Two common, functional polymorphisms in the promoter region of the beta-fibrinogen gene contribute to regulation of plasma fibrinogen concentration.

Plasma fibrinogen is a major risk factor for coronary heart disease, stroke, and peripheral artery disease. There is evidence that genetic variation in the beta-fibrinogen gene contributes to the rate of synthesis of fibrinogen, but the molecular mechanism underlying the genetic heritability of the plasma fibrinogen concentration is largely unknown. We evaluated the physiological roles of 5 common nucleotide substitutions in the promoter region of the beta-fibrinogen gene at positions -148, -249, -455, -854, and -993 from the transcriptional start site. Electrophoretic mobility shift assays revealed distinct differences in the binding characteristics of nuclear proteins between wild-type and mutant fragments of both the -455G/A and -854G/A polymorphisms, whereas no clear differences were observed for the -148C/T, -249C/T, and -993C/T sites. Transfection studies in HepG2 cells showed increased basal rates of transcription for both the G-to-A substitution at position -455 (+50%, P<0.05) and the G-to-A substitution at -854 (+51%, P<0.05). Additional transfection studies using proximal promoter constructs confirmed that both the -455A and -854A alleles independently enhance the basal rate of transcription of the beta-fibrinogen gene. The rare alleles of the nonrelated -455G/A and -854G/A polymorphisms were also associated with significantly increased plasma fibrinogen levels in healthy middle-aged men. Overall, the 2 polymorphisms together explained approximately 11% of the variation in plasma fibrinogen concentration. It is concluded that the -455G/A and -854G/A polymorphisms of the beta-fibrinogen gene are physiologically relevant mutations with a significant impact on the plasma fibrinogen concentration.

Drug progression model: a social control test.

A social control drug progression model was delineated and tested using a sample of 2,626 high school students from the southwestern United States. Along with the social control constructs of parental attachment, educational attachment, religious attachment, and conventional values, we incorporated alcohol, cigarette, and marijuana use into the model as intervening variables. The model explains 39% of the variation in the self-reported amphetamine use and 24% of the variation in "hard drug" use (cocaine, heroin, LSD, and PCP). The findings suggest that the integration of social control theory and drug progression improves the predictive power of the model of adolescent drug use.

Family, educational and peer influences on the alcohol use of female and male adolescents.

OBJECTIVE: This research provides estimates of how strongly family bonds, family drug use, age, educational commitment and peer drug use are associated with the frequency and amount of alcohol consumption among adolescents, and compares females and males. METHOD: Using questionnaire data from a random sample of 27,000 adolescents, structural equation modeling is used to evaluate the strength of several risk factors. RESULTS: The influence of family bonds is moderately strong but operates primarily through peers; adolescents with higher family bonds are less likely to have close friends who are involved with drugs. Family bonds have a relatively strong, positive association with educational commitment, and adolescents with a higher educational commitment tend to drink less frequently; and when they drink, they tend to consume smaller amounts. Living in a family where other family members have a problem with alcohol or other drugs increases the chance that an adolescent has friends who drink or use other drugs. CONCLUSIONS: Family bonding has small but significant direct effects and moderate indirect effects on both the frequency and amount of alcohol use. Family and peer influences are similar for both females and males. Living in a family where other family members have a drug problem increases the chance that an adolescent has friends who use drugs. Family bonding appears to be an important social control mechanism that may decrease the risk of alcohol abuse among adolescents.

Adolescent substance use and codependence.

This research evaluated the extent to which parental codependence was associated with adolescent substance use and other adolescent problem behaviors. The sample was comprised of 293 adolescents and their parents who were interviewed by trained intake workers. Using LISREL modeling, we found that the number of adolescent problem behaviors was associated with parental persecuting, suffering, and rescuing behaviors. Net of problem behaviors, adolescent substance use was associated with parental suffering but not with parental persecution or rescuing. As expected, there was a strong association between adolescent problem behaviors and substance use. The associations of substance use and problem behaviors with codependence were not moderated by religious preference or by being a member of a religion that teaches abstinence.