The functional "KL-VS" variant of KLOTHO is not associated with type 2 diabetes in 5028 UK Caucasians.
BACKGROUND
Klotho has an important role in insulin signalling and the development of ageing-like phenotypes in mice. The common functional "KL-VS" variant in the KLOTHO (KL) gene is associated with longevity in humans but its role in type 2 diabetes is not known. We performed a large case-control and family-based study to test the hypothesis that KL-VS is associated with type 2 diabetes in a UK Caucasian population.


METHODS
We genotyped 1793 cases, 1619 controls and 1616 subjects from 509 families for the single nucleotide polymorphism (SNP) F352V (rs9536314) that defines the KL-VS variant. Allele and genotype frequencies were compared between cases and controls. Family-based analysis was used to test for over- or under-transmission of V352 to affected offspring.


RESULTS
Despite good power to detect odds ratios of 1.2, there were no significant associations between alleles or genotypes and type 2 diabetes (V352 allele: odds ratio = 0.96 (0.84-1.09)). Additional analysis of quantitative trait data in 1177 healthy control subjects showed no association of the variant with fasting insulin, glucose, triglycerides, HDL- or LDL-cholesterol (all P > 0.05). However, the HDL-cholesterol levels observed across the genotype groups showed a similar, but non-significant, pattern to previously reported data.


CONCLUSIONS
This is the first large-scale study to examine the association between common functional variation in KL and type 2 diabetes risk. We have found no evidence that the functional KL-VS variant is a risk factor for type 2 diabetes in a large UK Caucasian case-control and family-based study.
Freathy
Rachel M
RM
Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK. rachel.freathy@pms.ac.uk
Weedon
Michael N
MN
Melzer
David
D
Shields
Beverley
B
Hitman
Graham A
GA
Walker
Mark
M
McCarthy
Mark I
MI
Hattersley
Andrew T
AT
Frayling
Timothy M
TM
D000328:Adult; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005966:Glucuronidase / Q000235:genetics*; D006801:Humans; D000090265:Klotho Proteins; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D006113:United Kingdom / Q000208:ethnology; D044465:White People
D005966:Glucuronidase; D000090265:Klotho Proteins