Genetic analysis of a murine QTL for diet restriction on chromosome 15.

Diet restriction (DR), the implementation of a reduced calorie diet, without starvation, increases lifespan in a number of model organisms including mammals. How DR extends lifespan remains unclear. Genetic studies have shown that life extension is not a universal response to DR; instead, the effects of DR are strain dependent. We previously mapped a quantitative trait locus (QTL) specifying differential response to DR to chromosome 15 in the inbred long-sleep (ILS) × inbred short-sleep (ISS) recombinant inbred panel of mice. This QTL named Fedr2 (fuel efficiency response to DR)-2 modifies body weight (BW) and hair growth (HG) in response to DR. The QTL has been previously mapped using the ISS.Lore5(LA) (5LA) congenic strain. Here, we have used the reciprocal congenic strain ILS.Lore5(SA) (5SA) to further investigate Fedr2. The 5LA congenic showed increased ability to maintain BW and HG under DR. For the reciprocal congenic, 5SA, we expected the reciprocal response that the 5SA congenic would have a lesser ability to maintain BW and HG under DR. This expectation was mostly met. The Fedr2 (S) allele conferred lower BW maintenance under DR in both females and males. For females, the difference in BW was significant for the entirety of DR, and for males, the difference became significant at week 17 of DR. For HG, the Fedr2 (S) allele conferred decreased HG ability under DR in males, but not for females. These results highlight the genetic basis for variation in DR response and support the previous observations that Fedr2 mediates BW and HG during DR.

Prevalence and predictors of injection drug use and risky sexual behaviors among adolescents in substance treatment.

BACKGROUND AND OBJECTIVES: The longitudinal risk for human immunodeficiency virus (HIV) infection following adolescent substance treatment is not known. Therefore, it is not known if adolescent substance treatment should include HIV prevention interventions. To address this important research gap, this study evaluates the longitudinal prevalence and predictors of injection drug use (IDU) and sex risk behaviors among adolescents in substance treatment. METHODS: Participants were 260 adolescents (13-18 years) in substance treatment and 201 community control adolescents (11-19 years). Participants were assessed at baseline and follow-up (mean time between assessments = 6.9 years for the clinical sample and 5.6 years for the community control sample). Outcomes included self-report lifetime history of IDU, number of lifetime sex partners and frequency of unprotected sexual intercourse. RESULTS: At baseline, 7.5% of the clinical sample, compared to 1.0% of the community control sample had a lifetime history of IDU (χ12=10.53, p = .001). At follow-up, 17.4% of the clinical sample compared to 0% of the community control sample had a lifetime history of IDU (χ12=26.61, p = .0005). The number of baseline substance use disorders and onset age of marijuana use significantly predicted the presence of lifetime IDU at follow-up, after adjusting for baseline age, race, and sex. The clinical sample reported more lifetime sex partners and more frequent unprotected sex than the community control sample at baseline and follow-up. CONCLUSIONS: Many adolescents in substance treatment develop IDU and report persistent risky sex. Effective risk reduction interventions for adolescents in substance treatment are needed that address both IDU and risky sex.

On the replication of genetic associations: timing can be everything!

The failure of researchers to replicate genetic-association findings is most commonly attributed to insufficient statistical power, population stratification, or various forms of between-study heterogeneity or environmental influences.(1) Here, we illustrate another potential cause for nonreplications that has so far not received much attention in the literature. We illustrate that the strength of a genetic effect can vary by age, causing "age-varying associations." If not taken into account during the design and the analysis of a study, age-varying genetic associations can cause nonreplication. By using the 100K SNP scan of the Framingham Heart Study, we identified an age-varying association between a SNP in ROBO1 and obesity and hypothesized an age-gene interaction. This finding was followed up in eight independent samples comprising 13,584 individuals. The association was replicated in five of the eight studies, showing an age-dependent relationship (one-sided combined p = 3.92 x 10(-9), combined p value from pediatric cohorts = 2.21 x 10(-8), combined p value from adult cohorts = 0.00422). Furthermore, this study illustrates that it is difficult for cross-sectional study designs to detect age-varying associations. If the specifics of age- or time-varying genetic effects are not considered in the selection of both the follow-up samples and in the statistical analysis, important genetic associations may be missed.