Skip to main content

Advertisement

SpringerLink
Log in

The KLF14 Variant is Associated with Type 2 Diabetes and HbA1C Level

  • Original Article
  • Published:
Biochemical Genetics Aims and scope Submit manuscript

Abstract

The purpose of this study was to scan variants in coding region of Krȕppel like factor14 (KLF14) locus and assess association related to type 2 diabetes (T2D) in Iranian population. We sequenced the coding region of KLF14 to scan variants in case–sibling study (92 individuals with T2D and 92 healthy older siblings). To confirm, we analyzed rs76603546 association with T2D in a larger unrelated case–control study by PCR–RFLP (475 cases and 512 controls). We analyzed the association of rs76603546 with HbA1C, BMI, fat mass, waist circumference, fasting glucose, cholesterol and HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) using one-way ANOVA analysis. Also, association of genotypes with T2D adjusted for confounding variables was analyzed using logistic regression. HaploReg v 4.1 was used to predict rs76603546 possible function. Sequencing results analysis revealed the association of C allele of rs76603546, synonymous variant C>T, [OR 2.10 (1.38–3.20), P value < 0.001] and CC genotype of rs76603546 [OR 4.3 (1.79–10.23), P value = 0.001] with susceptibility to T2D. PCR-Restriction Fragment Length Polymorphism (RFLP) results analysis confirmed the association of rs76603546 with T2D [C allele, OR 1.91 (1.59–2.29), P value = 0.002, CC genotype, OR 3.27 (2.26–4.73), P value = 0.002 and TC genotype, OR 1.74 (1.31–2.31), P value = 0.001]. The CC genotype of rs76603546 is associated with HbA1C level (P value < 0.001) and BMI (P value = 0.02). After adjustment with confounding variables, we observed association of CC genotype with T2D [OR 2.542 (1.25–3.77), P value = 0.03]. Among over 220 SNPs, rs76603546 was associated with T2D, HbA1C and BMI in our study.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Data Availability

All authors ensure that all data and materials as well as software application or custom code support their published claims and comply with field standards.

References

  • Abbasi-Shavazi MJ, McDonald P, Hosseini-Chavoshi M (2008) Modernization or cultural maintenance: the practice of consanguineous marriage in Iran. J Biosoc Sci 40:911–933

    Article  Google Scholar 

  • Alves JGB, Figueiroa JN, Meneses J, Alves GV (2012) Breastfeeding protects against type 1 diabetes mellitus: a case–sibling study. Breastfeeding Medicine 7:25–28

    Article  PubMed  Google Scholar 

  • Bush WS, Moore JH (2012) Genome-wide association studies. PLoS Comput Biol 8:e1002822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Civelek M, Lusis AJ (2011) Conducting the metabolic syndrome orchestra. Nat Genet 43:506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Consortium M (2011) Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes. Nat Genet 43:561–564

    Article  CAS  Google Scholar 

  • De Assuncao TM et al (2014) New role for Kruppel-like factor 14 as a transcriptional activator involved in the generation of signaling lipids. J Biol Chem 289:15798–15809

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, Gejman PV (2003) Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet 12:205–216

    Article  CAS  PubMed  Google Scholar 

  • Epstein MP et al (2015) A statistical approach for rare-variant association testing in affected sibships. The American Journal of Human Genetics 96:543–554

    Article  CAS  PubMed  Google Scholar 

  • Franklin CS et al (2010) The TCF7L2 diabetes risk variant is associated with HbA1C levels: a genome-wide association meta-analysis. Ann Hum Genet 74:471–478

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez C, Vallcaneras S, Calandra R, Calvar SG (2013) Involvement of KLF14 and egr-1 in the TGF-beta1 action on Leydig cell proliferation. Cytokine 61:670–675

    Article  CAS  PubMed  Google Scholar 

  • Genotype-Tissue Expression (GTEx) (2020) www.gtexportal.org/home/?geneId=KLF14

  • Guo Y et al (2015) Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production. J Clin Investig 125:3819

    Article  PubMed  PubMed Central  Google Scholar 

  • Hachiya T et al (2017) Genome-wide meta-analysis in Japanese populations identifies novel variants at the TMC6–TMC8 and SIX3–SIX2 loci associated with HbA 1c. Sci Rep 7:16147

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hoggart CJ, Parra EJ, Shriver MD, Bonilla C, Kittles RA, Clayton DG, McKeigue PM (2003) Control of confounding of genetic associations in stratified populations. Am J Hum Genet 72:1492–1504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang P et al (2013) Association of the KLF14 rs4731702 SNP and serum lipid levels in the Guangxi Mulao and Han populations. Biomed Res Int 2013:231515

    Article  PubMed  PubMed Central  Google Scholar 

  • IFD (2019) IDF diabetes atlas, 9th edn. International Diabetes Federation, Brussels

    Google Scholar 

  • Irvine RA, Lin IG, Hsieh C-L (2002) DNA methylation has a local effect on transcription and histone acetylation. Mol Cell Biol 22:6689–6696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kanazawa A et al (2005) Single nucleotide polymorphisms in the gene encoding Krüppel-like factor 7 are associated with type 2 diabetes. Diabetologia 48:1315–1322

    Article  CAS  PubMed  Google Scholar 

  • Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, Quon MJ (2000) Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 85:2402–2410

    Article  CAS  PubMed  Google Scholar 

  • Kolahdouz P, Yazd EF, Tajamolian M, Manaviat MR, Sheikhha MH (2015) The rs3917779 polymorphism of P-selectin’s significant association with proliferative diabetic retinopathy in Yazd, Iran. Graefe’s Arch Clin Exp Ophthalmol 253:1967–1972

    Article  CAS  Google Scholar 

  • Kowalski GM, Carey AL, Selathurai A, Kingwell BA, Bruce CR (2013) Plasma sphingosine-1-phosphate is elevated in obesity. PLoS ONE 8:e72449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lotfi MH, Saadati H, Afzali M (2013) Prevalence of diabetes in people aged≥ 30 years: the results of screen-ing program of Yazd Province, Iran, in 2012. J Res Health Sci 14:88–92

    Google Scholar 

  • Mao Y, Liu H, Liu Y, Tao S (2014) Deciphering the rules by which dynamics of mRNA secondary structure affect translation efficiency in Saccharomyces cerevisiae. Nucleic Acids Res 42:4813–4822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mita K, Ichimura S, Zama M, James TC (1988) Specifie codon usage pattern and its implications on the secondary structure of silk fibroin mRNA. J Mol Biol 203:917–925

    Article  CAS  PubMed  Google Scholar 

  • Nackley AG et al (2006) Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science 314:1930–1933

    Article  CAS  PubMed  Google Scholar 

  • Nica AC, Dermitzakis ET (2013) Expression quantitative trait loci: present and future. Philos Trans R Soc B 368:20120362

    Article  CAS  Google Scholar 

  • Parker-Katiraee L et al (2007) Identification of the imprinted KLF14 transcription factor undergoing human-specific accelerated evolution. PLoS Genet 3:e65

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rees S et al (2011) Replication of 13 genome-wide association (GWA)-validated risk variants for type 2 diabetes in Pakistani populations. Diabetologia 54:1368–1374

    Article  CAS  PubMed  Google Scholar 

  • Rifai N (1986) Lipoproteins and apolipoproteins. Composition, metabolism, and association with coronary heart disease. Arch Pathol Lab Med 110:694–701

    CAS  PubMed  Google Scholar 

  • Sarmento OF et al (2015) A novel role for Kruppel-like Factor 14 (KLF14) in T-regulatory cell differentiation CMGH. Cell Mol Gastroenterol Hepatol 1:188–202

    Article  PubMed  Google Scholar 

  • Saxena R et al (2013) Genome-wide association study identifies a novel locus contributing to type 2 diabetes susceptibility in Sikhs of Punjabi origin from India. Diabetes 62:1746–1755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siren R, Eriksson JG, Vanhanen H (2012) Waist circumference a good indicator of future risk for type 2 diabetes and cardiovascular disease. BMC Public Health 12:631. https://doi.org/10.1186/1471-2458-12-631

    Article  PubMed  PubMed Central  Google Scholar 

  • Sladek R, Prokopenko I (2016) Genome-wide association studies of type 2 diabetes. In: Barroso J (ed) The genetics of type 2 diabetes and related traits. Springer, New York, pp 13–61

    Chapter  Google Scholar 

  • Small KS et al (2011) Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes. Nat Genet 43:561–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thomas DC, Witte JS (2002) Point: population stratification: a problem for case-control studies of candidate-gene associations? Cancer Epidemiol Prev Biomark 11:505–512

    Google Scholar 

  • Truty MJ, Lomberk G, Fernandez-Zapico ME, Urrutia R (2009) Silencing of the transforming growth factor-β (TGFβ) receptor II by Krüppel-like factor 14 underscores the importance of a negative feedback mechanism in TGFβ signaling. J Biol Chem 284:6291–6300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsui S, Dai W, Lu L (2014) CCCTC-binding factor mediates effects of glucose on beta cell survival. Cell Prolif 47:28–37

    Article  CAS  PubMed  Google Scholar 

  • Turnpenny PD, Ellard S (2011) Emery’s elements of medical genetics. Elsevier, London

    Google Scholar 

  • Virtanen KA et al (2005) Increased fat mass compensates for insulin resistance in abdominal obesity and type 2 diabetes: a positron-emitting tomography study. Diabetes 54:2720–2726

    Article  CAS  PubMed  Google Scholar 

  • Vizcaíno JA et al (2016) 2016 update of the PRIDE database and its related tools. Nucleic Acids Res 44:D447–D456

    Article  PubMed  CAS  Google Scholar 

  • Voight BF et al (2010) Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42:579–589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang J et al (2014) Association of KCNQ1 and KLF14 polymorphisms and risk of type 2 diabetes mellitus: a global meta-analysis. Hum Immunol 75:342–347

    Article  CAS  PubMed  Google Scholar 

  • Wang N et al (2018) Long noncoding RNA Meg3 regulates mafa expression in mouse beta cells by inactivating Rad21, Smc3 or Sin3α. Cell Physiol Biochem 45:2031–2043

    Article  CAS  PubMed  Google Scholar 

  • Wei X et al (2017) A novel role for the Krüppel-like factor 14 on macrophage inflammatory response and atherosclerosis development. Cardiovasc Pathol 27:1–8

    Article  CAS  PubMed  Google Scholar 

  • World Health Organization (2011) Use of glycated haemoglobin (HbA1c) in diagnosis of diabetes mellitus: abbreviated report of a WHO consultation. World Health Organization, Geneva

    Google Scholar 

  • Wu C et al (2008) Gene set enrichment in eQTL data identifies novel annotations and pathway regulators. PLoS Genet 4:e1000070

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wu J et al (2019) Egr-1 transcriptionally activates protein phosphatase PTP1B to facilitate hyperinsulinemia-induced insulin resistance in the liver in type 2 diabetes. FEBS Lett 593:3054–3063

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Dr. M. Rahmanian and Dr. MH. Sheikhha for technical assistance, Yazd Diabetes Research Center for providing individuals with T2D information, and Mr. Tabatabai for sample collection.

Funding

This work was supported by the Shahid Sadoughi University of Medical Sciences Research Council [Grant Numbers 268471] and the ROJETechnologies Foundation [Grant Number R017-3251/2015].

Author information

Authors and Affiliations

  1. Department of Genetics, Faculty of Medicine, International Campus, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Ensieh Shahvazian & Saba Gharibi

  2. Department of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Mohammad Bagher Mahmoudi, Ehsan Farashahi Yazd & Bahram Moghimi

  3. Stem Cell Biology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Ehsan Farashahi Yazd

  4. Research & Development Department, ROJETechnologies, Yazd, Iran

    Pouria HosseinNia

  5. Yazd Cardiovascular Research Centre, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Masoud Mirzaei

  6. Yazd Reproductive Sciences Institute, Bu-Ali Ave., Timsar Fallahi St., Safaeieh, Yazd, Iran

    Ehsan Farashahi Yazd

Authors
  1. Ensieh Shahvazian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad Bagher Mahmoudi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ehsan Farashahi Yazd
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Saba Gharibi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bahram Moghimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pouria HosseinNia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Masoud Mirzaei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ehsan Farashahi Yazd.

Ethics declarations

Conflict of interest

There is no conflict of interest to declare.

Ethics Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Shahid Sadoughi University of Medical Sciences (2016/268471).

Informed Consent

Written informed consent was obtained from all participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10528_2020_10015_MOESM1_ESM.pdf

PCR-RFLP genotyping of rs76603546 in the KLF14 gene with restriction enzyme MspI. Three SNP genotypes, C/C, C/T and T/T, were detected. M: 100 bp DNA ladder. Identification of three genotypes at +336 position (rs76603546) using Automated Sanger Sequencing Method. CC genotype (a), TC genotype (b) and TT genotype (c) (PDF 124 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shahvazian, E., Mahmoudi, M.B., Farashahi Yazd, E. et al. The KLF14 Variant is Associated with Type 2 Diabetes and HbA1C Level. Biochem Genet 59, 574–588 (2021). https://doi.org/10.1007/s10528-020-10015-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10528-020-10015-w

Keywords

Search

Navigation