Polymorphisms in the Glucokinase-Associated, Dual-Specificity Phosphatase 12 (DUSP12) Gene Under Chromosome 1q21 Linkage Peak Are Associated With Type 2 Diabetes

Abstract

Linkage of type 2 diabetes to chromosome 1q21-q23 is well replicated across populations. In an initial 50-kb marker map (580 markers) across the linked region, one of the two strongest associations observed in Utah Caucasians was at marker rs1503814 (P < 0.00001 in pools, P < 0.004 in individuals). Based on this association, we typed additional markers and screened for sequence variation in the nearby DUSP12 gene. The strongest associations mapped to a highly conserved nongenic sequence just telomeric to rs1503814 and extended 10 kb telomeric through the DUSP12 gene and into the 5 end of the adjacent ATF6 gene. No coding variant could explain the association in the DUSP12 gene. An extended haplotype encompassing markers from ؊8,379 to ؉10,309 bp relative to the ATG start was more common in Caucasian case (0.381) than control subjects (0.285, P ‫؍‬ 0.005) and was uniquely tagged by a 194-bp allele at either of two simple tandem repeat variants or by the T allele at marker ؉7,580. Markers ؊8,379 and ؉7,580 were nominally associated with type 2 diabetes in African-American subjects (P < 0.05), but with different alleles. Marker rs1503814 was strongly associated with postchallenge insulin levels among family members (P ‫؍‬ 0.000002), but sequence variation in this region was not associated with type 2 diabetes in three other populations of European ancestry. Our data suggest that sequences in or upstream of DUSP12 may contribute to type 2 diabetes susceptibility, but the lack of replication suggests a small effect size. Diabetes

The search for type 2 diabetes susceptibility loci: The chromosome 1q story

“…Furthermore, an SNP in the 5' flanking region (rs1503814) was strongly associated with postglucose challenge insulin level (P = 0.000002) in Caucasian persons. However, other SNPs that should have tagged the risk haplotype were not associated with T2DM in Caucasian samples from France, the United Kingdom, or the Old Order Amish [21]. Thus, the role for this gene remains uncertain.…”

“…The gene was shown to activate glucokinase through dephosphorylation, thus potentially modulating glycolysis. We identified 19 variants associated with T2DM (P < 0.05) clustered between 8379 bp upstream to 7580 bp downstream of the ATG start [21]. The most significantly associated (P = 0.0008) marker in Caucasian persons was a simple tandem repeat, rs6143445, located at -8379 bp in the 5' flanking region, in a region of high sequence conservation among mammalian species.…”

Association of genetic variants of NOS1AP with type 2 diabetes in a Chinese population

“…In fact, several specific genes in this region, such as LMNA, ATF6 and DUSP12, were identified as possibly conferring risk of diabetes in some populations [31][32][33][34]. Meta-analysis of the eight populations of the International Type 2 Diabetes 1q Consortium, as well as analysis of the Shanghai Chinese population of this consortium suggested that NOS1AP might also be a susceptibility gene for type 2 diabetes [10].…”

The Role for Endoplasmic Reticulum Stress in Diabetes Mellitus

“…ATF6 has also been identified as a minor type 2 diabetes susceptibility gene in Pima Indians (197). In some cohorts, an association with insulin secretion was observed for a DNA variant that extends into the 5Ј end of the ATF6 gene (198). Further studies are needed on the genetic variation in key UPR genes in type 2 diabetes and on possible gene-environment interactions.…”