A Common CNR1 (Cannabinoid Receptor 1) Haplotype Attenuates the Decrease in HDL Cholesterol That Typically Accompanies Weight Gain

We have previously shown that genetic variability in CNR1 is associated with low HDL dyslipidemia in a multigenerational obesity study cohort of Northern European descent (209 families, median  = 10 individuals per pedigree). In order to assess the impact of CNR1 variability on the development of dyslipidemia in the community, we genotyped this locus in all subjects with class III obesity (body mass index >40 kg/m2) participating in a population-based biobank of similar ancestry. Twenty-two haplotype tagging SNPs, capturing the entire CNR1 gene locus plus 15 kb upstream and 5 kb downstream, were genotyped and tested for association with clinical lipid data. This biobank contains data from 645 morbidly obese study subjects. In these subjects, a common CNR1 haplotype (H3, frequency 21.1%) is associated with fasting TG and HDL cholesterol levels (p = 0.031 for logTG; p = 0.038 for HDL-C; p = 0.00376 for log[TG/HDL-C]). The strength of this relationship increases when the data are adjusted for age, gender, body mass index, diet and physical activity. Mean TG levels were 160±70, 155±70, and 120±60 mg/dL for subjects with 0, 1, and 2 copies of the H3 haplotype. Mean HDL-C levels were 45±10, 47±10, and 48±9 mg/dL, respectively. The H3 CNR1 haplotype appears to exert a protective effect against development of obesity-related dyslipidemia

Effect of H3 haplocopy on lipid traits (mean ± SD).

<p>Effect of H3 haplocopy on lipid traits (mean ± SD).</p

Association between median lipid traits and single SNPs, using an extended region of interest (p-values from a linear regression model in PLINK).

<p>Association between median lipid traits and single SNPs, using an extended region of interest (p-values from a linear regression model in PLINK).</p

Tag SNP minor allele frequencies.

<p>All SNPs used for haplotype construction are bold.</p>1<p>anticipated MAF based on CEPH cohort (abstracted from ABI website/product catalog).</p>2<p>observed MAF within 645 PMRP study subjects with Class 3 Obesity (BMI>40 kg/m²).</p

Association between CNR1 haplotype and median lipid traits (p-values are shown, calculated using a linear regression model in PLINK).

<p>*adjusted by age, gender, BMI, calories from fat and sport index.</p>†<p>Designation in Tes Baye paper (2008).</p>§<p>SNPs that used for haplotype construction (5′-3′): rs806370, rs806369, rs1049353, rs12720071, rs806368, rs806366.</p

Replication and refinement of the model (p-values are shown, calculated using a linear regression model in PLINK).

<p>Replication and refinement of the model (p-values are shown, calculated using a linear regression model in PLINK).</p

Gender stratified distribution of Body Mass Index (BMI) within the entire population-based PMRP biobank.

<p>All subjects with BMI>40 kg/m² (n = 477 female participants, and 168 male participants) were included in the current study cohort.</p

Patient characteristics.

<p>T CHOL: total cholesterol; LDL-C: low density lipoprotein cholesterol; HDL-C: high density lipoprotein cholesterol; TG: triglyceride.</p

Association between modeled lipid trait and single SNPs, over the same extended region of interest shown in Table 4 (Kruskal-Wallis p-values are shown).

<p>Association between modeled lipid trait and single SNPs, over the same extended region of interest shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015779#pone-0015779-t004" target="_blank">Table 4</a> (Kruskal-Wallis p-values are shown).</p

Scatterplot showing the relationship between BMI and dietary fat intake for PMRP participants.

<p>Using the entire PMRP biobank<b> (n = 20,000)</b>, percentage of daily calories due to fat has been plotted against BMI at the time of study entry. Trend-line is added (r = 0.086).</p