Association of stearoyl-CoA desaturase 1 activity with familial combined hyperlipidemia

Abstract

Objective: Stearoyl-CoA desaturase 1 (SCD1) is the rate-limiting enzyme involved in the synthesis of monounsaturated fatty acids, and in mice SCD1 activity is associated with plasma triglyceride levels. We used the fatty acid desaturation index (the plasma ratio of 18:1/18:0) as a marker of SCD1 activity to investigate the relationship of SCD1 to familial combined hyperlipidemia (FCHL).

Methods and results: The fatty acid desaturation index was measured in 400 individuals from 18 extended FCHL pedigrees. FCHL-affected individuals exhibited increased SCD1 activity when compared to unrelated controls (P < 0.0001). The fatty acid desaturation index was found to be highly heritable (h(2) = 0.48, P = 2.2 x 10(-11)) in this study sample. QTL analysis in 346 sibling pairs from 18 FCHL families revealed suggestive linkage of the desaturation index to chromosomes 3p26.1 to 3p13 (z = 2.7, P = 0.003), containing the peroxisome proliferator-activated receptor gamma (PPARgamma) gene, and 20p11.21 to 20q13.32 (z = 1.7, P = 0.04), containing the hepatocyte nuclear factor 4, alpha (HNF4alpha) gene. A specific haplotype of HNF4alpha was found to be associated with the desaturation index in these FCHL families (P = 0.002).

Conclusions: Our results demonstrate that the fatty acid desaturation index is a highly heritable trait that is associated with the dyslipidemia observed in FCHL.

Figure 1

Non-parametric z-scores > 1.64 (p<0.05) obtained for age- and sex- adjusted (solid black line), age- , sex-, tg-, and hdlc- adjusted (open circles) 18:1/18:0 desaturation index values and for 16:1/16:0 (dashed lines) in 18 extended FCHL families. Z-scores for the SCD1 gene locus (Chromosome 10) is also shown.

Figure 2

Genomic Structure and Linkage Disequilibrium Map of PPARγ. A) Positions of genotyped SNPs selected for analysis. B) The PPARγ gene +/− 1kb in 30 CEPH trios using the HAPMAP data (release no. 16c.1/phaseI, June 2005). Linkage disequilibrium is displayed using the Haploview Program v. 3.2 (available at www.broad.mit.edu/mpg/haploview/). Genotyped SNPs are boxed. D' values are shown.

Figure 2

Genomic Structure and Linkage Disequilibrium Map of PPARγ. A) Positions of genotyped SNPs selected for analysis. B) The PPARγ gene +/− 1kb in 30 CEPH trios using the HAPMAP data (release no. 16c.1/phaseI, June 2005). Linkage disequilibrium is displayed using the Haploview Program v. 3.2 (available at www.broad.mit.edu/mpg/haploview/). Genotyped SNPs are boxed. D' values are shown.