepatic expression of FADS1 (P?=?0.0018 for rs174556), but not FADS2 or FADS3 (P?>?0.05).Our findings revealed critical insight into the mechanism underlying FADS1 and its polymorphisms in modulating hepatic lipid deposition by altering gene transcription and controlling lipid composition in human livers.
| S-EPMC4280302 | biostudies-literature
Project description:Inflammation and altered polyunsaturated fatty acid (PUFA) levels have been implicated in bipolar disorder (BD). A recent genome-wide association study identified a locus in the fatty acid desaturase (FADS) gene cluster conferring susceptibility to BD. In this study, we examined PUFA levels in patients with BD in relation to proinflammatory cytokines, FADS genotype, and dietary habits. We enrolled 83 patients with BD and 217 healthy controls who underwent plasma PUFA measurement. A subsample of 65 patients and 90 controls underwent plasma interleukin (IL)-6 and tumor necrosis factor alpha (TNFα) measurement, and three FADS single nucleotide polymorphisms (SNPs) were genotyped. Information on fish consumption was obtained by a self-reported diet history questionnaire. In comparing PUFA levels between patients and controls, significant differences were found for all 7 PUFAs tested. Specifically, n-3 eicosapentaenoic acid (EPA) level was decreased, and n-6 arachidonic acid level was increased in the patients (p < 0.0001 for both). Plasma IL-6 and TNFα levels were both significantly increased in the patients. Plasma EPA level was negatively correlated with IL-6 and TNFα levels. The FADS genotype, which was associated with increased n-6 PUFA levels, was also associated with marked elevation in TNFα levels. Less frequent fish intake was associated with low EPA and high IL-6 level. Taken together, our results provide strong evidence for altered plasma PUFA and proinflammatory cytokine levels in patients with BD. Furthermore, FADS genotype and fish consumption may contribute not only to altered PUFA levels but also to inflammation in BD.
| S-EPMC6711984 | biostudies-literature
Project description:Background:The role of orexin-A in regulating metabolic homeostasis has been recognized, but its association with antipsychotic-induced metabolic abnormalities remains unclear. We investigated the association between orexin-A levels and metabolic syndrome in patients with schizophrenia treated with clozapine or less obesogenic antipsychotics compared with nonpsychiatric controls. Methods:Plasma orexin-A levels and metabolic parameters were determined in 159 patients with schizophrenia: 109 taking clozapine; 50 taking aripiprazole, amisulpride, ziprasidone, or haloperidol; and 60 nonpsychiatric controls. Results:Orexin-A levels were significantly higher in the group taking less obesogenic antipsychotics, followed by the clozapine group and the controls (F=104.6, P<.01). Higher orexin-A levels were correlated with better metabolic profiles in the patient groups but not in the controls. Regression analyses revealed that the patients with higher orexin-A levels had significantly lower risk of metabolic syndrome (adjusted odds ratio [OR]=0.04, 95% CI: 0.01-0.38 for the 2nd tertile; OR=0.04, 95% CI: 0.01-0.36 for the 3rd tertile, compared with the first tertile), after adjustment for age, sex, smoking history, types of antipsychotics (clozapine vs less obesogenic antipsychotics), duration of antipsychotic treatment, and disease severity. Conclusions:Our results revealed that the orexin-A level was upregulated in patients with schizophrenia treated with antipsychotics, especially for the group taking less obesogenic antipsychotics. Furthermore, higher orexin-A levels were independently associated with better metabolic profiles. These observations suggest that an upregulation of orexin-A has a protective effect against the development of metabolic abnormalities in patients with schizophrenia receiving antipsychotic treatment.
| S-EPMC6313111 | biostudies-literature
Project description:BackgroundAdequate availability of long-chain polyunsaturated fatty acids (LC-PUFAs) is important for human health from pregnancy to adulthood. Previous studies on fatty acid desaturase (FADS) gene single-nucleotide polymorphisms (SNPs) have been performed predominantly in Western populations and showed that FADS SNPs had a marked impact on LC-PUFA composition in blood and tissues.ObjectivesWe aimed to investigate the influence of fetal FADS genotypes on LC-PUFA composition in umbilical artery plasma lipids in Indonesian infants.DesignWe performed a cross-sectional study to assess for these associations.ResultsA total of 12 cord plasma n-6 (ω-6) and n-3 (ω-3) fatty acids were analyzed for associations with 18 FADS gene cluster SNPs from 390 women with single parturition from the Indonesian Prospective Study of Atopic Dermatitis in Infants (ISADI). Fetal FADS genotypes influenced cord plasma LC-PUFA composition, but, in contrast to previous studies from Western populations, the quantitatively predominant SNPs were associated with lower LC-PUFA content.ConclusionTo our knowledge, this study was the first in South East Asia on FADS genotypes and arterial cord blood fatty acids to show an association between fetal LC-PUFA composition and fetal FADS SNPs. The FADS genotype distribution differs markedly between different geographical populations. This trial was registered at clinicaltrials.gov as NCT02401178.
| S-EPMC6250987 | biostudies-literature
Project description:Impulsive risk taking contributes to deleterious outcomes among clinical populations. Indeed, pathological impulsivity and risk taking are common in patients with serious mental illness, and have severe clinical repercussions including novelty seeking, response disinhibition, aggression, and substance abuse. Thus, the current study seeks to examine self-reported impulsivity (Barratt Impulsivity Scale) and performance-based behavioral risk taking (Balloon Analogue Risk Task) in bipolar disorder and schizophrenia. Participants included 68 individuals with bipolar disorder, 38 with schizophrenia, and 36 healthy controls. Self-reported impulsivity was elevated in the bipolar group compared with schizophrenia patients and healthy controls, who did not differ from each other. On the risk-taking task, schizophrenia patients were significantly more risk averse than the bipolar patients and controls. Aside from the diagnostic group differences, there was a significant effect of antipsychotic (AP) medication within the bipolar group: bipolar patients taking AP medications were more risk averse than those not taking AP medications. This difference in risk taking because of AP medications was not explained by history of psychosis. Similarly, the differences in risk taking between schizophrenia and bipolar disorder were not fully explained by AP effects. Implications for clinical practice and future research are discussed.
| S-EPMC3870783 | biostudies-literature
Project description:Polyunsaturated fatty acids (PUFA) correlate with risk of dyslipidemia and cardiovascular diseases. Fatty acid desaturase (FADS) single nucleotide polymorphisms (SNPs) modulate circulating PUFA concentrations. This study examined influence of FADS1 and FADS2 genetic variants on desaturase activities and blood lipid concentrations in type 2 diabetes patients, and further assessed their interrelationships. Selected SNPs (FADS1: rs174547, rs174548, rs174550; FADS2: rs174575, rs174576, rs174583, rs498793 and rs2727270) were genotyped in 820 type 2 diabetes patients and compared with those reported in the HapMap. Patient subgroups (n = 176) without taking lipid-lowering medicine were studied to assess influence of tag SNPs including rs174547, rs174575, rs498793 and rs2727270 on delta-5 desaturase (D5D: 20:4 (n-6)/20:3 (n-6)) and delta-6 desaturase (D6D:18:3 (n-6)/18:2 (n-6)) activities, and blood lipids. FADS1 rs174547 TT/TC/CC and FADS2 rs2727270 CC/CT/TT were significantly (p for trend < 0.05) associated with reduced HDL-C, D5D and D6D activities. Upon adjustment for confounders, D5D (p = 0.006) correlated significantly and D6D marginally (p = 0.07) correlated with increased HDL-C levels, whereas rs174547 and rs2727270 polymorphisms were not associated. D6D andD5D activities may play a role in modulating HDL-C levels in type 2 diabetes. Future studies with larger sample sizes are needed to investigate how FADS genetic variations interact with desaturase activities or PUFAs in the metabolism of lipoproteins in diabetic patients.
| S-EPMC5486258 | biostudies-literature
Project description:Folate has been implicated in cardiovascular disease with atypical antipsychotic (AAPs) use, and individuals with methylenetetrahydrofolate reductase (MTHFR) and catechol-O-methyl transferase (COMT) variants are at greater risk. This study examined the relationship between the MTHFR 677C/T, MTHFR 1298A/C, and COMT Val158Met variants; metabolic syndrome; and lifestyle measures in schizophrenia and bipolar subjects. A total of 237 subjects with bipolar or schizophrenia receiving an antipsychotic for at least 6 months were included in this cross-sectional analysis. Subjects were screened for the metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel III criteria) and MTHFR 677C/T, MTHFR 1298A/C, and Val158Met genotypes. In addition, serum folate and homocysteine were measured along with lifestyle factors. The subject's mean age was 44.7 (SD, 11.7) years; 72% were white, and 51% male; 61% were receiving an AAP; the mean body mass index was 32.6 (SD, 8.2) kg/m, and 48% were current smokers. Overall, 41% met metabolic syndrome criteria (n = 98). There were no differences in age, sex, AAP exposure, or body mass index between genotype groups. Metabolic syndrome was related to age, smoking, and the MTHFR 677T and COMT 158Val alleles (? = 34.4, P < 0.0001). In addition, AAP use showed a trend association with metabolic syndrome (? = 3.21, P = 0.07). These data support our previous reports and add more data pointing to folate's role in mediating a link between mental illness and cardiovascular disease. Use of this information clinically may help to reduce the risk for AAP metabolic complications in those whose clinical care necessitates the use of AAPs.
| S-EPMC3622480 | biostudies-literature
Project description:Cognitive impairment is a core symptom domain of schizophrenia. The effect of antipsychotics, the cornerstone of treatment in schizophrenia, on this domain is not fully clear. There is some evidence suggesting that antipsychotics may partially improve cognitive function, and that this improvement may vary depending on the specific cognitive domain. However, this research is confounded by various factors, such as age, duration/stage of illness, medication adherence, and extrapyramidal side effects that complicate the relationship between antipsychotics and cognitive improvement. Furthermore, antipsychotics-particularly the second generation, or "atypical" antipsychotics-can induce serious metabolic side effects, such as obesity, dyslipidemia and type 2 diabetes, illnesses which themselves have been linked to impairments in cognition. Thus, the inter-relationships between cognition and metabolic side effects are complex, and this review aims to examine them in the context of schizophrenia and antipsychotic treatment. The review also speculates on potential mechanisms underlying cognitive functioning and metabolic risk in schizophrenia. We conclude that the available literature examining the inter-section of antipsychotics, cognition, and metabolic effects in schizophrenia is sparse, but suggests a relationship between metabolic comorbidity and worse cognitive function in patients with schizophrenia. Further research is required to determine if there is a causal connection between the well-recognized metabolic adverse effects of antipsychotics and cognitive deficits over the course of the illness of schizophrenia, as well as, to determine underlying mechanisms. In addition, findings from this review highlight the importance of monitoring metabolic disturbances in parallel with cognition, as well as, the importance of interventions to minimize metabolic abnormalities for both physical and cognitive health.
| S-EPMC6290646 | biostudies-literature
Project description:BACKGROUND:The aim was to investigate if fatty acid profile and estimated desaturase activities; stearoyl CoA-desaturase (SCD), delta-5-desaturase and delta-6-desaturase (D5D; D6D), differ between individuals with metabolically healthy (MH) and unhealthy (MU) phenotypes. We also explored these associations according to BMI categories. METHODS:Men and women at moderately elevated risk of cardiovascular disease were included in this cross-sectional study (n?=?321). If subjects met ?4 out of 5 criteria (elevated triglycerides, total and LDL-cholesterol, HbA1c and low HDL-cholesterol), they were classified as MU (n?=?52). If levels were within reference ranges for ?3 of the same criteria, subjects were classified as MH (n?=?150). Utilizing the entire population, a score ranging from 0 to 5 denoting the number of MU criteria met was computed. Estimated desaturase activities were calculated as product-to-precursor ratio of fatty acids in whole blood (SCD16 [16:1n7/16:0], SCD18 [18:1n9/18:0], D5D [18:3n6/18:2n6], D6D [20:4n6/20:3n6]). RESULTS:Individuals with MH had lower estimated SCD16 and SCD18 activities, whereas estimated D6D activity was higher compared to MU. Similar, SCD16 and SCD18 increased, whereas D6D decreased with increasing criteria of MU. Trends were similar across BMI categories. CONCLUSIONS:This study supports the notion of estimated desaturase activities as possible novel biomarkers of metabolic health irrespectively of BMI.
| S-EPMC7243306 | biostudies-literature