A variant in XPNPEP2 is associated with angioedema induced by angiotensin I-converting enzyme inhibitors.

Angiotensin I-converting enzyme inhibitors (ACEi), which are used to treat common cardiovascular diseases, are associated with a potentially life-threatening adverse reaction known as angioedema (AE-ACEi). We have previously documented a significant association between AE-ACEi and low plasma aminopeptidase P (APP) activity. With eight large pedigrees, we hereby demonstrate that this quantitative trait is partially regulated by genetic factors. We tested APP activity using a variance-component QTL analysis of a 10-cM genomewide microsatellite scan enriched with seven markers over two candidate regions. We found significant linkage (LOD = 3.75) to a locus that includes the XPNPEP2 candidate gene encoding membrane-bound APP. Mutation screening of this QTL identified a large coding deletion segregating in one pedigree and an upstream single-nucleotide polymorphism (C-2399A SNP), which segregates in the remaining seven pedigrees. Measured genotype analysis strongly suggests that the linkage signal for APP activity at this locus is accounted for predominantly by the SNP association. In a separate case-control study (20 cases and 60 controls), we found significant association of this SNP to ACEi-induced AE (P=.0364). In conclusion, our findings provide supporting evidence that the C-2399A variant in XPNPEP2 is associated with reduced APP activity and a higher incidence of AE-ACEi.

Using the cue-availability paradigm to assess cue reactivity.

BACKGROUND: A recent meta-analysis on cue-reactivity research revealed that cue-specific craving for alcohol is substantially less robust than craving measured for other drugs of abuse. The small effect sizes for alcohol underscore the need for more powerful methods of assessing cue reactivity in humans. The cue-availability paradigm is a modification of the conventional cue-reactivity paradigm and is intended to increase the sensitivity of measuring cue-reactivity to alcohol in humans. METHODS: Seventeen non-treatment-seeking alcoholics were tested individually on two different sessions (after priming with alcohol and after priming with placebo-alcohol). Subjects were presented with a total of 32 cue-availability trials. On each trial, subjects were presented with either a target cue (alcohol) or a neutral cue (water). Each cue was available for drinking on 50% of the trials (availability condition). Cue-reactivity measures were self-reports of craving and mood. RESULTS: The alcohol prime had a robust effect on craving. Irrespective of the availability of the cue for consumption or the type of cue, craving was consistently higher when subjects were primed with alcohol than with placebo-alcohol. Negative mood was also higher when it was assessed after the alcohol prime. Negative mood decreased in alcohol-primed subjects when the alcohol cue was available for consumption. The alcohol cue also had a significant, although more modest effect on craving. The alcohol cue consistently elicited higher levels of craving relative to the water cue. CONCLUSIONS: These data suggest that the priming effects of alcohol may be a significant factor contributing to the experience of craving and maintenance of drinking. The study also introduces the cue-availability as an additional new method for investigating manipulations of cue-reactivity in alcoholics.

Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative.

We conducted genomewide linkage analyses on 1,152 individuals from 250 families segregating for bipolar disorder and related affective illnesses. These pedigrees were ascertained at 10 sites in the United States, through a proband with bipolar I affective disorder and a sibling with bipolar I or schizoaffective disorder, bipolar type. Uniform methods of ascertainment and assessment were used at all sites. A 9-cM screen was performed by use of 391 markers, with an average heterozygosity of 0.76. Multipoint, nonparametric linkage analyses were conducted in affected relative pairs. Additionally, simulation analyses were performed to determine genomewide significance levels for this study. Three hierarchical models of affection were analyzed. Significant evidence for linkage (genomewide P<.05) was found on chromosome 17q, with a peak maximum LOD score of 3.63, at the marker D17S928, and on chromosome 6q, with a peak maximum LOD score of 3.61, near the marker D6S1021. These loci met both standard and simulation-based criteria for genomewide significance. Suggestive evidence of linkage was observed in three other regions (genomewide P<.10), on chromosomes 2p, 3q, and 8q. This study, which is based on the largest linkage sample for bipolar disorder analyzed to date, indicates that several genes contribute to bipolar disorder.

Genetic predisposition to external apical root resorption.

External apical root resorption (EARR) can be an undesirable sequela of orthodontic treatment. Previous studies have suggested that EARR has a substantial genetic component. Linkage and association were examined between polymorphisms of the interleukin IL-1 (IL-1A and IL-1B) genes and EARR in 35 white American families. Buccal swab cells were collected for DNA isolation and analysis. The EARR in the maxillary central incisors, the mandibular central incisors, and the mesial and distal roots of the mandibular first molar were analyzed separately and together by using both linkage and association methods of analysis. Highly significant (P =.0003) evidence of linkage disequilibrium of IL-1B polymorphism with the clinical manifestation of EARR was obtained. The analysis indicates that the IL-1B polymorphism accounts for 15% of the total variation of maxillary incisor EARR. Persons homozygous for the IL-1B allele 1 have a 5.6 fold (95% CI 1.9-21.2) increased risk of EARR greater than 2 mm as compared with those who are not homozygous for the IL-1 beta allele 1. Data indicate that allele 1 at the IL-1B gene, known to decrease the production of IL-1 cytokine in vivo, significantly increases the risk of EARR. These findings are consistent with an interpretation of EARR as a complex condition influenced by many factors, with the IL-1B gene contributing an important predisposition to this common problem. Defining genetic contributions to EARR is an important factor in understanding the contribution of environmental factors, such as habits and therapeutic biomechanics.

Saccadic eye movements are associated with a family history of alcoholism at baseline and after exposure to alcohol.

OBJECTIVE: To evaluate the influence of family history of alcoholism (FHA) on the response of saccadic eye movements to alcohol. METHOD: Saccadic performance was evaluated in 54 healthy adult subjects with a FHA (family history-positive) and 49 controls (family history-negative). Alcohol and placebo sessions were presented in counterbalanced order. Alcohol was administered intravenously to achieve and maintain a target breath alcohol concentration of 60 mg/100 ml (60%) for 160 min in each subject. During each session, saccadic eye movement testing was performed at baseline (before infusion of alcohol) and twice during the steady-state target breath alcohol concentration. The saccadic testing elicited visually guided saccades (VGS) and antisaccades (AS). Saccadic latency and velocity and the percentage of AS errors were quantified and analyzed using multivariate analysis of variance. RESULTS: The family history-positive and family history-negative groups showed an overall difference at baseline in AS and VGS latencies and velocities in the alcohol and placebo sessions ( p= 0.006). Alcohol delayed saccades such that AS and VGS latencies increased (p = 0.0001) and slowed the execution of saccades such that peak velocities decreased ( p = 0.0002). The percentage of AS errors decreased after alcohol administration, but no significant effect of alcohol (alcohol versus placebo session) was observed (p = 0.1). Latency of AS saccades demonstrated a significant overall FHA effect (p = 0.02) and a significant interaction between FHA and response to alcohol over time (p = 0.02). CONCLUSIONS: Differences in operational characteristics of the saccadic control system are associated with FHA in adult social drinkers, both at baseline and when the brain is exposed to ethanol at 60 mg/100 ml.

Is there a genetic relationship between alcoholism and depression?

The Collaborative Study on the Genetics of Alcoholism (COGA) seeks to identify genes contributing to alcoholism and related traits (i.e., phenotypes), including depression. Among alcoholic subjects the COGA study found an increased prevalence of depressive syndrome (i.e., depression that may or may not occur in conjunction with increased drinking). This combination of alcoholism and depression tends to run in families. Comorbid alcoholism and depression occurred substantially more often in first-degree relatives of COGA participants with alcoholism than in relatives of control participants. Based on these data, COGA investigators defined three phenotypes--"alcoholism," "alcoholism and depression," and "alcoholism or depression"--and analyzed whether these phenotypes were linked to specific chromosomal regions. These analyses found that the "alcoholism or depression" phenotype showed significant evidence for genetic linkage to an area on chromosome 1. This suggests that a gene or genes on chromosome 1 may predispose some people to alcoholism and others to depression (which may be alcohol induced).

Recent drinking history: association with family history of alcoholism and the acute response to alcohol during a 60 mg% clamp.

OBJECTIVE: Family history of alcoholism (FHA) is associated with increased drinking history, which can be a confounding factor in studies of the influence of FHA on the acute response to alcohol. The objective of this analysis was to investigate the association between recent drinking history (RDH) and FHA in a sample of family history positive (FHP; n = 55, 28 women) and family history negative (FHN; n = 55, 29 women) subjects, and to explore the influence of RDH on the response to alcohol during a 60 mg% clamp. METHOD: RDH was measured using daily diary and timeline followback methods. The total number of drinks in the 4-week (TD28) and 1-week (TD07) intervals prior to the study were determined, as well as the number of drinking days in the same intervals. Dependent measures of brain function were obtained at baseline (B0), immediately after the target BrAC was achieved (B1) and 105 minutes later (B2). The alcohol response was quantified as an initial response (ira = B1-B0) and an adaptive response (ada = B2-B1). The association between RDH and the ira and ada measures was tested using multivariate regression. RESULTS: The RDH measures showed a large variance across subjects, with no significant differences between FHP and FHN groups in the study sample. The initial responses for subjective perceptions of "high" and "intoxicated," Alcohol Sensation Scale scores and scores for the grooved pegboardtask were significantly negatively associated with TD28. Acute tolerance to perceptions of "high" and "intoxication" was significantly negatively associated with TD28. CONCLUSIONS: Heavy drinking history is associated with a decreased initial response to alcohol and greater acute tolerance to alcohol, particularly for subjective measures. Although RDH was not associated with FHA in this study, it may be an important determinant of the response to alcohol.