Referral patterns of Indiana oncologists for colorectal cancer genetic services.

We assessed the utilization and referral patterns of Indiana oncologists for colorectal cancer (CRC) genetic services. Surveys were sent to 151 oncologists practicing within the state, with a response rate of 40%. Half of respondents had previously referred patients for CRC genetic services. Those who had not cited reasons, including absence of an appropriate patient, lack of information about genetic services, and uncertainty regarding which patients to refer. Most were interested in materials that would assist in identifying patients for referral. As a result, a booklet was developed and given to participants. This study demonstrates the need for physician education about CRC genetic services.

The tachykinin receptor 3 is associated with alcohol and cocaine dependence.

BACKGROUND: A broad region on chromosome 4q was previously linked to the phenotype of alcohol dependence in the Collaborative Study on the Genetics of Alcoholism sample. A strong positional candidate gene was identified within this region: tachykinin receptor 3 gene (TACR3), which encodes tachykinin receptor 3 (NK3R), the receptor for the tachykinin 3 (neurokinin B) peptide. Pharmacological studies have provided evidence that the administration of NK3R agonists attenuates the intake of alcohol and NK3R can also mediate the acute and chronic behavioral effects of cocaine. METHODS: Thirty SNPs were genotyped throughout TACR3. Family based association analysis was performed in 219 European American families to detect an association with alcohol dependence. Subsequent analyses were performed to evaluate the evidence of association with other definitions of alcohol dependence as well as cocaine dependence. RESULTS: Seven of the 9 SNPs in the 3' region of TACR3 provided significant evidence of association with alcohol dependence (p

Association of NFKB1, which encodes a subunit of the transcription factor NF-kappaB, with alcohol dependence.

A broad region on chromosome 4q has been linked to alcohol dependence (alcoholism). We hypothesized that such broad linkage regions represent the combined action of multiple genes. Seeking to identify genes within that region that are associated with alcoholism, we have tested the association of NFKB1, located at 4q24, with alcoholism. NFKB1 encodes a 105 kDa transcription inhibitor that is cleaved to the 50 kDa DNA-binding subunit of the ubiquitous transcription factor NF-kappaB. NF-kappaB regulates many genes relevant to brain function, and its actions can be potentiated by ethanol; thus, NFKB1 is an excellent candidate gene for alcoholism. Nineteen SNPs in and near NFKB1 were analyzed in a sample of 219 multiplex alcoholic families of European American descent. Family-based association analyses detected significant evidence of association with eight SNPs and marginal evidence for five more. The association was driven by the affected individuals with earlier onset of alcoholism (55% of the sample with onset < or =21 years). Further analysis of the age of onset as a quantitative variable provided evidence for the association of 12 SNPs in this gene. Thus, variations in NFKB1 appear to affect the risk for alcoholism, particularly contributing to an earlier onset of the disease.

Lack of association of alcohol dependence and habitual smoking with catechol-O-methyltransferase.

OBJECTIVE: To test whether variation in the gene encoding the enzyme catechol-O-methyltransferase (COMT), which catalyzes the breakdown of dopamine and other catecholamine neurotransmitters, is associated with the risk for alcohol dependence and habitual smoking. METHODS: Single nucleotide polymophisms (SNPs) were genotyped in a sample of 219 multiplex alcohol-dependent families of European American descent from the Collaborative Study on the Genetics of Alcoholism (COGA). Family-based tests of association were performed to evaluate the evidence of association between the 18 SNPs distributed throughout COMT, including the functional Val158Met polymorphism, and the phenotypes of alcohol dependence, early onset alcohol dependence, habitual smoking, and comorbid alcohol dependence and habitual smoking. RESULTS: No significant, consistent evidence of association was found with alcohol dependence, early onset alcohol dependence, habitual smoking or the comorbid phenotype. There was no evidence that the functional Val158Met polymorphism, previously reported to be associated with these phenotypes, was associated with any of them. CONCLUSION: Despite the substantial size of this study, we did not find evidence to support an association between alcohol dependence or habitual smoking and variation in COMT.

Association of the aldehyde dehydrogenase 2 promoter polymorphism with alcohol consumption and reactions in an American Jewish population.

BACKGROUND: Reduction in activity of the mitochondrial aldehyde dehydrogenase 2 (ALDH2) enzyme due to genetic deficiency causes reactions related to alcohol consumption and lowers the risk of alcoholism. ALDH2*2 is the only functionally significant polymorphism of the ALDH2 gene. An additional polymorphic locus in the promoter (G to A substitution approximately 360 bp from the translation start site) may influence ALDH2 activity through effects on transcriptional activity. The A allele is predicted to be less active transcriptionally than the G allele. Therefore, we hypothesized that individuals with 1 or 2 A alleles would have exaggerated reactions to alcohol. METHODS: Fifty-three Jewish college students from a Midwestern University and 76 Jewish individuals living in a large Midwestern city (all of Ashkenazi descent) were tested for associations between ALDH2*G and ALDH2*A alleles and self-reported alcohol consumption and responses to alcohol. Genotype determination was performed using PCR and slot-blot hybridization. As alcohol drinking behavior differed substantially between the college students and the general population, as well as between males and females, the analyses were performed separately in each group. RESULTS: The frequency of the ALDH2*A allele was 0.87 in the 129 Jewish individuals tested. Among the general Jewish population, those who were homozygous for ALDH2*A drank fewer drinks per occasion than individuals who were not homozygous for the ALDH2*A allele, but did not drink significantly less frequently. When the other covariates (ADH1B genotype, gender, and population) were controlled for, there was a marginal association between ALDH2A genotype and quantity of alcohol consumed and the number of drinks consumed before feeling drowsy. CONCLUSION: This study suggests that the ALDH2*A allele status may correlate with variations in alcohol consumption patterns among Jews, independent of the effect of ADH1B genotype.

Unique facial features distinguish fetal alcohol syndrome patients and controls in diverse ethnic populations.

BACKGROUND: Effective management of fetal alcohol spectrum disorders (FASD) is dependent on the timely and reliable diagnosis of affected individuals. There are significant diagnostic difficulties because of the reduced prominence of facial features as children age to adulthood as well as potential population or ethnic differences in the most characteristic alcohol-related facial features. METHODS: A total of 276 subjects were recruited from 4 sites (Cape Town, South Africa; Helsinki, Finland; Buffalo, New York; and San Diego, California) and completed a detailed dysmorphology evaluation to classify subjects as either fetal alcohol syndrome (FAS; 43%) or control (57%). Computerized anthropometry was employed to identify facial features that could distinguish FAS patients from controls across a wide age range and across ethnically disparate study populations. RESULTS: Subjects were placed into 1 of 4 populations based on their ancestry (Cape Coloured, Finnish Caucasian, African American, or North American Caucasian). Analyses performed in each of the 4 study populations were able to identify a unique set of variables which provided excellent discrimination between the 2 groups (FAS, control). In each study group, at least one ocular-related measurement, shortened palpebral fissure, reduced outer canthal width, or reduced inner canthal width, was included in the final classification model. CONCLUSIONS: We found measurements that reflected reduced size of the eye orbit to be a consistent feature discriminating FAS and controls across each study population. However, each population had a unique, though often overlapping, set of variables which discriminated the 2 groups, suggesting important ethnic differences in the presentation of FAS. It is possible that these differences were accentuated by the wide age distribution of the study subjects.

Association of alcohol craving with alpha-synuclein (SNCA).

BACKGROUND: Studies have found that genomic variation in the gene SNCA, which encodes the protein alpha-synuclein, may contribute to the variation in alcohol consumption in an inbred rat model of alcohol preference. Studies in humans have provided support for an association between SNCA and craving for alcohol. METHODS: To examine the role of this gene in alcohol dependence and related phenotypes, 30 single nucleotide polymorphisms (SNPs) were genotyped across the SNCA gene in a sample of 219 multiplex alcoholic families of European American descent. Two phenotypes, alcohol dependence and alcohol craving, were analyzed using the pedigree disequilibrium test. RESULTS: There was no evidence of association between any of the SNCA SNPs and alcohol dependence (p>or=0.13). In contrast, 8 SNPs provided evidence of association (p<0.05) with the phenotype of alcohol craving. Haplotype analysis further supported evidence of an association with alcohol craving; a haplotype encompassing SNPs in intron 4 through the region downstream of the gene was overtransmitted to cravers and a second haplotype was overtransmitted to noncravers. CONCLUSIONS: These results suggest that variation in SNCA contributes to alcohol craving, a common, although not uniform, feature of alcohol dependence.

Association between GABRA1 and drinking behaviors in the collaborative study on the genetics of alcoholism sample.

BACKGROUND: A wealth of literature supports the role of gamma-aminobutyric acid (GABA) in neurobiological pathways contributing to alcohol dependence and related phenotypes. Animal studies have consistently tied rodent homologs of the GABAA receptor genes on human chromosome 5q to alcohol-related behaviors; however, human studies have produced mixed results. Family-based association analyses previously conducted in the Collaborative Study on the Genetics of Alcoholism (COGA) sample yielded no evidence of association with Diagnostic and Statistical Manual of Mental Disorder-fourth edition (DSM-IV) alcohol dependence and these genes. As a follow-up to that study, we examined several alcohol-related behaviors in the COGA sample as follows: (1) a broader definition of alcohol dependence, including DSM-III-R symptoms and Feighner criteria (referred to as COGA alcohol dependence); (2) withdrawal; (3) history of alcohol-induced blackouts; (4) level of response to alcohol; (5) age of onset of regular drinking; and (6) age at first drunkenness. METHODS: Family-based association tests were conducted, using multiple single-nucleotide polymorphisms (SNPs) in each of the 4 GABAA receptor genes on chromosome 5q. RESULTS: In GABRA1, we found evidence of association with several of the drinking behavior phenotypes, including COGA alcohol dependence, history of blackouts, age at first drunkenness, and level of response to alcohol. We did not find consistent evidence of association with the remaining genes and any of the phenotypes. CONCLUSIONS: We found evidence for association between GABRA1 and COGA alcohol dependence, history of blackouts, age at first drunkenness, and level of response to alcohol. These analyses suggest that efforts to characterize genetic contributions to alcohol dependence may benefit by examining alcohol-related behaviors in addition to clinical alcohol dependence diagnoses.

Association of alcohol dehydrogenase genes with alcohol dependence: a comprehensive analysis.

Linkage evidence indicated that gene(s) located on chromosome 4q, in the region of the alcohol dehydrogenase (ADH) genes, affected risk for alcoholism. We genotyped 110 single nucleotide polymorphisms (SNPs) across the seven ADH genes and analyzed their association with alcoholism in a set of families with multiple alcoholic members, using the pedigree disequilibrium test. There was strong evidence that variations in ADH4 are associated with alcoholism: 12 SNPs were significantly associated. The region of strongest association ran from intron 1 to 19.5 kb beyond the 3' end of the gene. Haplotype tag SNPs were selected for the block in the ADH4 gene that provided evidence of association and subsequently used in association analysis; the haplotype was significantly associated with alcoholism (P=0.01) There was weaker evidence that variations in ADH1A and ADH1B might also play a role in modifying risk. Among African-Americans, there was evidence that the ADH1B*3 allele was protective.