Preferential transmission of interleukin-1 receptor antagonist alleles in attention deficit hyperactivity disorder

Segman, Ronnen H.; Meltzer, A; Gross‐Tsur, Varda; Kosov, A; Frisch, Amos; Inbar, E; Darvasi, Ariel; Levy, Sharon; Goltser, T; Weizman, Abraham; Galili-Weisstub, Esti

doi:10.1038/sj/mp/4000919

Cited by 23 publications

(19 citation statements)

References 4 publications

(6 reference statements)

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“…Allele 2 of the IL1RN VNTR has been associated with type 1 diabetes mellitus, lichen sclerosus, psoriasis, ulcerative colitis, systemic lupus erythematosus, diabetic nephropathy, multiple sclerosis, osteoporotic fractures, essential hypertension, attention deficit hyperactivity disorder, and alopecia areata, as well as survival following severe sepsis (40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52). Polymorphisms within IL1B…”

Section: Maksymowych Et Almentioning

confidence: 99%

Association of the IL1 gene cluster with susceptibility to ankylosing spondylitis: An analysis of three Canadian populations

Maksymowych

Rahman

Reeve

et al. 2006

Arthritis & Rheumatism

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Objective. To examine the association between the IL1 gene cluster and susceptibility to ankylosing spondylitis (AS) in 3 independent case-control cohorts.Methods. We analyzed 394 patients and 446 controls from Alberta, Newfoundland, and Toronto, Canada. Samples were genotyped using a panel of 38 single-nucleotide polymorphism (SNP) markers within the IL1 gene cluster. Data from 20 informative and nonredundant SNP markers were analyzed using several association test strategies. First, we used the program WHAP to identify single-marker associations. Second, we used WHAP to analyze "sliding windows" of 3 contiguous markers along the entire extent of the IL1 gene cluster in order to identify haplotypic associations. Third, we used the linkage disequilibrium mapping program DMLE to estimate the posterior probability distribution of a disease locus.Results. A total of 14 SNP markers showed significant single-locus disease associations, the most significant being rs3783526 (IL1A) (P ‫؍‬ 0.0009 in the Alberta cohort, P ‫؍‬ 0.04 in the Newfoundland cohort) and rs1143627 (IL1B) (P ‫؍‬ 0.0005 in the Alberta cohort, P ‫؍‬ 0.02 in the Newfoundland cohort). Analysis of 3-marker sliding windows revealed significant and consistent associations with all of the haplotypes in the IL1A and IL1B loci in the Alberta cohort and with IL1B in the Newfoundland cohort, especially haplotypes rs1143634/rs1143630/rs3917356 and rs1143630/ rs3917356/rs3917354 (P ‫؍‬ 0.006-0.0001). With DMLE, a strong peak in the probability distribution was estimated near IL1A in both the Alberta and the Newfoundland populations.Conclusion. These results indicate that the IL1 locus, or a locus close to IL1, is associated with susceptibility to AS.

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Section: Maksymowych Et Almentioning

confidence: 99%

Association of the IL1 gene cluster with susceptibility to ankylosing spondylitis: An analysis of three Canadian populations

Maksymowych

Rahman

Reeve

et al. 2006

Arthritis & Rheumatism

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“…Elevated levels of proinflammatory cytokines such as interleukin-1beta (IL-1β), interleukin-6 (IL-6), tumor necrosis-factor alpha (TNF-α) and interferon-gamma (IFN-γ) have been observed in adult-onset neuropsychiatric disorders such as schizophrenia [4, 5], bipolar disorder [6, 7] and major depression [8, 9]. These proinflammatory cytokines have also been indicated to have a role in childhood neuropsychiatric disorders such as autism [10, 11] and ADHD [12]. In addition, recent studies have indicated that antipsychotics and antidepressants suppress the proinflammatory cytokines and increase the levels of anti-inflammatory cytokines [13, 14].…”

Section: Introductionmentioning

confidence: 99%

Proinflammatory Cytokines and Oxidative Stress Decrease the Transport of Dopamine Precursor Tyrosine in Human Fibroblasts

2017

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Background: Proinflammatory cytokines and oxidative stress responses have been extensively implicated in the pathophysiology of neuropsychiatric disorders over the past 2 decades. Moreover, disturbed transport of the dopamine precursor (i.e., the amino acid tyrosine) has been demonstrated, in different studies, across fibroblast cell membranes obtained from neuropsychiatric patients. However, the role and influences of proinflammatory cytokines and oxidative stress, and the reasons for disturbed tyrosine transport in neuropsychiatric disorders, are still not evaluated. Aims: The present study aimed to assess the role of proinflammatory cytokines and oxidative stress, indicated in many neuropsychiatric disorders, in tyrosine transportation, by using human skin-derived fibroblasts. Methods: Fibroblasts obtained from a healthy control were used in this study. Fibroblasts were treated with proinflammatory cytokines (IL-1β, IFN-γ, IL-6, TNF-α), their combinations, and oxidative stress, optimized for concentrations and incubation time, to analyze the uptake of ¹⁴C-tyrosine compared to untreated controls. Results and Conclusion: This study demonstrates that proinflammatory cytokines and oxidative stress decrease the transport of tyrosine (47% and 33%, respectively), which can alter dopamine synthesis. The functionality of the tyrosine transporter could be a new potential biomarker to target for discovering new drugs to counteract the effects of proinflammatory cytokines and oxidative stress in the pathophysiology of neuropsychiatric disorders.

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“…8,9 Tested genes have included DRD4, COMT, HTR2A, DAT1, dopamine beta-hydroxylase, dopa decarboxylase, CHRNA7, and interleukin 1, among others. [8][9][10][11][12][13][14][15][16] DRD4 is of interest as a candidate gene as it codes for a 7-transmembrane G-proteincoupled dopamine receptor, which is a member of the D2-like dopamine receptor family. DRD4 is expressed in regions implicated in ADHD [17][18][19] including the limbic system, frontal cortex, and globus pallidus.…”

Section: Introductionmentioning

confidence: 99%

Pedigree disequilibrium test (PDT) replicates association and linkage between DRD4 and ADHD in multigenerational and extended pedigrees from a genetic isolate

et al. 2004

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Association/linkage between dopamine D4 receptor (DRD4) polymorphisms and attentiondeficit/hyperactivity disorder (ADHD) has been suggested by case-control-and nuclear-familybased studies. Here, we present a candidate gene analysis for DRD4 using 14 extended and multigenerational families segregating ADHD derived from the 'Paisa' community of Antioquia, Colombia, a genetic isolate. Two DRD4 polymorphisms (a 120 bp tandem duplication at the promoter and a 48 bp-VNTR at exon 3), reported associated to ADHD, were genotyped. Parametric and non-parametric linkage analyses, and a family-based association test (FBAT), the pedigree disequilibrium test (PDT), were applied to search for evidence of association/ linkage. Two-point LOD scores were significantly negative, with values ranging from À3.21 (P ¼ 0.011158) to À7.66 (P ¼ 0.000091 at h ¼ 0). Non-parametrical analysis resulted in nonsignificant evidence for linkage. The PDT showed a moderate trend toward significance of association/linkage between the 7-repeat (7R) allele at the 48 bp VNTR and ADHD (P ¼ 0.0578). Furthermore, the haplotype analysis shows a significant association/linkage of the 7R-240 bp haplotype (P ¼ 0.0467) with ADHD. Results suggest that either a moderate DRD4 genetic effect, or linkage disequilibrium of DRD4 with an ADHD disease locus in the vicinity or the linkage to a phenotypic component of the ADHD spectrum could be underlying this association/linkage. These results provide further evidence for the association of ADHD to genetic variation in or near to DRD4 and replicate the previously reported association between ADHD and the 7R allele.

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Preferential transmission of interleukin-1 receptor antagonist alleles in attention deficit hyperactivity disorder

Abstract: Keywords: attention deficit hyperactivity disorder; ADHD; interleukin-1 receptor antagonist gene; transmission disequilibrium test

Cited by 23 publications

References 4 publications

Association of the IL1 gene cluster with susceptibility to ankylosing spondylitis: An analysis of three Canadian populations

Association of the IL1 gene cluster with susceptibility to ankylosing spondylitis: An analysis of three Canadian populations

Proinflammatory Cytokines and Oxidative Stress Decrease the Transport of Dopamine Precursor Tyrosine in Human Fibroblasts

Pedigree disequilibrium test (PDT) replicates association and linkage between DRD4 and ADHD in multigenerational and extended pedigrees from a genetic isolate

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