Assessment of haptoglobin alleles in autism spectrum disorders: Scientific Reports

F.A. Cupaioli, E. Mosca, C. Magri, M. Gennarelli, M. Moscatelli, M.E. Raggi, M. Landini, N. Galluccio, L. Villa, A. Bonfanti, A. Renieri, C. Fallerini, A. Minelli, A. Marabotti, L. Milanesi, A. Fasano, A. Mezzelani

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Gene-environment interactions, by means of abnormal macromolecular intestinal adsorption, is one of the possible causes of autism spectrum disorders (ASD) predominantly in patients with gastrointestinal disorders. Pre-haptoglobin-2 (zonulin), encoded by the Haptoglobin (HP) allele-2 gene, enhances the intestinal permeability by modulation of intercellular tight junctions. The two alleles of HP, HP1 and HP2, differ for 2 extra exons in HP2 that result in exon duplication undetectable by classic genome-wide association studies. To evaluate the role of HP2 in ASD pathogenesis and to set up a method to discriminate HP alleles, Italian subjects with ASD (n = 398) and healthy controls (n = 379) were genotyped by PCR analysis; subsequently, the PCR results were integrated with microarray genotypes (Illumina Human Omni 1S-8), obtained using a subset from the same subjects, and then we developed a computational method to predict HP alleles. On the contrary to our expectations, there was no association between HP2 and ASD (P > 0.05), and there was no significant allele association in subjects with ASD with or without gastrointestinal disorders (P > 0.05). With the aid of bioinformatics analysis, from a window frame of ~2 Mb containing 314 SNPs, we obtain imputation accuracy (r2) between 0.4 and 0.9 (median 0.7) and correct predictions were between 70% and 100% (median 90%). The conclusions endorse that enhanced intestinal permeability in subjects with ASD should not be imputed to HP2 but to other members of the zonulin family and/or to environmental factors. © 2020, The Author(s).
Original languageEnglish
Article number7758
Number of pages11
JournalSci. Rep.
Issue number1
Publication statusPublished - 2020


  • haptoglobin
  • allele
  • autism
  • case control study
  • child
  • female
  • genetics
  • haplotype
  • human
  • male
  • preschool child
  • single nucleotide polymorphism
  • Alleles
  • Autism Spectrum Disorder
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Female
  • Haplotypes
  • Haptoglobins
  • Humans
  • Male
  • Polymorphism, Single Nucleotide


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