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SummaryA polymorphic microsatellite in intron 6 of the human proteasome core particle PSMA6 gene (HSMS006), and four other microsatellites localized upstream on human chromosome 14q13.2 (HSMS801, HSMS702, HSMS701, HSMS602), were genotyped in 104 type 2 diabetic patients and 129 age-matched control subjects from Latvia and replicated in 91 type 2 diabetic patients and 88 age-matched healthy control subjects from the Botnia Study in Finland. In type 2 diabetic patients from both populations the HSMS006 (TG)22 allele was two times more frequent compared to the control group. In the Latvian population the (CAA)8 allele of the HSMS602 marker was less frequent in the diabetic group, as was the (AC)24 allele of microsatellite HSMS801. Allele frequencies of the HSMS701 and 702 repeats were similar in healthy controls and type 2 diabetic patients. In conclusion, our data suggest that variants in the PSMA6 gene on chromosome 14q13.2 are associated with type 2 diabetes.

Bioinformatic Analysis of Evolutional Conservatism and Functional Significance of Microsatellite Alleles of Human 14Q13.2 Region Associated with Type 2 Diabetes Mellitus The paper deals with bioinformatic and statistical analysis of the possible functional significance of the previously shown association of several microsatellite alleles in intron 6 of the human proteasome core particle PSMA6 gene (HSMS006) and four other microsatellites localised upstream in human chromosome 14q13.2 (HSMS801, HSMS702, HSMS701, HSMS602) with type 2 diabetes mellitus in Latvia and Botnia, Finland. Genotype analysis revealed that (CAA)8/(CAA)8 homozygotes of the HSMS602 marker were never found in Type 2 diabetes patients, although 6.56% of the individuals from the control groups were the (CAA)8/(CAA)8 homozygotes. For the HSMS801 marker the (AC)21/(AC)23 genotype was never found in the case group and in the control group it was detected with a frequency 4.40%; these differences were statistically significant (P < 0.05). In contrast to the Latvian population, the distribution of genotype frequencies in cases and controls taken from the Botnian dataset was almost similar. Haplotype analysis showed that in the Latvian population besides haplotypes including alleles differently represented in case and control groups, a combination of some alleles almost equally represented in both groups formed combinations that were more characteristic of either the case group or the control group. This indicates probable independent functional significance of these haplotypes that warrants further investigation. In the Botnian population, more allele combinations were observed, and the distribution of haplotypes in case and control groups differed from that observed in Latvia. The observed haplotype distributions might reflect differences between the studied populations: a homogenous and isolated Botnian vis-à-vis a mixed Latvian population. Linkage disequilibrium (LD) analysis of data on the Latvian population revealed nine of ten two-allele combinations manifesting a high LD. HSMS006 and HSMS602 combination had a low LD; among the analysed markers these were situated at the largest distance from one another. Data on the Botnian population showed that haplotypes in eight of ten combinations had a high LD, including the HSMS006 and HSMS602 combinations. It appears that the two populations differ also in linkage disequilibrium of two-loci haplotypes. Theoretical analysis of a potential functional role of the polymorphisms indicated the significance of the microsatellite length of HSMS602 and HSMS006 for the formation of DNA hairpins. The whole genomic region appears to be conservative in mammals.