Association of DRD2 and DRD3 polymorphisms with Parkinson's disease in a multiethnic consortium.

OBJECTIVE: To examine genetic associations of polymorphisms in the dopamine receptor D2 (DRD2) and D3 (DRD3) genes with risk of Parkinson's disease (PD). METHODS: The study included 1325 newly diagnosed patients with PD and 1735 controls from a consortium of five North American case-control studies. We collected risk factor information by in-person or telephone interview. Six DRD2 and two DRD3 polymorphisms were genotyped using a common laboratory. Odds ratios were estimated using logistic regression. RESULTS: Among non-Hispanic whites, homozygous carriers of Taq1A DRD2 (rs1800497) polymorphism had an increased risk of PD compared to homozygous wildtype carriers (OR=1.5, 95% CI 1.0-2.3). In contrast, the direction of association for Taq1A polymorphism was opposite for African-Americans, showing an inverse association with PD risk (OR=0.10, 95% CI 0.2-0.7). Among white Hispanics who carried two alleles, the Ser9Gly DRD3 (rs6280) polymorphism was associated with a decreased risk of PD (OR=0.4, 95% CI 0.2-0.8). The inverse association of smoking with PD risk was not modified by any of the DRD2 or DRD3 polymorphisms. CONCLUSIONS: DRD2 polymorphisms are unlikely to be true disease-causing variants; however, three DRD2 polymorphisms (including Taq1A) may be in linkage disequilibrium with possible disease associated variants in the DRD2-ANKK1-NCAM1-TTC12 gene cluster.

Coffee, ADORA2A, and CYP1A2: the caffeine connection in Parkinson's disease.

BACKGROUND AND PURPOSE: In 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine animal models of Parkinson's disease (PD), caffeine protects neurons by blocking the adenosine receptor A2A (ADORA2A). Caffeine is primarily metabolized by cytochrome P450 1A2 (CYP1A2). Our objective was to examine whether ADORA2A and CYP1A2 polymorphisms are associated with PD risk or modify the caffeine-PD association. METHODS: Parkinson's Epidemiology and Genetic Associations Studies in the United States (PEGASUS) included five population-based case-control studies. One laboratory genotyped four ADORA2A and three CYP1A2 polymorphisms in 1325 PD cases and 1735 age- and sex-matched controls. Information regarding caffeine (coffee) consumption and other lifestyle factors came from structured in-person or telephone interviews. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression. RESULTS: Two ADORA2A polymorphisms were inversely associated with PD risk - rs71651683, a 5' variant (adjusted allelic OR = 0.51, 95% CI 0.33-0.80, permutation-adjusted P = 0.015) and rs5996696, a promoter region variant (adjusted OR for AC and CC genotypes compared with the AA wild-type genotype were 0.76 (95% CI 0.57-1.02) and 0.37 (95% CI 0.13-1.01), respectively (permutation-adjusted P for trend = 0.04). CYP1A2 polymorphisms were not associated with PD risk; however, the coffee-PD association was strongest among subjects homozygous for either variant allele rs762551 (P(interaction) = 0.05) or rs2470890 (P(interaction) = 0.04). CONCLUSION: In this consortium study, two ADORA2A polymorphisms were inversely associated with PD risk, but there was weak evidence of interaction with coffee consumption. In contrast, the coffee-PD association was strongest among slow metabolizers of caffeine who were homozygous carriers of the CYP1A2 polymorphisms.

Injection of illicit drugs into the granulation tissue of chronic ulcers.

Chronic skin ulcers are rare among healthy young adults. Local injection of cocaine and heroin has been identified as a cause of chronic skin ulcers in young adults abusing intravenous drugs. These patients use both engorged veins surrounding the ulcers and the granulation tissue itself for the injection of drugs. We believe that chronic skin ulcers in young adults should be a marker for intravenous drug abuse, and should be considered in the differential diagnosis of nonhealing wounds.

The natural history of cytogenetically abnormal fetuses detected at midtrimester amniocentesis which are not terminated electively: new data and estimates of the excess and relative risk of late fetal death associated with 47,+21 and some other abnormal karyotypes.

We report the results of an ongoing survey of rates of spontaneous death of fetuses with chromosome abnormalities detected at second-trimester amniocentesis in which the mother did not elect abortion. Estimated excess risks (and conservative 90% confidence intervals) of spontaneous fetal death for various cytogenetic abnormalities are as follows: 47,+21, 25.6% (18.0%-34.0%); 47,+18, 63.8% (49.3%-79.8%); 47,+13, 36.5% (11%-69.7%); 45,X, 65.3% (41.0%-84.2%); and mosaic 45,X/46,XX, 10.8% (1.0%-26.8%). There is little evidence for an excess risk of fetal death, at least following amniocentesis, for 47,XXX, 47,XXY, or 47,XYY. The excess risks of fetal death were adjusted for the likelihood that a fetus of normal karyotype would undergo spontaneous fetal death in a population of older maternal age similar to that in which prenatal cytogenetic diagnosis is undertaken. The absolute fetal death rates when this factor is ignored are about 3.5% higher (i.e., may be derived by adding 3.5% to the values given). The excess risks are those which are most appropriate for use in estimating the contribution of chromosome abnormalities to spontaneous fetal death.

Transfer of melanosomes in a skin equivalent model in vitro.

The transfer of pigment granules from melanocytes to keratinocytes was studied using a new living skin equivalent (SE) model in vitro. The model was constructed by plating human neonatal melanocytes onto a dermal equivalent (DE) before it was overgrown with keratinocytes. The dermal component of the SE arises in vitro through the action of fibroblasts, which compact matrix proteins into a tissue. It becomes keratinized as keratinocytes migrate out of 2-mm punch biopsies of human neonatal skin embedded in the DE; keratinocytes from the biopsies covered the lattice in 14 days. A basal lamina develops at the dermal-epidermal junction in vitro. Exposure of some SEs to UVB irradiation for 14 days stimulated and enhanced pigment transfer. Pigment transfer from melanocytes to keratinocytes was documented in light and electron microscopic studies. Melanosomes, identified by their pigment as well as by dopa oxidase staining, were dispersed throughout the keratinocyte cytoplasm. We conclude that the SE model is valuable for studying the relationship between melanocytes and keratinocytes in vitro; since the SE has been shown to serve as a skin replacement, pigmenting it may be expected to increase its usefulness.

Systemic mastocytosis with extensive large cutaneous mastocytomas: surgical management.

A case of systemic mastocytosis is reported with an observation period of 20 years. During these two decades multiple manifestations of the disease appeared including urticaria pigmentosis, episodic histamine release, gastro-intestinal involvement and hepatosplenomegaly. The most extraordinary, and possibly unique phenomenon, has been the development of a massive proliferation of large mastocytomas mainly, but not exclusively, limited to the lower extremities. For different reasons (mechanical disability, bleeding, cosmesis), these tumors have required repeated admissions for surgical removal. The most successful technique has involved use of the ultrasonic scalpel.

The use of antihistamine to retard the growth of fibroblasts derived from human skin, scar, and keloid.

Sixty percent of the fibroblast strains derived from normal skin, scar, and keloid reached elevated growth plateaus when cultured in the presence of histamine. A pharmacologic level of the antihistamine diphenhydramine hydrochloride was able to suppress the stimulation in all the keloid strains that were histamine-sensitive.