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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1193.)
© 2008 American Heart Association, Inc.

Clinical and Population Studies

Association of Stearoyl-CoA Desaturase 1 Activity With Familial Combined Hyperlipidemia

Rebecca Mar-Heyming; Makoto Miyazaki; Daphna Weissglas-Volkov; Nicholas A. Kolaitis; Narimaan Sadaat; Christopher Plaisier; Päivi Pajukanta; Rita M. Cantor; Tjerk W.A. de Bruin; James M. Ntambi; Aldons J. Lusis

From the Departments of Medicine (A.J.L.), Human Genetics (R.M.H., C.P., P.P., D.W.-V., R.M.C., A.J.L.), Microbiology and Molecular Genetics (N.A.K., N.S., A.J.L.), and Pediatrics (R.M.C.), David Geffen School of Medicine at UCLA, Los Angeles, Calif; the Department of Biochemistry (M.M., J.N.), University of Wisconsin-Madison; and the Department of Medicine and Cardiovascular Research Institute, Maastricht (T.W.A.d.B.), Academic Hospital, Maastricht, the Netherlands.

Correspondence to Aldons J. Lusis, PhD, Department of Medicine, Division of Cardiology, 47-123 Center for the Health Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095. E-mail jlusis{at}mednet.ucla.edu

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 (h²=0.48, P=2.2x10^–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 (PPAR) gene, and 20p11.21 to 20q13.32 (z=1.7, P=0.04), containing the hepatocyte nuclear factor 4, alpha (HNF4) gene. A specific haplotype of HNF4 was found to be associated with the desaturation index in these FCHL families (P=0.002).

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

We used the fatty acid desaturation index to investigate the relationship of SCD1 to FCHL. The fatty acid desaturation index was elevated in FCHL individuals (P<0.0001). Specific haplotypes of HNF4 (P=0.002) were modestly associated with the desaturation index.

Key Words: familial combined hyperlipidemia • genetics • Stearoyl-CoA desaturase 1 • peroxisome proliferator-activated receptor gamma • hepatocyte nuclear factor 4 alpha

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