Analysis of the contribution to type 2 diabetes susceptibility of sequence variation in the gene encoding stearoyl-CoA desaturase, a key regulator of lipid and carbohydrate metabolism.
OBJECTIVE
Stearoyl-CoA desaturase (SCD) is emerging as a key regulator of lipid and carbohydrate metabolism. Scd-null mice display a beneficial metabolic phenotype characterised by resistance to obesity, diabetes and hyperlipidaemia. The human homologue, SCD, maps to a region of chromosome 10 linked to type 2 diabetes, and SCD activity correlates with insulin sensitivity. Given this strong positional and biological candidacy, the present study sought to establish whether sequence variation in SCD influences susceptibility to type 2 diabetes and related traits.


METHODS
The SCD gene was resequenced in 23 diabetic subjects. Six variants within coding and adjacent sequence, including a non-synonymous SNP in exon 5 (M224L), were selected for genotyping in a primary set of 608 diabetic subjects and 600 control subjects.


RESULTS
There was no association (at the allele, genotype or haplotype level) with type 2 diabetes, although genotype frequencies at the +14301 A>C SNP in the 3' untranslated region showed borderline association (p~0.06) when evidence for linkage was taken into account. However, replication studies (350 young-onset diabetic patients; 747 controls) failed to confirm any relationship with diabetes for this variant. No significant associations were seen for diabetes-related traits including BMI and waist-to-hip ratio.


CONCLUSIONS
The present study, the first reported analysis of this gene, indicates that the SCD variants typed do not explain chromosome-10-encoded susceptibility to type 2 diabetes. Although this study provided no evidence that SCD sequence variation influences diabetes susceptibility or related traits, SCD remains a major target for pharmaceutical and/or environmental manipulation.
Liew
C F
CF
Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Road, Oxford, OX3 7LJ, UK.
Groves
C J
CJ
Wiltshire
S
S
Zeggini
E
E
Frayling
T M
TM
Owen
K R
KR
Walker
M
M
Hitman
G A
GA
Levy
J C
JC
O'rahilly
S
S
Hattersley
A T
AT
Johnston
D G
DG
McCarthy
M I
MI
D000328:Adult; D050260:Carbohydrate Metabolism; D002241:Carbohydrates; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007438:Introns / Q000235:genetics; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values; D013230:Stearoyl-CoA Desaturase / Q000235:genetics*
D002241:Carbohydrates; D013230:Stearoyl-CoA Desaturase