Association between the estrogen receptor TA polymorphism and Harm avoidance.

In the last decade a large number of studies focused on the recognition of gene variants modulating temperamental traits. The gene coding for the estrogen receptor alpha (ESR1) appears to be an interesting candidate and it has been found to be linked to Harm avoidance (HA). The aim of the present study was to investigate whether the ESR1 TA dinucleotide repeat polymorphism is associated with HA temperamental trait in a sample of Caucasian University students. One hundred ninety healthy subjects were genotyped for ESR1 TA dinucleotide repeat polymorphism and were administered the Temperament and Character Inventory (TCI). ESR1 TA repeat lengths were dichotomized into short and long categories. ANOVA was used to examine the influence of ESR1 variants (short/long) on the means of the TCI HA scores. HA was significantly associated with age and gender in our sample, being higher in older and female subjects. In the global sample as well as in men and women separately, individuals carrying the S/S variant showed significantly higher HA scores. Further analysis on the HA subscales revealed that specific differences could exist between men and women. Our results further suggest a possible role of ESR1 variants on HA. Further research is needed to replicate our findings as well as to better explore the neuro-biological mechanisms of the modulation of ESR1 on HA.

The additive effect of neurotransmitter genes in pathological gambling.

As access to gambling increases there is a corresponding increase in the frequency of addiction to gambling, known as pathological gambling. Studies have shown that a number of different neurotransmitters are affected in pathological gamblers and that genetic factors play a role. Polymorphisms at 31 different genes involved in dopamine, serotonin, norepinephrine, GABA and neurotransmitters were genotyped in 139 pathological gamblers and 139 age, race, and sex-matched controls. Multivariate regression analysis was used with the presence or absence of pathological gambling as the dependent variable, and the 31 coded genes as the independent variables. Fifteen genes were included in the regression equation. The most significant were the DRD2, DRD4, DAT1, TPH, ADRA2C, NMDA1, and PS1 genes. The r(2) or fraction of the variance was less than 0.02 for most genes. Dopamine, serotonin, and norepinephrine genes contributed approximately equally to the risk for pathological gambling. These results indicate that genes influencing a range of brain functions play an additive role as risk factors for pathological gambling. Multi-gene profiles in specific individuals may be of assistance in choosing the appropriate treatment.

Association of the neutral endopeptidase (MME) gene with anxiety.

Enkephalins have been implicated in the regulation of mood, anxiety, reward, euphoria and pain. One of the major enzymes for enkephalin degradation is neutral endopeptidase [enkephalinase, membrane metalloendopeptidase (MME)]. We identified a dinucleotide polymorphism in the 5' region of the MME gene. Subjects were placed into three genotypes, 3/3, 3/x, and x/x since the 3 allele was the most common of the six alleles. Using one-way analysis of variance, we examined the association of these genotypes with the mean SCL-90 scores for anxiety, depression, obsessive-compulsive and phobic anxiety symptoms in 120 Caucasian males from an addiction treatment unit. There was a significant association between the MME genotypes and the SCL-90 scores for phobic anxiety, obsessive-compulsive and anxiety at a Bonferroni corrected alpha value of 0.0125. These results support a role of genetic variants of enkephalin metabolism in anxiety.

Multivariate analysis of associations of 42 genes in ADHD, ODD and conduct disorder.

In a previous study (Comings DE et al. Comparison of the role of dopamine, serotonin, and noradrenergic genes in ADHD, ODD and conduct disorder. Multivariate regression analysis of 20 genes. Clin Genet 2000: 57: 178-196) we examined the role of 20 dopamine, serotonin and norepinephrine genes in attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD), using a multivariate analysis of associations (MAA) technique. We have now brought the total number of genes examined to 42 by adding an additional 22 candidate genes. These results indicate that even with the inclusion of these additional genes the noradrenergic genes still played a greater role in ADHD than any other group. Six other neurotransmitter genes were included in the regression equation - cholinergic, nicotinic, alpha 4 receptor (CHNRA4), adenosine A2A receptor (ADOA2A), nitric oxide synthase (NOS3), NMDAR1, GRIN2B, and GABRB3. In contrast to ADHD and ODD, CD preferentially utilized hormone and neuropeptide genes These included CCK, CYP19 (aromatase cytochrome P-450), ESR1, and INS (p = 0.005). This is consistent with our prior studies indicating a role of the androgen receptor (AR) gene in a range of externalizing behavors. We propose that the MAA technique, by focusing on the additive effect of multiple genes and on the cummulative effect of functionally related groups of genes, provides a powerful approach to the dissection of the genetic basis of polygenic disorders.

Comparison of the role of dopamine, serotonin, and noradrenaline genes in ADHD, ODD and conduct disorder: multivariate regression analysis of 20 genes.

The present study is based on the proposal that complex disorders resulting from the effects of multiple genes are best investigated by simultaneously examining multiple candidate genes in the same group of subjects. We have examined the effect of 20 genes for dopamine, serotonin, and noradrenergic metabolism on a quantitative score for attention deficit hyperactivity disorder (ADHD) in 336 unrelated Caucasian subjects. The genotypes of each gene were assigned a score from 0 to 2, based on results from the literature or studies in an independent set of subjects (literature-based scoring), or results based on analysis of variance for the sample (optimized gene scoring). Multivariate linear regression analysis with backward elimination was used to determine which genes contributed most to the phenotype for both coding methods. For optimized gene scoring, three dopamine genes contributed to 2.3% of the variance, p = 0.052; three serotonin genes contributed to 3%, p = 0.015; and six adrenergic genes contributed to 6.9%, p = 0.0006. For all genes combined, 12 genes contributed to 11.6% of the variance, p = 0.0001. These results indicate that the adrenergic genes play a greater role in ADHD than either the dopaminergic or serotonergic genes combined. The results using literature-based gene scoring were similar. An examination of two additional comorbid phenotypes, conduct disorder and oppositional defiant disorder (ODD), indicated they shared genes with ADHD. For ODD different genotypes of the same genes were often used. These results support the value of the simultaneous examination of multiple candidate genes.

A multivariate analysis of 59 candidate genes in personality traits: the temperament and character inventory.

Cloninger (Cloninger CR. Neurogenetic adaptive mechanisms in alcoholism. Science 1987: 236: 410-416) proposed three basic personality dimensions for temperament: novelty seeking, harm avoidance, and reward dependence. He suggested that novelty seeking primarily utilized dopamine pathways, harm avoidance utilized serotonin pathways, and reward dependence utilized norepinephrine pathways. Subsequently, one additional temperament dimension (persistence) and three character dimensions (cooperativeness, self-directedness, and self-transcendence) were added to form the temperament and character inventory (TCI). We have utilized a previously described multivariate analysis technique (Comings DE, Gade-Andavolu R, Gonzalez N et al. Comparison of the role of dopamine, serotonin, and noradrenergic genes in ADHD, ODD and conduct disorder. Multivariate regression analysis of 20 genes. Clin Genet 2000: 57: 178-196; Comings DD, Gade-Andavolu R, Gonzalez N et al. Multivariate analysis of associations of 42 genes in ADHD, ODD and conduct disorder. Clin Genet 2000: in press) to examine the relative role of 59 candidate genes in the seven TCI traits and test the hypothesis that specific personality traits were associated with specific genes. While there was some tendency for this to be true, a more important trend was the involvement of different ratios of functionally related groups of genes, and of different genotypes of the same genes, for different traits.

Additive effect of three noradrenergic genes (ADRA2a, ADRA2C, DBH) on attention-deficit hyperactivity disorder and learning disabilities in Tourette syndrome subjects.

Halperin et al. (Halperin JM. Newcorn JH, Koda VH, Pick L, McKay KE, Knott P. Noradrenergic mechanisms in ADHD children with and without reading disabilities: a replication and extension. J Am Acad Child Adolesc Psychiatry 1997: 36: 1688 1696) reported a significant increase in plasma norepinephrine (NE) in attention-deficit hyperactivity disorder (ADHD) children with reading and other cognitive disabilities compared to ADHD children without learning disabilities (LD). We examined the hypothesis that ADHD + LD was associated with NE dysfunction at a molecular genetic level by testing for associations and additive effects between polymorphisms at three noradrenergic genes the adrenergic alpha2A receptor (ADRA2A), adrenergic alpha2C receptor (ADRA2C), and dopamine beta-hydroxylase (DBH) genes. A total of 336 subjects consisting of 274 individuals with Tourette syndrome (TS) and 62 normal controls were genotyped. Regression analysis showed a significant correlation between scores for ADHD, a history of LD, and poor grade-school academic performance that was greatest for the additive effect of all three genes. Combined, these three genes accounted for 3.5% of the variance of the ADHD score (p = 0.0005). There was a significant increase in the number of variant NE genes progressing from subjects without ADHD (A-) or learning disorders (LD-) to A + LD - to A - LD + to A + LD + (p = 0.0017), but no comparable effect for dopamine genes. These data support an association between NE genes and ADHD, especially in ADHD + LD subjects.

The proenkephalin gene (PENK) and opioid dependence.

We tested the hypothesis that the alleles at the (CA)n repeat of the proenkephalin gene (PENK) might be associated with opioid addiction in 31 non-Hispanic Caucasian subjects with opioid dependence (heroin), 89 ethnically matched subjects with substance dependence other than opioid dependence and 132 controls. Among the subjects with opioid dependence, 66% carried the > or = 81 bp allele compared with 40% of subjects with other types of substance abuse (chi2 = 11.31, p < 0.004) and 49% of controls (chi2 = 6.0, p < 0.015). These results are consistent with a role of the PENK gene in opioid dependence.

Association between the gamma-aminobutyric acid A3 receptor gene and multiple sclerosis.

BACKGROUND: In a prior study we observed an association between the dopamine D2 receptor gene (DRD2) and the age of onset and/or diagnosis of multiple sclerosis (MS). We hypothesized that this effect was mediated through the dopaminergic control of the release of prolactin, a modulator of immune response. Since gamma-aminobutyric acid also modulates the release of prolactin, we examined the possible association between alleles of the GABRA3 (gamma-aminobutyric acid A3 receptor) gene and MS. DESIGN: We examined the GABRA3 alleles of 189 subjects with MS who died of their disease. They were divided into test group 1 (n=64) and retest group 2 (n=56). Each group had a separate set of controls (group 1, n=109; group 2, n=430). All subjects were white. All were tested at a dinucleotide cytosine-adenosine repeat polymorphism with 6 alleles representing 11 to 16 repeats. RESULTS: In the first group there was a significant difference in the frequency of the GABRA3 alleles (P<.002), with the most notable difference being an increase in the frequency of the 16-repeat allele in subjects with MS and a relative decrease in the other alleles. In the replication group there was again a significant difference in the distribution of the GABRA3 alleles (P<.001), and again the greatest difference was an increase in the frequency of the 16-repeat allele in subjects with MS. For both groups combined, a significant difference in the frequency of the 16-repeat allele was noted (chi2=46.30; P<.001). CONCLUSIONS: These results suggest the GABRA3 gene may be a risk factor for MS. As with the DRD2 gene, the effect may be mediated through its regulation of prolactin release.

AIDS-associated cryptosporidiosis with gastric stricture and a therapeutic response to paromomycin.

AIDS-associated cryptosporidiosis has been associated with severe, watery diarrhea and with multifocal biliary stricture. Gastric involvement has not been reported prominently. We report here the case of a 28-yr-old AIDS patient who developed typical watery diarrhea, followed by subtotal gastric obstruction secondary to antral stricturing. Biopsy of the stricture revealed severe inflammation and marked cryptosporidial infestation. Extensive workup excluded causes of stricture. He was empirically treated with paromomycin, with a surprisingly positive therapeutic response and clinical resolution of obstruction. Antral stricture may be another manifestation of cryptosporidial infection in AIDS. Paromomycin deserves further evaluation as an agent for treatment of this infection.

Malignant hemangiopericytoma of the gingiva: report of a case.

A case of malignant hemangiopericytoma arising in the left maxillary gingiva in a 2-year-old boy is presented. This represents an extremely rare intraoral lesion that is impossible to diagnose clinically. Histologic diagnosis was made by use of special staining techniques, immunohistochemical stains, and electron microscopic evaluation. This tumor shows a high incidence of local recurrence with a poor prognosis. The mainstay of treatment is wide local excision and adequate postoperative follow-up.

Disseminated histoplasmosis in the acquired immunodeficiency syndrome. Report of five cases from a nonendemic area.

Disseminated histoplasmosis is predominantly a disease of the immunocompromised. However, it has been reported infrequently in patients with the acquired immunodeficiency syndrome (AIDS), and then almost exclusively from patients residing in endemic areas. We report five cases of disseminated histoplasmosis in patients with AIDS in a nonendemic area. The initial diagnosis was made by fiberoptic bronchoscopy in three patients and by bone marrow and liver biopsy specimens in one patient each. All patients had fungemia, septic shock, and multiple organ involvement. Three patients had a fulminant course and died within four weeks. Two patients had more prolonged courses, with one survival period of ten months. We conclude that patients with AIDS are at high risk to contract disseminated histoplasmosis with an extremely high morbidity and mortality. This risk is not limited to residents of endemic areas.

Granulomatous inflammation in the acquired immune deficiency syndrome.

Granulomas were found in 16 biopsied specimens from eight patients with the acquired immune deficiency syndrome (AIDS), a disease characterized by a profound suppression of the T-cell arm of immunity. The pathogens were Mycobacterium avium-intracellulare (1), Mycobacterium tuberculosis (3), Histoplasma capsulatum (2), Candida albicans (1), and unidentified in one patient. The sites of granuloma formation included the lung in two, the pleura in one, the liver in three, the bone marrow in six, the skin in one, and the lymph node in three cases. The granulomas were epithelioid in nature, with aggregates of epithelioid histiocytes and macrophages. They were by and large small and loosely formed, with minimal or absent lymphocytic cuffing. Although it is a well-recognized concept that T-cell and macrophage interaction plays an important role in the granulomatous inflammatory response, granulomas have been produced in experimental animals independent of cell-mediated immune mechanisms. Granuloma formation in AIDS patients may well represent a clinical example of such a phenomenon.