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      Genetic Variants of Angiotensin-Converting Enzyme Are Linked to Autism: A Case-Control Study

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          Abstract

          Background

          Autism is a disease of complex nature with a significant genetic component. The importance of renin-angiotensin system (RAS) elements in cognition and behavior besides the interaction of angiotensin II (Ang II), the main product of angiotensin-converting enzyme (ACE), with neurotransmitters in CNS, especially dopamine, proposes the involvement of RAS in autism. Since the genetic architecture of autism has remained elusive, here we postulated that genetic variations in RAS are associated with autism.

          Methods

          Considering the relation between the three polymorphisms of ACE (I/D, rs4343 and rs4291) with the level of ACE activity, we have investigated this association with autism, in a case-control study. Genotype and allele frequencies of polymorphisms were determined in DNAs extracted from venous blood of 120 autistic patients and their age and sex-matched healthy controls, using polymerase chain reaction (PCR) and PCR–restriction fragment length polymorphism (PCR–RFLP) methods.

          Results

          There were strong associations between both DD genotype of ACE I/D and the D allele, with autism (P = 0.006, OR = 2.9, 95% CI = 1.64–5.13 and P = 0.006, OR = 2.18, 95% CI = 1.37–3.48 respectively). Furthermore, a significant association between the G allele of rs4343 and autism was observed (P = 0.006, OR = 1.84, 95%CI = 1.26–2.67). Moreover, haplotype analysis revealed an association between DTG haplotype and autism (P = 0.008).

          Conclusion

          Our data suggests the involvement of RAS genetic diversity in increasing the risk of autism.

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          Most cited references43

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          Arlequin (version 3.0): An integrated software package for population genetics data analysis

          Laurent Excoffier, Guillaume Laval, Stefan Schneider (2007)
          Arlequin ver 3.0 is a software package integrating several basic and advanced methods for population genetics data analysis, like the computation of standard genetic diversity indices, the estimation of allele and haplotype frequencies, tests of departure from linkage equilibrium, departure from selective neutrality and demographic equilibrium, estimation or parameters from past population expansions, and thorough analyses of population subdivision under the AMOVA framework. Arlequin 3 introduces a completely new graphical interface written in C++, a more robust semantic analysis of input files, and two new methods: a Bayesian estimation of gametic phase from multi-locus genotypes, and an estimation of the parameters of an instantaneous spatial expansion from DNA sequence polymorphism. Arlequin can handle several data types like DNA sequences, microsatellite data, or standard multi-locus genotypes. A Windows version of the software is freely available on http://cmpg.unibe.ch/software/arlequin3.
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            A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures

            D Rossignol, R Frye (2011)
            Recent studies have implicated physiological and metabolic abnormalities in autism spectrum disorders (ASD) and other psychiatric disorders, particularly immune dysregulation or inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures (‘four major areas'). The aim of this study was to determine trends in the literature on these topics with respect to ASD. A comprehensive literature search from 1971 to 2010 was performed in these four major areas in ASD with three objectives. First, publications were divided by several criteria, including whether or not they implicated an association between the physiological abnormality and ASD. A large percentage of publications implicated an association between ASD and immune dysregulation/inflammation (416 out of 437 publications, 95%), oxidative stress (all 115), mitochondrial dysfunction (145 of 153, 95%) and toxicant exposures (170 of 190, 89%). Second, the strength of evidence for publications in each area was computed using a validated scale. The strongest evidence was for immune dysregulation/inflammation and oxidative stress, followed by toxicant exposures and mitochondrial dysfunction. In all areas, at least 45% of the publications were rated as providing strong evidence for an association between the physiological abnormalities and ASD. Third, the time trends in the four major areas were compared with trends in neuroimaging, neuropathology, theory of mind and genetics (‘four comparison areas'). The number of publications per 5-year block in all eight areas was calculated in order to identify significant changes in trends. Prior to 1986, only 12 publications were identified in the four major areas and 51 in the four comparison areas (42 for genetics). For each 5-year period, the total number of publications in the eight combined areas increased progressively. Most publications (552 of 895, 62%) in the four major areas were published in the last 5 years (2006–2010). Evaluation of trends between the four major areas and the four comparison areas demonstrated that the largest relative growth was in immune dysregulation/inflammation, oxidative stress, toxicant exposures, genetics and neuroimaging. Research on mitochondrial dysfunction started growing in the last 5 years. Theory of mind and neuropathology research has declined in recent years. Although most publications implicated an association between the four major areas and ASD, publication bias may have led to an overestimation of this association. Further research into these physiological areas may provide insight into general or subset-specific processes that could contribute to the development of ASD and other psychiatric disorders.
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              Brain serotonin and dopamine transporter bindings in adults with high-functioning autism.

              M Futatsubashi, Norio Mori, Nori Takei … (2009)
              Autism is a neurodevelopmental disorder that is characterized by repetitive and/or obsessive interests and behavior and by deficits in sociability and communication. Although its neurobiological underpinnings are postulated to lie in abnormalities of the serotoninergic and dopaminergic systems, the details remain unknown. To determine the occurrence of changes in the binding of serotonin and dopamine transporters, which are highly selective markers for their respective neuronal systems. Using positron emission tomography, we measured the binding of brain serotonin and dopamine transporters in each individual with the radioligands carbon 11 ((11)C)-labeled trans-1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([(11)C](+)McN-5652) and 2beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane ([(11)C]WIN-35,428), respectively. Statistical parametric mapping was used for between-subject analysis and within-subject correlation analysis with respect to clinical variables. Participants recruited from the community. Twenty men (age range, 18-26 years; mean [SD] IQ, 99.3 [18.1]) with autism and 20 age- and IQ-matched control subjects. Serotonin transporter binding was significantly lower throughout the brain in autistic individuals compared with controls (P < .05, corrected). Specifically, the reduction in the anterior and posterior cingulate cortices was associated with the impairment of social cognition in the autistic subjects (P < .05, corrected). A significant correlation was also found between repetitive and/or obsessive behavior and interests and the reduction of serotonin transporter binding in the thalamus (P < .05, corrected). In contrast, the dopamine transporter binding was significantly higher in the orbitofrontal cortex of the autistic group (P < .05, corrected in voxelwise analysis). In the orbitofrontal cortex, the dopamine transporter binding was significantly inversely correlated with serotonin transporter binding (r = -0.61; P = .004). The brains of autistic individuals have abnormalities in both serotonin transporter and dopamine transporter binding. The present findings indicate that the gross abnormalities in these neurotransmitter systems may underpin the neurophysiologic mechanism of autism. Our sample was not characteristic or representative of a typical sample of adults with autism in the community.
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                Author and article information

                Contributors
                Masaki Mogi: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 15 April 2016
                Publication date Collection: 2016
                Volume: 11
                Issue: 4
                Electronic Location Identifier: e0153667
                Affiliations
                [1 ]Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
                [2 ]Department of Pharmacology, School of Pharmacy, Shiraz University of Medical Sciences, International Branch, Shiraz, Iran
                [3 ]Department of Psychiatry, School of Medicine, Hafez Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
                [4 ]Cancer Immunology Group, Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
                [5 ]Department of Speech Therapy, School of Rehabilitation, Shiraz University of Medical Sciences, Shiraz, Iran
                [6 ]Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
                Ehime University Graduate School of Medicine, JAPAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: NF NE AAS MB. Performed the experiments: NG FF. Analyzed the data: EB. Wrote the paper: NE EB.

                ‡ These authors also contributed equally to this work.

                Article
                Publisher ID: PONE-D-15-54273
                DOI: 10.1371/journal.pone.0153667
                PMC ID: 4833406
                PubMed ID: 27082637
                SO-VID: 89fa6bfd-7535-42c3-a048-7a3beac91cd7
                Copyright © © 2016 Firouzabadi et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 21 December 2015
                Date accepted : 1 April 2016
                Page count
                Figures: 0, Tables: 2, Pages: 10
                Funding
                The authors have no support or funding to report.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Psychology
                Subject: Developmental Psychology
                Subject: Autism Spectrum Disorder
                Subject: Autism
                Subject: Social Sciences
                Subject: Psychology
                Subject: Developmental Psychology
                Subject: Autism Spectrum Disorder
                Subject: Autism
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Developmental Neuroscience
                Subject: Neurodevelopmental Disorders
                Subject: Autism
                Subject: Medicine and Health Sciences
                Subject: Neurology
                Subject: Neurodevelopmental Disorders
                Subject: Autism
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Chemical Compounds
                Subject: Organic Compounds
                Subject: Amines
                Subject: Catecholamines
                Subject: Dopamine
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Organic Chemistry
                Subject: Organic Compounds
                Subject: Amines
                Subject: Catecholamines
                Subject: Dopamine
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Neurochemistry
                Subject: Neurotransmitters
                Subject: Biogenic Amines
                Subject: Catecholamines
                Subject: Dopamine
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Neurochemistry
                Subject: Neurotransmitters
                Subject: Biogenic Amines
                Subject: Catecholamines
                Subject: Dopamine
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Hormones
                Subject: Catecholamines
                Subject: Dopamine
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Heredity
                Subject: Genetic Mapping
                Subject: Variant Genotypes
                Subject: Biology and Life Sciences
                Subject: Evolutionary Biology
                Subject: Population Genetics
                Subject: Haplotypes
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Population Genetics
                Subject: Haplotypes
                Subject: Biology and Life Sciences
                Subject: Population Biology
                Subject: Population Genetics
                Subject: Haplotypes
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Nervous System
                Subject: Central Nervous System
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Nervous System
                Subject: Central Nervous System
                Subject: Biology and Life Sciences
                Subject: Behavior
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Genetics of Disease
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Neurochemistry
                Subject: Neurotransmitters
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Neurochemistry
                Subject: Neurotransmitters
                Custom metadata
                Data Availability All relevant data are within the paper.

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