Diseases associated with expression evidence

With respect to the dopamine Dj-hke receptors, including the dopamine receptor, which is ten times more sensitive to dopamine and has a much more narrow tissue expression than the dopamine Dj receptor, few studies have found evidence of coding variants associated with a disease state (41,42). Untranslated promoter SNPs, however, have been associated with various disease states (60). These studies, while equivocal, suggest association with bipolar disorder, alcohohsm, and attention-deficit disorder to name a few (60-65). 

By contrast, studies of the dopamine D -like receptors have found evidence for the association of the receptor with disease (66) these studies have been replicated (41,42). From among the multitude of these studies, only selected examples are reviewed here. For example, evidence both for and against the association of the dopamine D -like receptors with schizophrenia has been reported. Polymorphisms of the dopamine receptor, including the third intracellular loop VNTR, alter dopamine receptor expression. In addition to association with schizophrenia (3,67-70), the dopamine polymorphisms have been associated with the genetic basis of the variable efficacy of antipsychotics such as clozapine (or neuromuscular toxicity—tardive dyskinesia) (69,71,72). Similarly, promoter SNPs have been associated with altered clozapine efficacy (67,68,73). 

Although most human cancers are acquired diseases, all types may occur in heritable or nonheritablc forms, and heritabiUty may be associated with a dominant or recessive expression at a single locus, or with a constitutional chromosome anomaly. The changes associated with inherited predisposition to cancer must involve genetic alterations or mutational events at the sites of chromosome anomalies. There is now evidence for this in retinoblastomas. 

Increased apoptosis. Evidence of increased apoptosis in SLE is demonstrated by the fact that lymphocytes of both SLE patients and lupus mice show an increased rate of apoptosis ex vivo (E6, V4, L22). In addition, elevated levels of circulating oligonucleosomes are noted in SLE (R21, A19). The reason for increased apoptosis in SLE patients was revealed by studies of two environmental factors linked with SLE UV radiation and viral infection. UV radiation (UVB) was shown to cause apoptosis of keratinocytes and formation of surface blebs. The Ro antigen is then expressed in the surface of the blebs and may contribute to the induction of autoimmunity to Ro (C4). Viral infection, on the other hand, is well associated with disease relapse. 

Additionally, patients with familial adenomatous polyposis, an autosomal-dominant disease characterized by numerous small intestinal and colonic polyps with a nearly universal progression to colon cancer, have a favorable response to NSAIDs. Administration of NSAID (usually sulindac) to patients with this disorder reduces the number and size of polyps (DuBois et al., 1996). Recent biochemical evidence indicates that colon polyps and colon cancer are frequendy associated with induction of Cox-2 in the lesion as assessed by expression of Cox-2 mRNA and protein. Such induction appears to correlate with growth of the lesion, and inhibition of Cox-2 correlates with apoptosis of the involved cells (Gupta and DuBois, 1998). 

---