[show abstract][hide abstract] ABSTRACT: The integrin-β 3 gene (ITGB3), located on human chromosome 17q21.3, was previously identified as a quantitative trait locus (QTL) for 5-HT blood levels and has been implicated as a candidate gene for autism spectrum disorder (ASD). We performed a family-based association study in 281 simplex and 12 multiplex Caucasian families. ITGB3 haplotypes are significantly associated with autism (HBAT, global P=0.038). Haplotype H3 is largely over-transmitted to the affected offspring and doubles the risk of an ASD diagnosis (HBAT P=0.005; odds ratio (OR)=2.000), at the expense of haplotype H1, which is under-transmitted (HBAT P=0.018; OR=0.725). These two common haplotypes differ only at rs12603582 located in intron 11, which reaches a P-value of 0.072 in single-marker FBAT analyses. Interestingly, rs12603582 is strongly associated with pre-term delivery in our ASD patients (P=0.008). On the other hand, it is SNP rs2317385, located at the 5' end of the gene, that significantly affects 5-HT blood levels (Mann-Whitney U-test, P=0.001; multiple regression analysis, P=0.010). No gene-gene interaction between ITGB3 and SLC6A4 has been detected. In conclusion, we identify a significant association between a common ITGB3 haplotype and ASD. Distinct markers, located toward the 5' and 3' ends of the gene, seemingly modulate 5-HT blood levels and autism liability, respectively. Our results also raise interest into ITGB3 influences on feto-maternal immune interactions in autism.
European journal of human genetics: EJHG 03/2011; 19(3):353-9. · 3.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: The PON1 gene, previously found associated with autism spectrum disorders (ASDs), encodes a serum protein responsible for the detoxification of organophosphates (OPs) and able to exert several enzymatic activities. PON1 arylesterase, but not diazoxonase activity, was significantly decreased in 174 ASD patients compared to 175 first-degree relatives and 144 controls (P=2.65×10⁻¹⁶). First degree relatives displayed intermediate activities, closer to patient than to control levels. Differences between patients, first-degree relatives and controls were especially evident among 164 Italians compared to 329 Caucasian-Americans, because arylesterase activity was significantly higher in Italian controls, compared to Caucasian-American controls (P=2.84×10⁻¹⁶). Arylesterase activity and PON protein concentrations were not significantly correlated, supporting a functional inhibition of arylesterase activity in ASD patients over quantitative changes in protein amounts. Serum arylesterase activity, in combination with PON1 genotypes at two single nucleotide polymorphisms (SNPs) known to influence protein amounts (rs705379: C-108T) and substrate specificity (rs662: Q192R), was able to discriminate ASD patients from controls with elevated sensitivity and specificity, depending on genotype and ethnic group. Serum arylesterase activity and genotyping at these two SNPs could thus represent an informative biochemical/genetic test, able to aid clinicians in estimating autism risk in ethnic groups with higher baseline arylesterase activity levels.
Psychiatry Research 12/2010; 180(2-3):105-13. · 2.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: Autism is a highly heritable behavioral disorder. Yet, two decades of genetic investigation have unveiled extremely few cases that can be solely explained on the basis of de novo mutations or cytogenetic abnormalities. Vertical viral transmission represents a nongenetic mechanism of disease compatible with high parent-to-offspring transmission and with low rates of disease-specific genetic abnormalities. Vertically transmitted viruses should be found more frequently in the affected tissues of autistic individuals compared to controls. Our initial step was thus to assess by nested polymerase chain reaction (PCR) and DNA sequence analysis the presence of cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus type 1 (HSV1), herpes simplex virus type 2 (HSV2), human herpes virus 6 (HHV6), BK virus (BKV), JC virus (JCV), and simian virus 40 (SV40) in genomic DNA extracted from postmortem temporocortical tissue (Brodmann areas 41/42) belonging to 15 autistic patients and 13 controls. BKV, JCV, and SV40 combined are significantly more frequent among autistic patients compared to controls (67% versus 23%, respectively; P < .05). The majority of positives yielded archetypal sequences, whereas six patients and two controls unveiled single-base pair changes in two or more sequenced clones. No association is present with the remaining viruses, which are found in relatively few individuals (N <or= 3). Also polyviral infections tend to occur more frequently in the brains of autistic patients compared to controls (40% versus 7.7%, respectively; P = .08). Follow-up studies exploring vertical viral transmission as a possible pathogenetic mechanism in autistic disorder should focus on, but not be limited to, the role of polyomaviruses.
Journal of NeuroVirology 03/2010; 16(2):141-9. · 2.85 Impact Factor