HHEX

General Information

Full gene name:hematopoietically expressed homeobox Entrez Gene ID:3087 Location:10q23.33 Synonyms:HMPH, HEX, PRH, PRHX, HOX11L-PEN Type:protein-coding

User SNPs

SNPs given by the user that are near or inside this gene:

SNP	Distance (bp)	Direction
rs1111875	7474	downstream

NCBI Summary

This gene encodes a member of the homeobox family of transcription factors, many of which are involved in developmental processes. Expression in specific hematopoietic lineages suggests that this protein may play a role in hematopoietic differentiation. [provided by RefSeq, Jul 2008]

OMIM

OMIM ID:`OMIM ID 604420 `_

NCBI Phenotypes

• Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.
• Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.
• Identification of new genetic risk variants for type 2 diabetes.
• Confirmation of multiple risk Loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population.
• A genome-wide association study identifies novel risk loci for type 2 diabetes.
• Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases.
• NHGRI GWA Catalog
• Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.
• Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.
• Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.
• Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms.
• A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.

Gene Ontology

• multicellular organism growth
• DNA conformation change
• protein homodimerization activity
• response to peptide hormone stimulus
• negative regulation of transcription by transcription factor localization
• cytoplasm
• response to wounding
• pancreas development
• common bile duct development
• negative regulation of angiogenesis
• forebrain morphogenesis
• embryonic heart tube development
• embryonic organ development
• cell differentiation
• hepatic duct development
• chromatin binding
• TBP-class protein binding
• cell proliferation
• protein binding
• hepatoblast differentiation
• eukaryotic initiation factor 4E binding
• protein-DNA complex
• in utero embryonic development
• protein localization to nucleus
• mRNA export from nucleus
• negative regulation of transcription by competitive promoter binding
• DNA binding, bending
• HMG box domain binding
• negative regulation of transcription from RNA polymerase II promoter
• transcription, DNA-dependent
• thyroid gland development
• positive regulation of Wnt receptor signaling pathway
• Wnt receptor signaling pathway
• primary lung bud formation
• repressing transcription factor binding
• regulation of cell proliferation
• gall bladder development
• poly(A)+ mRNA export from nucleus
• cell cycle
• anterior/posterior pattern specification
• nucleus
• transcription regulatory region DNA binding
• transcription factor binding
• B cell differentiation
• interkinetic nuclear migration
• vasculogenesis
• primitive streak formation
• sequence-specific DNA binding transcription factor activity
• hepatocyte differentiation
• sequence-specific DNA binding
• positive regulation of transcription from RNA polymerase II promoter
• negative regulation of vascular endothelial growth factor receptor signaling pathway
• myeloid leukocyte differentiation
• endoderm development
• negative regulation of transcription, DNA-dependent

KEGG Pathways

• Transcriptional misregulation in cancer
• Maturity onset ``diabetes` of the young <http://www.genome.jp/dbget-bin/show_pathway?hsa04950+3087>`_

GeneRIFs

• HEX may play a role in differentiation of the epithelial breast cell [PMID 16854221]
• Single nucleotide polymorphism (SNP) analysis revealed that the sequence variant (rs5015480) near HHEX and two SNPs (rs7756992 and rs9465871) in CDKAL1 were associated with the susceptibility of type 2 diabetes mellitus in females, but not in males. [PMID 21368910]
• Single nucleotid polymorphismallele represents a risk allele for beta-cell dysfunction and, mayconfer increased susceptibility of beta-cells toward adverse environmental factors and type 2 diabetes. [PMID 18039816]
• Type 2 diabetes susceptibility alleles at HHEX are associated with low body mass index at 8 years in children who were born large for gestational age. [PMID 20460429]
• Observational study of gene-disease association, gene-gene interaction, gene-environment interaction, and genetic testing. (HuGE Navigator) [PMID 20075150]
• Meta-analysis and HuGE review of gene-disease association. (HuGE Navigator) [PMID 19602701]
• Observational study of gene-disease association, gene-gene interaction, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator) [PMID 20879858]
• PRH is a negative regulator of eIF4E in myeloid cells, interacting with eIF4E through a conserved binding site typically found in translational regulators [PMID 12554669]
• Affinity Capture-Western; Two-hybrid [PMID 10597310]
• Our data indicate that common genetic variants in two genes previously related to obesity (FTO) and diabetes (HHEX) by genome-wide association scans were not associated with endometrial cancer risk. [PMID 20647405]
• PRH is a key regulator of the VEGF signaling pathway and describe a mechanism whereby PRH plays an important role in tumorigenesis and leukemogenesis. [PMID 20176809]
• region of PRH contains a novel proline-rich dimerisation domain that mediates oligomerisation [PMID 16540119]
• Pax8 regulates the transcriptional activity of Hex promoter; several Pax8 binding sites in the Hex promoter are present [PMID 15062550]
• Single-nucleotide polymorphisms in the HHEX gene are associated with susceptibility to type 2 diaabetes across the boundary of race. [PMID 17971426]
• Observational study and genome-wide association study of gene-disease association. (HuGE Navigator) [PMID 19401414]
• The association of low birth weight and type 2 diabetes risk alleles of the HHEX-IDE locus is confirmed in children of mothers with type 1 diabetes. [PMID 19622614]
• Meta-analysis of gene-disease association. (HuGE Navigator) [PMID 21059810]
• Type 2 diabetes susceptibility of HHEX was confirmed in Japanese. [PMID 19033397]
• Single nucleotide polymorphism in HHEX is associated with type 2 diabetes. [PMID 18991055]
• the interaction between Hhex and SOX13 may contribute to control Wnt/TCF1 signaling in the early embryo. [PMID 20028982]
• Uncategorized study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator) [PMID 19956635]
• Genetic variation predisposes to type 2 diabetes. [PMID 17632701]
• PRH interacts with the HC8 subunit of the proteasome in the context of both 20 and 26 S proteasomes and is associated with the proteasome in K562 hematopoietic cells; the proline-rich PRH N-terminal domain is responsible for this interaction. [PMID 12826010]
• Affinity Capture-Western [PMID 12826010]
• Variations confer impaired glucose- and tolbutamide-induced insulin release in middle-aged and young healthy subjects. [PMID 17827400]
• HHEX, IDE and SLC30A8 showed strongest tissue-specific mRNA expression bias and are associated with increased risk of type 2 diabete. [PMID 20703447]
• HHEX, is more likely to represent the genuine signals of T2DM in the Tunisian population. [PMID 21510814]
• HHEX (PRH) interacts with TLE1. [PMID 15187083]
• Affinity Capture-MS [PMID 21890473]
• Observational study of gene-disease association, gene-gene interaction, and gene-environment interaction. (HuGE Navigator) [PMID 20889853]
• The associations between SNPs of TCF7L2, CDKAL1, SLC30A8 and HHEX and the development of DR and DN. [PMID 22487833]
• Observational study of gene-disease association. (HuGE Navigator) [PMID 20929593]
• Observational study of gene-disease association and gene-environment interaction. (HuGE Navigator) [PMID 20802253]
• Results demonstrate that transcriptional repression by PRH is dependent on TLE availability and suggest that subnuclear localization of TLE plays an important role in transcriptional repression by PRH. [PMID 18713067]
• HHEX is a common type 2 diabetes-susceptibility gene across different ethnic groups. [PMID 17928989]
• variants near the HHEX gene contribute to the risk of type 2 diabetes in a Dutch population [PMID 18231124]
• Variations within the HHEX gene conferred the impaired insulin secretion and changes of insulin degradation but no alteration in insulin sensitivity in carriers of risk for gluccose intolerance. [PMID 19117022]
• HHEX has been implicated in pancreas development and the regulation of insulin secretion and risk of type 2 diabetes. [PMID 20080751]
• Observational study of gene-disease association and gene-gene interaction. (HuGE Navigator) [PMID 20571754]
• Hex, a hematopoietically expressed homeobox protein, induces transcription of the SM22alpha gene by facilitating the interaction between SRF and its cognate binding site in embryonic fibroblasts. [PMID 15242862]
• HEX/Hex is a novel bile acid-induced FXR/Fxr target gene during adaptation of hepatocytes to chronic bile acid exposure. [PMID 19072826]
• Meta-analysis and genome-wide association study of gene-disease association. (HuGE Navigator) [PMID 17463249]
• Variations are not linked to diabetes mellitus. [PMID 17618412]
• translocation involving nucleoporin 98 (NUP98) fused to the DNA-binding domain of the hematopoietically expressed homeobox gene found in acute myeloid leukemia [PMID 18388181]
• Gene variants of CDKAL1, PPARG, IGF2BP2, HHEX, TCF7L2, and FTO predispose to type 2 diabetes in the German KORA 500 K study population. [PMID 18597214]
• Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator) [PMID 18544707]
• there is an association between PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 and type 2 diabetes in the Chinese population [PMID 19862325]
• Observational study and meta-analysis of gene-disease association. (HuGE Navigator) [PMID 20927120]
• Data show that SNPs in HHEX did not confer a significant risk for type 2 diabetes in Pima Indians. [PMID 19008344]
• genomic organization and chromosome 10 mapping [PMID 11701950]
• Located on chromosome 10 and suscptibility of polymorphisms are related to type 2 diabetes. [PMID 19053027]
• Data confirmed the associations of single nucleotide polymorphisms in HHEX with risk for type 2 diabetes in Asians. [PMID 18469204]
• HEX may not affect the differentiation of endothelial cells but acts as a negative regulator of angiogenesis. [PMID 12588764]
• CDKAL1 and HHEX/IDE diabetes-associated alleles are associated with decreased pancreatic beta-cell function, including decreased beta-cell glucose sensitivity that relates insulin secretion to plasma glucose concentration. [PMID 17804762]
• Hex can act as a T lineage oncogene when misexpressed in hematopoietic precursor cells [PMID 14555989]
• There was no association of the genetic polymorhism rs1111875 of HHEX with the occurrence of polycystic ovary syndrome in the Chinese population. [PMID 20041287]
• Data report a novel association between the fetal ADCY5 type 2 diabetes risk allele and decreased birthweight, and confirm in meta-analyses associations between decreased birthweight and the type 2 diabetes risk alleles of HHEX-IDE and CDKAL1. [PMID 20490451]
• Tgf-beta mediated repression of flk-1/KDR and mediated repression of flk-1/KDR and VEGF signaling involves the inducible formation of inhibitory Hex-GATA signaling Hex-GATA involves the formation of Hex-GATA complexes. [PMID 15016828]
• the same genetic HHEX-IDE variant, which is associated with type 2 diabetes from previous studies, also influences pediatric body mass index [PMID 19933996]
• The association of 6 loci with type 2 diabetes risk in Japanese patients is reported. [PMID 18162508]
• PRH octamers wrap DNA in order to bring about transcriptional repression [PMID 18755198]
• Two-hybrid [PMID 16189514]
• Two-hybrid [PMID 16189514]

PubMed Articles

Recent articles:

• Perry JR et al. “Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases.” PLoS Genet. 2012 May;8(5):e1002741. PMID 22693455
• Fu LL et al. “[Association analysis of genetic polymorphisms of TCF7L2, CDKAL1, SLC30A8, HHEX genes and microvascular complications of type 2 diabetes mellitus].” Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2012 Apr;29(2):194-9. PMID 22487833
• Wagner SA et al. “A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.” Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. PMID 21890473
• Sawcer S et al. “Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.” Nature. 2011 Aug 10;476(7359):214-9. PMID 21833088
• Ryoo H et al. “Heterogeneity of genetic associations of CDKAL1 and HHEX with susceptibility of type 2 diabetes mellitus by gender.” Eur J Hum Genet. 2011 Jun;19(6):672-5. PMID 21368910
• Kifagi C et al. “Association of genetic variations in TCF7L2, SLC30A8, HHEX, LOC387761, and EXT2 with Type 2 diabetes mellitus in Tunisia.” Genet Test Mol Biomarkers. 2011 Jun;15(6):399-405. PMID 21510814
• Zhai G et al. “Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms.” PLoS Genet. 2011 Apr;7(4):e1002025. PMID 21533175
• Cai Y et al. “Meta-analysis of the effect of HHEX gene polymorphism on the risk of type 2 diabetes.” Mutagenesis. 2011 Mar;26(2):309-14. PMID 21059810
• Wang Y et al. “Quantitative assessment of the influence of hematopoietically expressed homeobox variant (rs1111875) on type 2 diabetes risk.” Mol Genet Metab. 2011 Feb;102(2):194-9. PMID 21056935
• Webster RJ et al. “The longitudinal association of common susceptibility variants for type 2 diabetes and obesity with fasting glucose level and BMI.” BMC Med Genet. 2010 Oct 8;11:140. PMID 20929593

Top Pubmed articles linked to gene HHEX matching any search term:

• Iwata M et al. “Genetic risk score constructed using 14 susceptibility alleles for type 2 diabetes is associated with the early onset of diabetes and may predict the future requirement of insulin injections among Japanese individuals.” Diabetes Care. 2012 Aug;35(8):1763-70. PMID 22688542
• Rosengren AH et al. “Reduced Insulin Exocytosis in Human Pancreatic β-Cells With Gene Variants Linked to Type 2 Diabetes.” Diabetes. 2012 Jul;61(7):1726-33. PMID 22492527
• Linder K et al. “Allele summation of diabetes risk genes predicts impaired glucose tolerance in female and obese individuals.” PLoS One. 2012;7(6):e38224. PMID 22768041
• Gupta V et al. “Association of TCF7L2 and ADIPOQ with Body Mass Index, Waist-Hip Ratio, and Systolic Blood Pressure in an Endogamous Ethnic Group of India.” Genet Test Mol Biomarkers. 2012 May 14;. PMID 22583123
• Ekelund M et al. “Genetic prediction of postpartum diabetes in women with gestational diabetes mellitus.” Diabetes Res Clin Pract. 2012 May 14;. PMID 22591707
• Kurzawski M et al. “Analysis of common type 2 diabetes mellitus genetic risk factors in new-onset diabetes after transplantation in kidney transplant patients medicated with tacrolimus.” Eur J Clin Pharmacol. 2012 May 9;. PMID 22569928
• Winkler C et al. “Lack of association of type 2 diabetes susceptibility genotypes and body weight on the development of islet autoimmunity and type 1 diabetes.” PLoS One. 2012;7(4):e35410. PMID 22558147
• Qian Y et al. “Genetic variants of IDE-KIF11-HHEX at 10q23.33 associated with type 2 diabetes risk: a fine-mapping study in Chinese population.” PLoS One. 2012;7(4):e35060. PMID 22506066
• Fu LL et al. “[Association analysis of genetic polymorphisms of TCF7L2, CDKAL1, SLC30A8, HHEX genes and microvascular complications of type 2 diabetes mellitus].” Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2012 Apr;29(2):194-9. PMID 22487833
• Kim JJ et al. “Polycystic ovary syndrome is not associated with polymorphisms of the TCF7L2, CDKAL1, HHEX, KCNJ11, FTO and SLC30A8 genes.” Clin Endocrinol (Oxf). 2012 Mar 24;. PMID 22443257
• Ryoo H et al. “Heterogeneity of genetic associations of CDKAL1 and HHEX with susceptibility of type 2 diabetes mellitus by gender.” Eur J Hum Genet. 2011 Jun;19(6):672-5. PMID 21368910
• Shu XO et al. “Identification of new genetic risk variants for type 2 diabetes.” PLoS Genet. 2010 Sep 16;6(9). PMID 20862305
• Winkler C et al. “BMI at age 8 years is influenced by the type 2 diabetes susceptibility genes HHEX-IDE and CDKAL1.” Diabetes. 2010 Aug;59(8):2063-7. PMID 20460429
• Voight BF et al. “Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.” Nat Genet. 2010 Jul;42(7):579-89. PMID 20581827
• Gupta V et al. “A validation study of type 2 diabetes-related variants of the TCF7L2, HHEX, KCNJ11, and ADIPOQ genes in one endogamous ethnic group of north India.” Ann Hum Genet. 2010 Jul;74(4):361-8. PMID 20597906
• Lin Y et al. “Association study of genetic variants in eight genes/loci with type 2 diabetes in a Han Chinese population.” BMC Med Genet. 2010 Jun 15;11:97. PMID 20550665
• Wen J et al. “Investigation of type 2 diabetes risk alleles support CDKN2A/B, CDKAL1, and TCF7L2 as susceptibility genes in a Han Chinese cohort.” PLoS One. 2010 Feb 10;5(2):e9153. PMID 20161779
• Talmud PJ et al. “Utility of genetic and non-genetic risk factors in prediction of type 2 diabetes: Whitehall II prospective cohort study.” BMJ. 2010 Jan 14;340:b4838. PMID 20075150
• Tan JT et al. “Polymorphisms identified through genome-wide association studies and their associations with type 2 diabetes in Chinese, Malays, and Asian-Indians in Singapore.” J Clin Endocrinol Metab. 2010 Jan;95(1):390-7. PMID 19892838
• Brito EC et al. “Previously associated type 2 diabetes variants may interact with physical activity to modify the risk of impaired glucose regulation and type 2 diabetes: a study of 16,003 Swedish adults.” Diabetes. 2009 Jun;58(6):1411-8. PMID 19324937