Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 28, Issue 6, Pages 1193-1199Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.107.160150
Keywords
familial combined hyperlipidemia; genetics; Stearoyl-CoA desaturase 1; peroxisome proliferator-activated receptor gamma; hepatocyte nuclear factor 4 alpha
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Funding
- NHGRI NIH HHS [T32 HG002536, T32 HG02536] Funding Source: Medline
- NHLBI NIH HHS [P01 HL028481-250010, P01 HL028481, P01 HL28481, HL082762, R01 HL082762] Funding Source: Medline
- NIDDK NIH HHS [R01DK62388] Funding Source: Medline
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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 (PPAR gamma) gene, and 20p11.21 to 20q13.32 (z = 1.7, P = 0.04), containing the hepatocyte nuclear factor 4, alpha (HNF4 alpha) gene. A specific haplotype of HNF4 alpha 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.
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