Variation in three SNPs in the calpain-10 gene not implicated in conferring
susceptibility to type 2 diabetes in a large Finnish cohort.

Fingerlin, T.E., Erdos, M.R., Watanabe, R.M., Valle, T.T., Tuomilehto, J., Bergman,
R.N., Boehnke, M., and Collins, F.S., for the FUSION Study Group.

In recent study of Mexican Americans (MA) Horikawa et al. found that an intronic SNP,
UCSNP-43, in the calpain-10 gene showed evidence for linkage and association with
type 2 diabetes (T2D), with the common G allele the at-risk allele.  Further analyses
identified a pair of three-SNP (UCSNP-43, 19, 63) haplotypes that in combination
were strongly associated with T2D.  Homozygotes for either of the two haplotypes
were not at increased risk. We genotyped UCSNP-43, 56, and 63 (UCSNP-56 is in
complete linkage disequilibrium with UCSNP-19 and was more easily typed) in 906
Finnish subjects from the FUSION study:  506 index cases with T2D, 179 non-diabetic
spouses of index cases or their siblings, and 221 normal glucose tolerant elderly
control subjects.  We found no significant differences in allele or genotype
frequencies between cases and spouses and elderly controls for any of the three
SNPs (all p-values > 0.25).  We also estimated haplotype frequencies for cases and
spouses and elderly controls using the three SNPs.  Preliminary results suggest that
the high-risk haplotype combination identified by Horikawa et al. is rare in our
sample.  Within each study group, we compared T2D-related traits (insulin secretion
and sensitivity measures, lipid profiles, age-of-onset, and BMI) between subjects
with and without the common G allele and among subjects with each of the three
genotypes (GG, GA, AA) at UCSNP-43 after adjusting for age and gender.  We found
no important differences.  These results suggest that in this Finnish population 1)
UCSNP-43 neither confers susceptibility to T2D nor strongly influences several
T2D-related traits and 2) the high-risk haplotype combination identified in the MA
population cannot play a substantial role in conferring susceptibility to T2D due
to the low frequency of that haplotype combination in Finnish T2D families.