A more thorough understanding of the genetic architecture underlying obesity-related lipid disorders could someday facilitate cardiometabolic risk reduction through early clinical intervention based upon improved characterization of individual risk. In recent years, there has been tremendous interest in understanding the endocannabinoid system as a novel therapeutic target for the treatment of obesity-related dyslipidemia. Aims N-arachidonylethanolamine activates G-protein-coupled receptors within the endocannabinoid system. Fatty acid amide hydrolase (FAAH) is a primary catabolic regulator of N-acylethanolamines, including arachidonylethanolamine. Genetic variants in FAAH have inconsistently been associated with obesity. It is conceivable that genetic variability in FAAH directly influences lipid homeostasis. The current study characterizes the relationship between FAAH and obesity-related dyslipidemia, in one of the most rigorously-phenotyped obesity study cohorts in the USA. Materials & methods Members of 261 extended families (pedigrees ranging from 4 to 14 individuals) were genotyped using haplotype tagging SNPs obtained for the FAAH locus, including 5 kb upstream and 5 kb downstream. Each SNP was tested for basic obesity-related phenotypes (BMI, waist and hip circumference, waist:hip ratio, fasting glucose, fasting insulin and fasting lipid levels) in 1644 individuals within these 261 families. Each SNP was also tested for association with insulin responsiveness using data obtained from a frequently sampled intravenous glucose tolerance test in 399 individuals (32 extended families). Results A well characterized coding SNP in FAAH (rs324420) was associated with increased BMI, increased triglycerides, and reduced levels of high-density lipoprotein cholesterol. Mean (standard deviation) high-density lipoprotein cholesterol level was 40.5 (14.7) mg/dl for major allele homozygotes, 39.1 (10.4) mg/dl for heterozygotes, and 34.8 (8.1) mg/dl for minor allele homozygotes (p < 0.01, Family-Based Association Test). This SNP was not associated with insulin sensitivity, acute insulin response to intravenous glucose, glucose effectiveness or glucose disposition index. Conclusion Genetic variability in FAAH is associated with dyslipidemia, independent of insulin response.

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.

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Reduced frequency of invariant natural killer T (iNKT)-cells has been indicated as a contributing factor to type 1 diabetes (T1D) development in NOD mice. To further understand the genetic basis of the defect, we generated (NOD X ICR)F2 mice to map genes that control iNKT-cell development. We determined frequencies of thymic and splenic iNKT-cells as well as the ratio of CD4-positive and -negative subsets in the spleens of 209 F2 males. Quantitative trait loci (QTL) analysis revealed 5 loci that exceed the significant threshold for the frequency of thymic and/or splenic iNKT-cells on Chromosomes (Chr) 1, 5, 6, 12, and 17. Three significant loci on Chr 1, 4, and 5 were found for the ratio of CD4-positive and -negative splenic iNKT-cells. Comparisons to previously known mouse T1D susceptibility (Idd) loci revealed two significant QTL peak locations respectively mapped to Idd regions on Chr 4 and 6. The peak marker location of the significant Chr 12 iNKT QTL maps to within 0.5Mb of a syntenic human T1D locus. Collectively, our results reveal several novel loci controlling iNKT-cell development and provide additional information for future T1D genetic studies.

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