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

• Published in: Diabetologia Vol. 47; no. 12; pp. 2168 - 2175
• Main Authors: LIEW, C. F, GROVES, C. J, HATTERSLEY, A. T, JOHNSTON, D. G, MCCARTHY, M. I, WILTSHIRE, S, ZEGGINI, E, FRAYLING, T. M, OWEN, K. R, WALKER, M, HITMAN, G. A, LEVY, J. C, O'RAHILLY, S
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01-12-2004; Springer Nature B.V
• Subjects: Adult; Biological and medical sciences; Carbohydrate Metabolism; Carbohydrates; Chromosomes; Diabetes; Diabetes Mellitus, Type 2 - enzymology; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinology; Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Exons - genetics; Fatty acids; Female; Genes; Genetic Predisposition to Disease; Genetic Variation; Genotype & phenotype; Humans; Insulin resistance; Introns - genetics; Kinases; Lipid Metabolism; Lipids; Male; Medical sciences; Medicine; Metabolism; Middle Aged; Pathogenesis; Polymorphism, Single Nucleotide; Reference Values; Stearoyl-CoA Desaturase - genetics; Endocrinopathy; Type 2 diabetes; Enzyme; Linkage disequilibrium; Metabolic diseases; Chromosome; Lipids; Stearoyl-CoA desaturase; Metabolism; Sensitivity; Association; Gene; Genetic linkage; Chromosome 10; Carbohydrate; Oxidoreductases
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-004-1575-4

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.
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.
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.
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.