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PLoS One. 2016 Apr 15;11(4):e0153667. doi: 10.1371/journal.pone.0153667. eCollection 2016.

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

Author information

  • 1Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 2Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran.
  • 3Department of Pharmacology, School of Pharmacy, Shiraz University of Medical Sciences, International Branch, Shiraz, Iran.
  • 4Department of Psychiatry, School of Medicine, Hafez Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 5Cancer Immunology Group, Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 6Department of Speech Therapy, School of Rehabilitation, Shiraz University of Medical Sciences, Shiraz, Iran.



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.


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.


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).


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

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