[PDF][PDF] Genomewide search for type 2 diabetes mellitus susceptibility loci in Finnish families: the Botnia study

CM Lindgren, MM Mahtani, E Widen… - The American Journal of …, 2002 - cell.com
CM Lindgren, MM Mahtani, E Widen, MI McCarthy, MJ Daly, A Kirby, MP Reeve, L Kruglyak
The American Journal of Human Genetics, 2002cell.com
Type 2 diabetes mellitus is a heterogeneous inherited disorder characterized by chronic
hyperglycemia resulting from pancreatic β-cell dysfunction and insulin resistance. Although
the pathogenic mechanisms are not fully understood, manifestation of the disease most
likely requires interaction between both environmental and genetic factors. In the search for
such susceptibility genes, we have performed a genomewide scan in 58 multiplex families
(comprising 440 individuals, 229 of whom were affected) from the Botnia region in Finland …
Type 2 diabetes mellitus is a heterogeneous inherited disorder characterized by chronic hyperglycemia resulting from pancreatic β-cell dysfunction and insulin resistance. Although the pathogenic mechanisms are not fully understood, manifestation of the disease most likely requires interaction between both environmental and genetic factors. In the search for such susceptibility genes, we have performed a genomewide scan in 58 multiplex families (comprising 440 individuals, 229 of whom were affected) from the Botnia region in Finland. Initially, linkage between chromosome 12q24 and impaired insulin secretion had been reported, by Mahtani et al., in a subsample of 26 families. In the present study, we extend the initial genomewide scan to include 32 additional families, update the affectation status, and fine map regions of interest, and we try to replicate the initial stratification analysis. In our analysis of all 58 families, we identified suggestive linkage to one region, chromosome 9p13-q21 (nonparametric linkage [NPL] score 3.9; P<.0002). Regions with nominal P values <.05 include chromosomes 2p11 (NPL score 2.0 [P<.03]), 3p24-p22 (NPL score 2.2 [P<.02]), 4q32-q33 (NPL score 2.5 [P<.01]), 12q24 (NPL score 2.1 [P<.03]), 16p12-11 (NPL score 1.7 [P<.05]), and 17p12-p11 (NPL score 1.9 [P<.03]). When chromosome 12q24 was analyzed in only the 32 additional families, a nominal P value <.04 was observed. Together with data from other published genomewide scans, these findings lend support to the hypothesis that regions on chromosome 9p13-q21 and 12q24 may harbor susceptibility genes for type 2 diabetes.
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