Genetic Variation in the FAAH Gene and Metabolic Syndrome–related Phenotypes

Abstract

TO THE EDITOR: We read with great interest the article “Variants in the CNR1 and the FAAH Genes and Adiposity Traits in the Community” by Lieb et al. about a lack of association of common variants of the CNR1 and FAAH genes with surrogate measures of adiposity in a large community-based sample of individuals (1). The authors performed a comprehensive analysis of common variation across these two genes and observed no evidence for association of any variant with BMI, waist circumference, and visceral adipose tissue volume. In a smaller (n = 420) but well-characterized sample of adult men of self-reported European ancestry (aged 34.4 ± 0.4 years, mean ± s.e.), selected from a population-based study in Argentinean people, we explored the role of the C/T rs6703669-FAAH variant in the genetic susceptibility of metabolic syndrome–related phenotypes. The variant was selected as a tagSNP capturing common variation in the promoter region of the gene (pair-wise approach at r2 = 0.8, minor allele frequency >10%). Genotyping was performed by allele-specific PCR and genotypes were in Hardy–Weinberg equilibrium. In agreement with Lieb et al., we found no evidence of association between the variant and any of the obesity-related phenotypes: BMI as a continuous trait (logarithmically transformed) P = 0.9, waist circumference P = 0.25, obesity status as a discrete trait P = 0.24, and measurement of body fat content by bioelectrical impedance P = 0.4. Nevertheless, when we analyzed the serum lipid variables in relation to the rs6703669, a significant association was observed with plasma levels of triglycerides: homozygous CC 105.1 ± 5.9, heterozygous CT 131.3 ± 7.5 and homozygous TT 119.2 ± 15.5 mg/dl, P < 0.015, adjusted by log-transformed age and BMI. Accordingly, hypertriglyceridemia evaluated as a discrete trait (plasma triglycerides ≥150 mg/dl), also showed significant association with the variant (OR per T allele: 1.31, 95% CI 1.04–1.66, P < 0.022). Finally, we evaluated the possible association of the rs6703669 and other metabolic syndrome–related phenotypes and observed a significant association with arterial hypertension (dichotomized as a discrete trait): OR per T allele: 1.43, 95% CI 1.06–1.95, P = 0.01, after adjusting by log-transformed age and BMI. Similarly, the quantitative trait diastolic arterial blood pressure was significantly associated with the variant (P < 0.023): homozygous CC: 74.2 ± 0.6, heterozygous CT: 76.2 ± 0.7 and homozygous TT: 78.1 ± 1.7 mm Hg. In summary, the findings of Lieb et al. can also be generalized to Argentinean population, as an example of replication in a different group of European descent. However, these results do not exclude other possible effects of the variants of the FAAH on metabolic syndrome–related phenotypes, for instance arterial blood pressure or plasma triglycerides. These data, which need to be confirmed in larger samples, may be of interest because the use of FAAH as a therapeutic target in hypertension is under evaluation not only because of the potential beneficial effect of endocannabinoid-related drugs on arterial blood pressure but also on the development of the hypertensive cardiac hypertrophy (2,3). This study was partially supported by PICT 05-25920 (Agencia Nacional de Promoción Científica y Tecnológica). A.L.B., S.S., C.G., and C.J.P. belong to Consejo Nacional de Investigaciones Científicas y Técnicas. A.L.B. is recipient of a Health Ministry Fellowship (Beca Ramón Carrillo-Arturo Oñativia Ministerio de Salud y Ambiente de la Nación) Convocatoria 2008. The authors declared no conflict of interest.