IRS1, KCNJ11, PPARγ2 and HNF-1α: do amino acid polymorphisms in these candidate genes support a shared aetiology between type 1 and type 2 diabetes?

• Published in: Diabetes, obesity & metabolism Vol. 8; no. 1; pp. 75 - 82
• Main Authors: Johansen, A., Jensen, D. P., Bergholdt, R., Mortensen, H. B., Pociot, F., Nerup, J., Hansen, T., Pedersen, O.
• Format: Journal Article
• Language: English
• Published: Oxford, UK; Malden, USA Blackwell Science Ltd 01.01.2006
• Subjects: gene; genetics; HNF-1alpha; insulin; insulin secretion; insulin sensitivity; IRS1; Kir6.2; polymorphisms; type 1 diabetes; type 2 diabetes
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/j.1463-1326.2005.00471.x

Aims:  Type 1 diabetes mellitus (T1DM) is a chronic disorder primarily triggered by environmental and immunological factors in genetically susceptible individuals. Despite the fact that there are indications of common aetiological features of T1DM and type 2 diabetes (T2DM), variation in genes involved in insulin secretion and insulin signalling has to a large extent been ignored as potential modifiers in the pathogenesis of T1DM. Recent studies suggest, however, that proven T2DM susceptibility gene variants may be involved in the pathogenesis of T1DM. The objective of this study was to estimate the impact of four selected amino acid polymorphisms –IRS‐1 Gly972Arg, Kir6.2 Glu23Lys, HNF‐1α Ala98Val and PPARγ2 Pro12Ala in a Danish population of T1DM families. Methods:  All variants were genotyped in 490 simplex‐ and multiplex‐T1DM families applying polymerase chain reaction‐restriction fragment length polymorphism, and results were evaluated by means of a transmission disequilibrium test (TDT) analysis. Results:  TDT analysis revealed that the Arg972 IRS‐1, the Lys23 Kir6.2 and the Val98 HNF‐1α variants were transmitted from heterozygous parents to affected probands at frequencies of 49.1%, 47.0% and 54.1%, respectively (p > 0.05 for all). This was similar to the rate of transmission to unaffected siblings. The transmission rate of the Ala12 PPARγ2 variant to affected probands was 46.5% (p > 0.05) which differed significantly from the transmission to unaffected offspring (p = 0.024). A combined analysis of the present and published pertinent data of 1691 transmissions showed a significantly decreased transmission of the PPARγ2 Ala12 allele to affected probands (p = 0.0045). Conclusions:  The Pro12Ala variant of PPARγ2 is associated with T1DM, the minor Ala allele conferring a reduced risk. This same finding has been reported in patients with T2DM.