Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom.
Variation in CAPN10, the gene encoding the ubiquitously expressed cysteine protease calpain-10, has been associated with type 2 diabetes in Mexican Americans and in two northern-European populations, from Finland and Germany. We have studied CAPN10 in white subjects of British/Irish ancestry, using both family-based and case-control studies. In 743 sib pairs, there was no evidence of linkage at the CAPN10 locus, which thereby excluded it as a diabetes-susceptibility gene, with an overall sib recurrence risk, lambda(S), of 1.25. We examined four single-nucleotide polymorphisms (SNP-44, -43, -19, and -63) previously either associated with type 2 diabetes or implicated in transcriptional regulation of calpain-10 expression. We did not find any association between SNP-43, -19, and -63, either individually or as part of the previously described risk haplotypes. We did, however, observe significantly increased (P=.033) transmission of the less common C allele at SNP-44, to affected offspring in parents-offspring trios (odds ratio 1.6). An independent U.K. case-control study and a small discordant-sib study did not show significant association individually. In a combined analysis of all U.K. studies (P=.015) and in combination with a Mexican American study (P=.004), the C allele at SNP-44 is associated with type 2 diabetes. Sequencing of the coding region of CAPN10 in a group of U.K. subjects revealed four coding polymorphisms-L34V, T504A, R555C, and V666I. The T504A polymorphism was in perfect linkage disequilibrium with the diabetes-associated C allele at SNP-44, suggesting that the synthesis of a mutant protein and/or altered transcriptional regulation could contribute to diabetes risk. In conclusion, we were not able to replicate the association of the specific calpain-10 alleles identified by Horikawa et al. but suggest that other alleles at this locus may increase type 2 diabetes risk in the U.K. population.
Evans
J C
JC
Department of Diabetes and Vascular Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, Exeter, EX2 5AX, United Kingdom.
Frayling
T M
TM
Cassell
P G
PG
Saker
P J
PJ
Hitman
G A
GA
Walker
M
M
Levy
J C
JC
O'Rahilly
S
S
Rao
P V
PV
Bennett
A J
AJ
Jones
E C
EC
Menzel
S
S
Prestwich
P
P
Simecek
N
N
Wishart
M
M
Dhillon
R
R
Fletcher
C
C
Millward
A
A
Demaine
A
A
Wilkin
T
T
Horikawa
Y
Y
Cox
N J
NJ
Bell
G I
GI
Ellard
S
S
McCarthy
M I
MI
Hattersley
A T
AT
D000483:Alleles; D002154:Calpain / Q000235:genetics*; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D008040:Genetic Linkage; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008969:Molecular Sequence Data; D006113:United Kingdom / Q000453:epidemiology; D044465:White People / Q000235:genetics
D002154:Calpain; C415197:calpain 10