Evidence that COMT genotype and proline interact on negative-symptom outcomes in schizophrenia and bipolar disorder.

Elevated peripheral proline is associated with psychiatric disorders, and there is evidence that proline is a neuromodulator. The proline dehydrogenase (PRODH) gene, which encodes the enzyme that catalyzes proline catabolism, maps to human chromosome 22q11.2, a region conferring risk of schizophrenia. In the Prodh-null mouse, an interaction between elevated peripheral proline and another 22q11.2 gene, catechol-O-methyltransferase (COMT), on neurotransmission and behavior has been reported. We explored the relationship between fasting plasma proline levels and COMT Val(158)Met genotype on symptoms (positive, negative and total) in schizophrenia patients. In an exploratory study we also examined symptom change in patients with bipolar disorder. There was a significant interaction between peripheral proline and COMT on negative symptoms in schizophrenia (P<0.0001, n=95). In COMT Val/Val patients, high proline was associated with low Scale for the Assessment of Negative Symptom (SANS) scores. In contrast, high proline was associated with high SANS scores in patients carrying a Met allele. The relationship between proline and COMT also appears to modify negative symptoms across psychiatric illness. In bipolar disorder, a significant interaction was also observed on negative-symptom change (P=0.007, n=43). Negative symptoms are intractable and largely unaddressed by current medications. These data indicate a significant interaction between peripheral proline and COMT genotype, influencing negative symptoms in schizophrenia and bipolar disorder. That high proline has converse effects on symptoms by COMT genotype, may have implications for therapeutic decisions.

Expression profiling reveals differences in immuno-inflammatory gene expression between the two disease forms of sheep paratuberculosis.

Paratuberculosis is a chronic enteropathy of ruminants caused by Mycobacterium avium subspecies paratuberculosis (MAP); infection of sheep results in two disease forms - paucibacillary (tuberculoid) and multibacillary (lepromatous) associated with the differential polarization of the immune response. In addition the majority of MAP-infected animals show no pathology and remain asymptomatic. Microarray and real-time RT-qPCR analyses were used to compare gene expression in ileum from sheep with the two disease forms and asymptomatic sheep, to further understand the molecular basis of the pathologies. Microarrays identified 36 genes with fold-change of >1.5 and P< or = 0.05 in at least one comparison; eight candidates were chosen for RT-qPCR validation. Sequence analysis of two candidates, CXCR4 and IGFBP6, identified three SNPs in each; five were found in all three forms of disease and showed no significant relationship to pathological type. The IGFBP6 G(3743) A SNP was not detected in asymptomatic sheep. The data show that the two forms of disease are associated with distinct molecular profiles highlighted by the differential expression of chemokine and chemokine receptor transcripts, the protein products of which might be implicated in the different cell infiltrates of the pathologies. The cells within the lesions also show evidence of abnormal activation; they express high levels of cytokine transcripts but have reduced expression levels of transcripts for T cell receptor associated molecules.