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


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.
Mar-Heyming
Rebecca
R
Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Miyazaki
Makoto
M
Weissglas-Volkov
Daphna
D
Kolaitis
Nicholas A
NA
Sadaat
Narimaan
N
Plaisier
Christopher
C
Pajukanta
Päivi
P
Cantor
Rita M
RM
de Bruin
Tjerk W A
TW
Ntambi
James M
JM
Lusis
Aldons J
AJ
D000328:Adult; D002874:Chromosome Mapping; D050171:Dyslipidemias / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006239:Haplotypes / Q000235:genetics; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000201:enzymology* / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000235:genetics; D010375:Pedigree; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism*
D005227:Fatty Acids; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D047495:PPAR gamma; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase