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5-Lipoxygenase (ALOX5): Genetic susceptibility to type 2 diabetes and vitamin D effects on monocytes
•ALOX5 rs4987105 polymorphism is associated with T2D.•ALOX5 CC risk genotype is linked to lower vitamin D and increased CRP levels.•IL-1β + calcitriol treatment increased ALOX5, LTA4H and LTB4R1 mRNA expression.•ALOX5 andLTA4H mRNA expression were increased in T2D patients compared to HC. The arachi...
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| Published in: | The Journal of steroid biochemistry and molecular biology 2019-03, Vol.187, p.52-57 |
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| creator | Nejatian, Nojan Häfner, Ann-Kathrin Shoghi, Firouzeh Badenhoop, Klaus Penna-Martinez, Marissa |
| description | •ALOX5 rs4987105 polymorphism is associated with T2D.•ALOX5 CC risk genotype is linked to lower vitamin D and increased CRP levels.•IL-1β + calcitriol treatment increased ALOX5, LTA4H and LTB4R1 mRNA expression.•ALOX5 andLTA4H mRNA expression were increased in T2D patients compared to HC.
The arachidonate 5-lipoxygenase (ALOX5) pathway has been implicated in chronic inflammatory disease which may be influenced by vitamin D due to vitamin D response elements (VDRE). We investigated an ALOX5 polymorphism (rs4987105) in patients with type 2 diabetes (T2D) and the in vitro effects of calcitriol (1,25(OH)2D3) on ALOX5 metabolism in monocytes of T2D patients and healthy controls (HC). 533 T2D and 473 HC were genotyped for the rs4987105 polymorphism. In addition, the 25(OH)D3 and 1,25(OH)2D3 plasma levels were measured in both cohorts. Further C-reactive protein (CRP) was determined in T2D patients. Our results demonstrate, that genotype CC and the allele C of ALOX5 rs4987105 polymorphism were more frequent in T2D compared to HC (OR = 1.44; 95% CI: 1.12–1.84; p |
| doi_str_mv | 10.1016/j.jsbmb.2018.10.022 |
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The arachidonate 5-lipoxygenase (ALOX5) pathway has been implicated in chronic inflammatory disease which may be influenced by vitamin D due to vitamin D response elements (VDRE). We investigated an ALOX5 polymorphism (rs4987105) in patients with type 2 diabetes (T2D) and the in vitro effects of calcitriol (1,25(OH)2D3) on ALOX5 metabolism in monocytes of T2D patients and healthy controls (HC). 533 T2D and 473 HC were genotyped for the rs4987105 polymorphism. In addition, the 25(OH)D3 and 1,25(OH)2D3 plasma levels were measured in both cohorts. Further C-reactive protein (CRP) was determined in T2D patients. Our results demonstrate, that genotype CC and the allele C of ALOX5 rs4987105 polymorphism were more frequent in T2D compared to HC (OR = 1.44; 95% CI: 1.12–1.84; p < 0.05). Lower levels of both vitamin D metabolites (p < 0.0001 respectively) were found in the CC genotyped T2D patients compared to CC genotyped HC. In addition, CC genotyped T2D patients had higher levels of CRP compared to CT and TT genotyped T2D patients, (p < 0.01). In order to evaluate the impact of calcitriol in primary isolated monocytes, we isolated monocytes of 20 T2D patients and 20 HC. The cells were treated with 1,25(OH)2D3 and interleukin-1beta (IL-1β) for 24 h. The following genes were analysed for expression changes: ALOX5, leukotriene A4 hydrolase (LTA4H), leukotriene B4 receptor type 1 (LTB4R1) and CD14. Treatment with IL-1β+1,25(OH)2D3 increased ALOX5, LTA4H and LTB4R1 and CD14 mRNA in both T2D patients and HC (p < 0.0001, respectively). In addition, IL-1β+1,25(OH)2D3 treatment led to higher ALOX5, LTA4H and CD14 mRNA levels in T2D patients compared to HC (p < 0.001, p < 0.05, p ≤ 0.05, respectively). In conclusion, ALOX5 rs4987105 allele C confers susceptibility to T2D, lower vitamin D metabolites and higher CRP levels complement this association. Additionally, IL-1β+1,25(OH)2D3 treatment on, ALOX5, LTA4H and CD14 mRNA indicate a diabetes specific modulation. These findings identify a novel pathway in T2D potentially amenable for individualized therapeutic targeting.]]></description><identifier>ISSN: 0960-0760</identifier><identifier>EISSN: 1879-1220</identifier><identifier>DOI: 10.1016/j.jsbmb.2018.10.022</identifier><identifier>PMID: 30521849</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>1α,25-Dihydroxy vitamin D3 ; 25-Hydroxyvitamin D ; Alleles ; Arachidonate 5-lipoxygenase ; C-reactive protein ; Calcitriol ; CD14 antigen ; Diabetes ; Diabetes mellitus ; Diabetes mellitus (non-insulin dependent) ; Gene polymorphism ; Hydrolase ; IL-1β ; Inflammatory diseases ; Leukotriene A4 hydrolase ; Leukotriene B4 receptor type 1 ; Leukotriene B4 receptors ; Lipoxygenase ; Metabolites ; Monocytes ; mRNA ; Patients ; Plasma levels ; Polymorphism ; Regulatory sequences ; Therapeutic targets ; Type 2 diabetes mellitus ; Vitamin D</subject><ispartof>The Journal of steroid biochemistry and molecular biology, 2019-03, Vol.187, p.52-57</ispartof><rights>2018 Elsevier Ltd</rights><rights>Copyright © 2018 Elsevier Ltd. All rights reserved.</rights><rights>Copyright Elsevier BV Mar 2019</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c387t-a3bcbffd7585c16bdb5717d0cae9ac6a9ce1c53b29afcd0a92a7802c645606463</citedby><cites>FETCH-LOGICAL-c387t-a3bcbffd7585c16bdb5717d0cae9ac6a9ce1c53b29afcd0a92a7802c645606463</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30521849$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nejatian, Nojan</creatorcontrib><creatorcontrib>Häfner, Ann-Kathrin</creatorcontrib><creatorcontrib>Shoghi, Firouzeh</creatorcontrib><creatorcontrib>Badenhoop, Klaus</creatorcontrib><creatorcontrib>Penna-Martinez, Marissa</creatorcontrib><title>5-Lipoxygenase (ALOX5): Genetic susceptibility to type 2 diabetes and vitamin D effects on monocytes</title><title>The Journal of steroid biochemistry and molecular biology</title><addtitle>J Steroid Biochem Mol Biol</addtitle><description><![CDATA[•ALOX5 rs4987105 polymorphism is associated with T2D.•ALOX5 CC risk genotype is linked to lower vitamin D and increased CRP levels.•IL-1β + calcitriol treatment increased ALOX5, LTA4H and LTB4R1 mRNA expression.•ALOX5 andLTA4H mRNA expression were increased in T2D patients compared to HC.
The arachidonate 5-lipoxygenase (ALOX5) pathway has been implicated in chronic inflammatory disease which may be influenced by vitamin D due to vitamin D response elements (VDRE). We investigated an ALOX5 polymorphism (rs4987105) in patients with type 2 diabetes (T2D) and the in vitro effects of calcitriol (1,25(OH)2D3) on ALOX5 metabolism in monocytes of T2D patients and healthy controls (HC). 533 T2D and 473 HC were genotyped for the rs4987105 polymorphism. In addition, the 25(OH)D3 and 1,25(OH)2D3 plasma levels were measured in both cohorts. Further C-reactive protein (CRP) was determined in T2D patients. Our results demonstrate, that genotype CC and the allele C of ALOX5 rs4987105 polymorphism were more frequent in T2D compared to HC (OR = 1.44; 95% CI: 1.12–1.84; p < 0.05). Lower levels of both vitamin D metabolites (p < 0.0001 respectively) were found in the CC genotyped T2D patients compared to CC genotyped HC. In addition, CC genotyped T2D patients had higher levels of CRP compared to CT and TT genotyped T2D patients, (p < 0.01). In order to evaluate the impact of calcitriol in primary isolated monocytes, we isolated monocytes of 20 T2D patients and 20 HC. The cells were treated with 1,25(OH)2D3 and interleukin-1beta (IL-1β) for 24 h. The following genes were analysed for expression changes: ALOX5, leukotriene A4 hydrolase (LTA4H), leukotriene B4 receptor type 1 (LTB4R1) and CD14. Treatment with IL-1β+1,25(OH)2D3 increased ALOX5, LTA4H and LTB4R1 and CD14 mRNA in both T2D patients and HC (p < 0.0001, respectively). In addition, IL-1β+1,25(OH)2D3 treatment led to higher ALOX5, LTA4H and CD14 mRNA levels in T2D patients compared to HC (p < 0.001, p < 0.05, p ≤ 0.05, respectively). In conclusion, ALOX5 rs4987105 allele C confers susceptibility to T2D, lower vitamin D metabolites and higher CRP levels complement this association. Additionally, IL-1β+1,25(OH)2D3 treatment on, ALOX5, LTA4H and CD14 mRNA indicate a diabetes specific modulation. These findings identify a novel pathway in T2D potentially amenable for individualized therapeutic targeting.]]></description><subject>1α,25-Dihydroxy vitamin D3</subject><subject>25-Hydroxyvitamin D</subject><subject>Alleles</subject><subject>Arachidonate 5-lipoxygenase</subject><subject>C-reactive protein</subject><subject>Calcitriol</subject><subject>CD14 antigen</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Gene polymorphism</subject><subject>Hydrolase</subject><subject>IL-1β</subject><subject>Inflammatory diseases</subject><subject>Leukotriene A4 hydrolase</subject><subject>Leukotriene B4 receptor type 1</subject><subject>Leukotriene B4 receptors</subject><subject>Lipoxygenase</subject><subject>Metabolites</subject><subject>Monocytes</subject><subject>mRNA</subject><subject>Patients</subject><subject>Plasma levels</subject><subject>Polymorphism</subject><subject>Regulatory sequences</subject><subject>Therapeutic targets</subject><subject>Type 2 diabetes mellitus</subject><subject>Vitamin D</subject><issn>0960-0760</issn><issn>1879-1220</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNp9kc1rFTEUxYNY7Gv1LxAk4KYu5vUmmcyH0EWptS086EbBXcjHHcnwZjJOMsX5783zVRcuXF04_O69h3MIectgy4BVl_22j2YwWw6sycoWOH9BNqyp24JxDi_JBtoKCqgrOCVnMfYAIASrX5FTAZKzpmw3xMli56fwc_2Oo45IL653j9_kh4_0DkdM3tK4RItT8sbvfVppCjStE1JOndcGE0aqR0effNKDH-knil2HNkUaRjqEMdg1I6_JSaf3Ed88z3Py9fPtl5v7Yvd493BzvSusaOpUaGGs6TpXy0ZaVhlnZM1qB1Zjq22lW4vMSmF4qzvrQLdc1w1wW5WygqqsxDm5ON6d5vBjwZjU4LP7_V6PGJaoOJMNL6EVkNH3_6B9WOYxu8tUy0TJa9ZkShwpO4cYZ-zUNPtBz6tioA4lqF79LkEdSjiIuYS89e759mIGdH93_qSegasjgDmMJ4-zitbjaNH5OYenXPD_ffALA5CYPA</recordid><startdate>20190301</startdate><enddate>20190301</enddate><creator>Nejatian, Nojan</creator><creator>Häfner, Ann-Kathrin</creator><creator>Shoghi, Firouzeh</creator><creator>Badenhoop, Klaus</creator><creator>Penna-Martinez, Marissa</creator><general>Elsevier Ltd</general><general>Elsevier BV</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20190301</creationdate><title>5-Lipoxygenase (ALOX5): Genetic susceptibility to type 2 diabetes and vitamin D effects on monocytes</title><author>Nejatian, Nojan ; Häfner, Ann-Kathrin ; Shoghi, Firouzeh ; Badenhoop, Klaus ; Penna-Martinez, Marissa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c387t-a3bcbffd7585c16bdb5717d0cae9ac6a9ce1c53b29afcd0a92a7802c645606463</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>1α,25-Dihydroxy vitamin D3</topic><topic>25-Hydroxyvitamin D</topic><topic>Alleles</topic><topic>Arachidonate 5-lipoxygenase</topic><topic>C-reactive protein</topic><topic>Calcitriol</topic><topic>CD14 antigen</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes mellitus (non-insulin dependent)</topic><topic>Gene polymorphism</topic><topic>Hydrolase</topic><topic>IL-1β</topic><topic>Inflammatory diseases</topic><topic>Leukotriene A4 hydrolase</topic><topic>Leukotriene B4 receptor type 1</topic><topic>Leukotriene B4 receptors</topic><topic>Lipoxygenase</topic><topic>Metabolites</topic><topic>Monocytes</topic><topic>mRNA</topic><topic>Patients</topic><topic>Plasma levels</topic><topic>Polymorphism</topic><topic>Regulatory sequences</topic><topic>Therapeutic targets</topic><topic>Type 2 diabetes mellitus</topic><topic>Vitamin D</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nejatian, Nojan</creatorcontrib><creatorcontrib>Häfner, Ann-Kathrin</creatorcontrib><creatorcontrib>Shoghi, Firouzeh</creatorcontrib><creatorcontrib>Badenhoop, Klaus</creatorcontrib><creatorcontrib>Penna-Martinez, Marissa</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of steroid biochemistry and molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nejatian, Nojan</au><au>Häfner, Ann-Kathrin</au><au>Shoghi, Firouzeh</au><au>Badenhoop, Klaus</au><au>Penna-Martinez, Marissa</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>5-Lipoxygenase (ALOX5): Genetic susceptibility to type 2 diabetes and vitamin D effects on monocytes</atitle><jtitle>The Journal of steroid biochemistry and molecular biology</jtitle><addtitle>J Steroid Biochem Mol Biol</addtitle><date>2019-03-01</date><risdate>2019</risdate><volume>187</volume><spage>52</spage><epage>57</epage><pages>52-57</pages><issn>0960-0760</issn><eissn>1879-1220</eissn><abstract><![CDATA[•ALOX5 rs4987105 polymorphism is associated with T2D.•ALOX5 CC risk genotype is linked to lower vitamin D and increased CRP levels.•IL-1β + calcitriol treatment increased ALOX5, LTA4H and LTB4R1 mRNA expression.•ALOX5 andLTA4H mRNA expression were increased in T2D patients compared to HC.
The arachidonate 5-lipoxygenase (ALOX5) pathway has been implicated in chronic inflammatory disease which may be influenced by vitamin D due to vitamin D response elements (VDRE). We investigated an ALOX5 polymorphism (rs4987105) in patients with type 2 diabetes (T2D) and the in vitro effects of calcitriol (1,25(OH)2D3) on ALOX5 metabolism in monocytes of T2D patients and healthy controls (HC). 533 T2D and 473 HC were genotyped for the rs4987105 polymorphism. In addition, the 25(OH)D3 and 1,25(OH)2D3 plasma levels were measured in both cohorts. Further C-reactive protein (CRP) was determined in T2D patients. Our results demonstrate, that genotype CC and the allele C of ALOX5 rs4987105 polymorphism were more frequent in T2D compared to HC (OR = 1.44; 95% CI: 1.12–1.84; p < 0.05). Lower levels of both vitamin D metabolites (p < 0.0001 respectively) were found in the CC genotyped T2D patients compared to CC genotyped HC. In addition, CC genotyped T2D patients had higher levels of CRP compared to CT and TT genotyped T2D patients, (p < 0.01). In order to evaluate the impact of calcitriol in primary isolated monocytes, we isolated monocytes of 20 T2D patients and 20 HC. The cells were treated with 1,25(OH)2D3 and interleukin-1beta (IL-1β) for 24 h. The following genes were analysed for expression changes: ALOX5, leukotriene A4 hydrolase (LTA4H), leukotriene B4 receptor type 1 (LTB4R1) and CD14. Treatment with IL-1β+1,25(OH)2D3 increased ALOX5, LTA4H and LTB4R1 and CD14 mRNA in both T2D patients and HC (p < 0.0001, respectively). In addition, IL-1β+1,25(OH)2D3 treatment led to higher ALOX5, LTA4H and CD14 mRNA levels in T2D patients compared to HC (p < 0.001, p < 0.05, p ≤ 0.05, respectively). In conclusion, ALOX5 rs4987105 allele C confers susceptibility to T2D, lower vitamin D metabolites and higher CRP levels complement this association. Additionally, IL-1β+1,25(OH)2D3 treatment on, ALOX5, LTA4H and CD14 mRNA indicate a diabetes specific modulation. These findings identify a novel pathway in T2D potentially amenable for individualized therapeutic targeting.]]></abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>30521849</pmid><doi>10.1016/j.jsbmb.2018.10.022</doi><tpages>6</tpages></addata></record> |
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| subjects | 1α,25-Dihydroxy vitamin D3 25-Hydroxyvitamin D Alleles Arachidonate 5-lipoxygenase C-reactive protein Calcitriol CD14 antigen Diabetes Diabetes mellitus Diabetes mellitus (non-insulin dependent) Gene polymorphism Hydrolase IL-1β Inflammatory diseases Leukotriene A4 hydrolase Leukotriene B4 receptor type 1 Leukotriene B4 receptors Lipoxygenase Metabolites Monocytes mRNA Patients Plasma levels Polymorphism Regulatory sequences Therapeutic targets Type 2 diabetes mellitus Vitamin D |
| title | 5-Lipoxygenase (ALOX5): Genetic susceptibility to type 2 diabetes and vitamin D effects on monocytes |
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