Association of Haptoglobin-1 allele with Autism.

Gene-environment interaction, through abnormal intestinal adsorption, has been proposed as possible mechanism for autism pathogenesis in those patients lacking of causative genetic variants. Haptoglobin (HP) is a haemoglobin binding and acute-phase plasma protein, encoded by two co-dominant alleles, HP-1 and HP-2, producing pre-HP-1 and pre-HP-2 proteins that mature in HP-1 and HP-2, respectively. Due to a 1.7Kb copy number variation in the HP gene, the HP-2 allele has two extra exons with respect to HP-1 (Fig. 1). Thus the HP protein is a dimer in homozygous subjects for HP-1 allele and is multimer in homozygous HP-2. Endogenous pre-HP-2 protein deregulates intestinal tight-junctions through EGFR and PAR2 activation, increases intestinal permeability and has been associated with autoimmune and inflammatory diseases as well as with psychiatric conditions (Fasano, 2011; Sturgeon and Fasano, 2016). Since the association between HP alleles and autism has just been investigated in a very small sample size of patients and controls (Rose et al., 2018), we genotyped, by PCR analysis, HP in a cohort of Italian patients with autism (n=406) and in controls (n=367). The aim was to evaluate the possible association of HP-2 and autism spectrum disorder (ASD). Contrary to what we expected, HP-1 allele distribution was different between patients and controls (36.3% and 29.4%, respectively) and significantly associated with autism (P=0.0041). Since a subgroup of patients and controls have already been genotyped by Illumina Human Omni-15-8 v.1.0 and Affy-6.0 chips, respectively, we are trying to impute HP alleles from flanking SNP haplotypes. HP alleles will therefore be predicted in publicly available large cohorts of patients with autism.