The association of genetic variants in Krüppel‐like factor 11 and Type 2 diabetes in the Japanese population

Abstract

AimsKrüppel-like factor 11 (KLF11) is a transcriptional factor of the zinc finger domain family that regulates the expression of insulin. In North European populations, its common functional variant Q62R (rs35927125) is a strong genetic factor for Type 2 diabetes (P = 0.00033, odds ratio for G allele = 1.29, 95% CI 1.12–1.49). We examined the contribution of KLF11 variants to the susceptibility to Type 2 diabetes in a Japanese population.MethodsBy re-sequencing Japanese individuals (n = 24, partly 96), we screened all four exons, exon/intron boundaries and flanking regions of KLF11. Verified single nucleotide polymorphisms (SNPs) were genotyped in 731 initial samples (369 control and 362 case subjects). Subsequently, we tested for association in 1087 samples (524 control and 563 case subjects), which were collected in different districts of Japan from the initial samples.ResultsWe identified eight variants, including a novel A/C variant on intron 3, but no mis-sense mutations. In an association study, we failed to find any significant result of SNPs (minor allele frequency 8.2–46.2%) after correcting for multiple testing. Similarly, no haplotypes were associated with Type 2 diabetes. It is notable that the G allele in rs35927125 was completely absent in 1818 Japanese individuals.ConclusionsGenetic variants in KLF11 are unlikely to have a major effect of Type 2 diabetes in the Japanese population, although they were significantly associated in North European populations. These observations might help to determine the role of KLF11 variants in Type 2 diabetes in different populations.

Mammalian Krüppel-Like Factors in Health and Diseases

“…A variant of the promoter of KLF11 has also been linked to insulin sensitivity in a Danish population (167). However, similar studies failed to demonstrate an association of any genetic variants of KLF11 with type 2 diabetes in Japanese or native American populations (236, 260, 418). …”

Identification of Minimal Promoter and Genetic Variants of Kruppel-like Factor 11 Gene and Association Analysis with Type 2 Diabetes in Japanese

“…Thus, KLF11 is a candidate diabetogenic gene in Japanese. Tanahashi et al reported identification of eight variants, but were unable to find any missense mutation or association of common KLF11 variants in late-onset Type2 diabetes in 1818 Japanese subjects [26].…”

“…No association of KLF11 variants with T2DM was found and no haplotypes were found to show susceptibility to T2DM. We examined one variant, rs4073397, located 21 kb upstream from the coding region and outside of the LD block of the KLF11 region, that shows a marginal association with T2DM in Japanese [26], but we could not replicate the association in this study with power similar to that of the former report (P = 0.268 and 0.576 for allele and genotype analysis, respectively; OR 1.2; RAF 0.5; α = 0.05; 1-β = 63.9%).…”

Krüppel-Like Factor-11, a Transcription Factor Involved in Diabetes Mellitus, Suppresses Endothelial Cell Activation via the Nuclear Factor-κB Signaling Pathway

“…11 Furthermore, alterations in the coupling of KLF11 to HDACs due to variations in the sequence of the KLF11 promoter and protein have been found in selected human populations affected by type 2 diabetes mellitus (T2DM). 12-15 Noteworthy, in spite of its strong-association with diabetes, the role of KLF11 in inflammatory responses that affect the cardiovascular system remains to be addressed. Consequently, the current study sought to define whether KLF11 influences the EC response to pro-inflammatory stimuli.…”