Loading…
Mutation screening and association of human retinoid X receptor γ variation with lipid levels in familial type 2 diabetes
Both type 2 diabetes (T2DM) and familial combined hyperlipidemia have been mapped to human chromosome 1q21–q24. This region includes the retinoid X receptor γ (RXR γ) , which is a strong candidate for both glucose and lipid metabolism. Retinoid X receptors form heterodimers with a variety of nuclear...
Saved in:
| Published in: | Molecular genetics and metabolism 2002-05, Vol.76 (1), p.14-22 |
|---|---|
| Main Authors: | , , , , |
| Format: | Article |
| Language: | English |
| Subjects: | |
| Citations: | Items that this one cites Items that cite this one |
| Online Access: | Get full text |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| cited_by | cdi_FETCH-LOGICAL-c361t-6574b9ec3ff58ae8bb397cf94340a3503da0878f4cffcc3c6d3efde7c5ebeb523 |
|---|---|
| cites | cdi_FETCH-LOGICAL-c361t-6574b9ec3ff58ae8bb397cf94340a3503da0878f4cffcc3c6d3efde7c5ebeb523 |
| container_end_page | 22 |
| container_issue | 1 |
| container_start_page | 14 |
| container_title | Molecular genetics and metabolism |
| container_volume | 76 |
| creator | Wang, Hua Chu, Winston Hemphill, Christopher Hasstedt, Sandra J. Elbein, Steven C. |
| description | Both type 2 diabetes (T2DM) and familial combined hyperlipidemia have been mapped to human chromosome 1q21–q24. This region includes the retinoid X receptor
γ
(RXR
γ)
, which is a strong candidate for both glucose and lipid metabolism. Retinoid X receptors form heterodimers with a variety of nuclear receptors, including peroxisome-proliferator-activated receptors α and γ (
PPARα and
PPARγ), and are synergistic targets for drugs that alter glucose and lipid metabolism. We hypothesized that
RXRγ variation could explain the linkage of diabetes and lipid disorders to this region. We screened each of the 10 exons, the flanking intronic sequences, the 3
′ untranslated region, and the 5
′ flanking region. We identified 14 variants, none of which altered the coding sequence. Of the 10 variants examined in a diabetes case-control study, three showed nominal (
p |
| doi_str_mv | 10.1016/S1096-7192(02)00016-1 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_72010523</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S1096719202000161</els_id><sourcerecordid>72010523</sourcerecordid><originalsourceid>FETCH-LOGICAL-c361t-6574b9ec3ff58ae8bb397cf94340a3503da0878f4cffcc3c6d3efde7c5ebeb523</originalsourceid><addsrcrecordid>eNqFkN1qFTEQgINUetpjH8GSq6IXq8lmf85elVK0ChUvrOBdyCYTO2U32SbZI_W1fI8-kznukV4WBmaY-WYGPkJec_aOM968_8ZZ1xQt78o3rHzLWO4V_AU5Wtolaw7-1xlZkeMY7zLD6646JCte8rZu2-aI_P4yJ5XQOxp1AHDoflLlDFUxeo3LxFt6O4_K0QAJnUdDf-RSw5R8oI9_6FaFPfkL0y0dcMrIAFsYIkVHrRpxQDXQ9DABLalB1UOC-Iq8tGqIcLLPa_L944eby0_F9derz5cX14UWDU9FU7dV34EW1tYbBZu-F12rbVeJiilRM2EU27QbW2lrtRa6MQKsgVbX0ENfl2JNzpa7U_D3M8QkR4wahkE58HOUWRZnmctgvYA6-BgDWDkFHFV4kJzJnXT5T7rcGZUsx0665HnvdP9g7kcwT1t7yxk4X4BsBLYIQUaN4DQYzB6TNB6fefEXmNyU3g</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>72010523</pqid></control><display><type>article</type><title>Mutation screening and association of human retinoid X receptor γ variation with lipid levels in familial type 2 diabetes</title><source>Elsevier</source><creator>Wang, Hua ; Chu, Winston ; Hemphill, Christopher ; Hasstedt, Sandra J. ; Elbein, Steven C.</creator><creatorcontrib>Wang, Hua ; Chu, Winston ; Hemphill, Christopher ; Hasstedt, Sandra J. ; Elbein, Steven C.</creatorcontrib><description>Both type 2 diabetes (T2DM) and familial combined hyperlipidemia have been mapped to human chromosome 1q21–q24. This region includes the retinoid X receptor
γ
(RXR
γ)
, which is a strong candidate for both glucose and lipid metabolism. Retinoid X receptors form heterodimers with a variety of nuclear receptors, including peroxisome-proliferator-activated receptors α and γ (
PPARα and
PPARγ), and are synergistic targets for drugs that alter glucose and lipid metabolism. We hypothesized that
RXRγ variation could explain the linkage of diabetes and lipid disorders to this region. We screened each of the 10 exons, the flanking intronic sequences, the 3
′ untranslated region, and the 5
′ flanking region. We identified 14 variants, none of which altered the coding sequence. Of the 10 variants examined in a diabetes case-control study, three showed nominal (
p<0.05) associations with T2DM. We subsequently typed four variants in all members of the 63 multiplex families used in our previous linkage analysis. No individual variant showed excess transmission to offspring with T2DM using a transmission disequilibrium test and only a single rare haplotype showed evidence of an association with T2DM. Likewise, neither individual variants nor haplotypes were associated with either fasting or post-challenge glucose in non-diabetic subjects. In contrast, three of the four variants were associated with fasting free fatty acid (FFA) levels (
p=0.024–0.00044) and two variants were associated with triglyceride levels (
p<0.05). These findings were supported by the association of several haplotypes with FFA and triglyceride levels.
RXRγ haplotypes were also associated with several measures of pancreatic β-cell function, consistent with the proposed role of lipid metabolism in insulin secretion. These data suggest that
RXRγ may contribute to disordered lipid metabolism in members of familial T2DM kindreds, but this gene is unlikely to explain the linkage of T2DM with this region.</description><identifier>ISSN: 1096-7192</identifier><identifier>EISSN: 1096-7206</identifier><identifier>DOI: 10.1016/S1096-7192(02)00016-1</identifier><identifier>PMID: 12175776</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Blood Glucose - metabolism ; Cholesterol, HDL - blood ; Diabetes Mellitus, Type 2 - blood ; Diabetes Mellitus, Type 2 - genetics ; Fatty Acids, Nonesterified - blood ; Free fatty acids ; Glucose tolerance ; Haplotypes ; Humans ; Insulin - blood ; Linkage Disequilibrium ; Lipid metabolism ; Mutation ; Polymorphism ; Polymorphism, Single Nucleotide ; Receptors, Retinoic Acid - genetics ; Retinoid X receptor ; Retinoid X Receptors ; Sequence Analysis, DNA ; Transcription Factors - genetics ; Triglycerides ; Triglycerides - blood ; Type 2 diabetes</subject><ispartof>Molecular genetics and metabolism, 2002-05, Vol.76 (1), p.14-22</ispartof><rights>2002 Elsevier Science (USA)</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c361t-6574b9ec3ff58ae8bb397cf94340a3503da0878f4cffcc3c6d3efde7c5ebeb523</citedby><cites>FETCH-LOGICAL-c361t-6574b9ec3ff58ae8bb397cf94340a3503da0878f4cffcc3c6d3efde7c5ebeb523</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12175776$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Hua</creatorcontrib><creatorcontrib>Chu, Winston</creatorcontrib><creatorcontrib>Hemphill, Christopher</creatorcontrib><creatorcontrib>Hasstedt, Sandra J.</creatorcontrib><creatorcontrib>Elbein, Steven C.</creatorcontrib><title>Mutation screening and association of human retinoid X receptor γ variation with lipid levels in familial type 2 diabetes</title><title>Molecular genetics and metabolism</title><addtitle>Mol Genet Metab</addtitle><description>Both type 2 diabetes (T2DM) and familial combined hyperlipidemia have been mapped to human chromosome 1q21–q24. This region includes the retinoid X receptor
γ
(RXR
γ)
, which is a strong candidate for both glucose and lipid metabolism. Retinoid X receptors form heterodimers with a variety of nuclear receptors, including peroxisome-proliferator-activated receptors α and γ (
PPARα and
PPARγ), and are synergistic targets for drugs that alter glucose and lipid metabolism. We hypothesized that
RXRγ variation could explain the linkage of diabetes and lipid disorders to this region. We screened each of the 10 exons, the flanking intronic sequences, the 3
′ untranslated region, and the 5
′ flanking region. We identified 14 variants, none of which altered the coding sequence. Of the 10 variants examined in a diabetes case-control study, three showed nominal (
p<0.05) associations with T2DM. We subsequently typed four variants in all members of the 63 multiplex families used in our previous linkage analysis. No individual variant showed excess transmission to offspring with T2DM using a transmission disequilibrium test and only a single rare haplotype showed evidence of an association with T2DM. Likewise, neither individual variants nor haplotypes were associated with either fasting or post-challenge glucose in non-diabetic subjects. In contrast, three of the four variants were associated with fasting free fatty acid (FFA) levels (
p=0.024–0.00044) and two variants were associated with triglyceride levels (
p<0.05). These findings were supported by the association of several haplotypes with FFA and triglyceride levels.
RXRγ haplotypes were also associated with several measures of pancreatic β-cell function, consistent with the proposed role of lipid metabolism in insulin secretion. These data suggest that
RXRγ may contribute to disordered lipid metabolism in members of familial T2DM kindreds, but this gene is unlikely to explain the linkage of T2DM with this region.</description><subject>Blood Glucose - metabolism</subject><subject>Cholesterol, HDL - blood</subject><subject>Diabetes Mellitus, Type 2 - blood</subject><subject>Diabetes Mellitus, Type 2 - genetics</subject><subject>Fatty Acids, Nonesterified - blood</subject><subject>Free fatty acids</subject><subject>Glucose tolerance</subject><subject>Haplotypes</subject><subject>Humans</subject><subject>Insulin - blood</subject><subject>Linkage Disequilibrium</subject><subject>Lipid metabolism</subject><subject>Mutation</subject><subject>Polymorphism</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Receptors, Retinoic Acid - genetics</subject><subject>Retinoid X receptor</subject><subject>Retinoid X Receptors</subject><subject>Sequence Analysis, DNA</subject><subject>Transcription Factors - genetics</subject><subject>Triglycerides</subject><subject>Triglycerides - blood</subject><subject>Type 2 diabetes</subject><issn>1096-7192</issn><issn>1096-7206</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><recordid>eNqFkN1qFTEQgINUetpjH8GSq6IXq8lmf85elVK0ChUvrOBdyCYTO2U32SbZI_W1fI8-kznukV4WBmaY-WYGPkJec_aOM968_8ZZ1xQt78o3rHzLWO4V_AU5Wtolaw7-1xlZkeMY7zLD6646JCte8rZu2-aI_P4yJ5XQOxp1AHDoflLlDFUxeo3LxFt6O4_K0QAJnUdDf-RSw5R8oI9_6FaFPfkL0y0dcMrIAFsYIkVHrRpxQDXQ9DABLalB1UOC-Iq8tGqIcLLPa_L944eby0_F9derz5cX14UWDU9FU7dV34EW1tYbBZu-F12rbVeJiilRM2EU27QbW2lrtRa6MQKsgVbX0ENfl2JNzpa7U_D3M8QkR4wahkE58HOUWRZnmctgvYA6-BgDWDkFHFV4kJzJnXT5T7rcGZUsx0665HnvdP9g7kcwT1t7yxk4X4BsBLYIQUaN4DQYzB6TNB6fefEXmNyU3g</recordid><startdate>20020501</startdate><enddate>20020501</enddate><creator>Wang, Hua</creator><creator>Chu, Winston</creator><creator>Hemphill, Christopher</creator><creator>Hasstedt, Sandra J.</creator><creator>Elbein, Steven C.</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20020501</creationdate><title>Mutation screening and association of human retinoid X receptor γ variation with lipid levels in familial type 2 diabetes</title><author>Wang, Hua ; Chu, Winston ; Hemphill, Christopher ; Hasstedt, Sandra J. ; Elbein, Steven C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c361t-6574b9ec3ff58ae8bb397cf94340a3503da0878f4cffcc3c6d3efde7c5ebeb523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Blood Glucose - metabolism</topic><topic>Cholesterol, HDL - blood</topic><topic>Diabetes Mellitus, Type 2 - blood</topic><topic>Diabetes Mellitus, Type 2 - genetics</topic><topic>Fatty Acids, Nonesterified - blood</topic><topic>Free fatty acids</topic><topic>Glucose tolerance</topic><topic>Haplotypes</topic><topic>Humans</topic><topic>Insulin - blood</topic><topic>Linkage Disequilibrium</topic><topic>Lipid metabolism</topic><topic>Mutation</topic><topic>Polymorphism</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Receptors, Retinoic Acid - genetics</topic><topic>Retinoid X receptor</topic><topic>Retinoid X Receptors</topic><topic>Sequence Analysis, DNA</topic><topic>Transcription Factors - genetics</topic><topic>Triglycerides</topic><topic>Triglycerides - blood</topic><topic>Type 2 diabetes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Hua</creatorcontrib><creatorcontrib>Chu, Winston</creatorcontrib><creatorcontrib>Hemphill, Christopher</creatorcontrib><creatorcontrib>Hasstedt, Sandra J.</creatorcontrib><creatorcontrib>Elbein, Steven C.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular genetics and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Hua</au><au>Chu, Winston</au><au>Hemphill, Christopher</au><au>Hasstedt, Sandra J.</au><au>Elbein, Steven C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mutation screening and association of human retinoid X receptor γ variation with lipid levels in familial type 2 diabetes</atitle><jtitle>Molecular genetics and metabolism</jtitle><addtitle>Mol Genet Metab</addtitle><date>2002-05-01</date><risdate>2002</risdate><volume>76</volume><issue>1</issue><spage>14</spage><epage>22</epage><pages>14-22</pages><issn>1096-7192</issn><eissn>1096-7206</eissn><abstract>Both type 2 diabetes (T2DM) and familial combined hyperlipidemia have been mapped to human chromosome 1q21–q24. This region includes the retinoid X receptor
γ
(RXR
γ)
, which is a strong candidate for both glucose and lipid metabolism. Retinoid X receptors form heterodimers with a variety of nuclear receptors, including peroxisome-proliferator-activated receptors α and γ (
PPARα and
PPARγ), and are synergistic targets for drugs that alter glucose and lipid metabolism. We hypothesized that
RXRγ variation could explain the linkage of diabetes and lipid disorders to this region. We screened each of the 10 exons, the flanking intronic sequences, the 3
′ untranslated region, and the 5
′ flanking region. We identified 14 variants, none of which altered the coding sequence. Of the 10 variants examined in a diabetes case-control study, three showed nominal (
p<0.05) associations with T2DM. We subsequently typed four variants in all members of the 63 multiplex families used in our previous linkage analysis. No individual variant showed excess transmission to offspring with T2DM using a transmission disequilibrium test and only a single rare haplotype showed evidence of an association with T2DM. Likewise, neither individual variants nor haplotypes were associated with either fasting or post-challenge glucose in non-diabetic subjects. In contrast, three of the four variants were associated with fasting free fatty acid (FFA) levels (
p=0.024–0.00044) and two variants were associated with triglyceride levels (
p<0.05). These findings were supported by the association of several haplotypes with FFA and triglyceride levels.
RXRγ haplotypes were also associated with several measures of pancreatic β-cell function, consistent with the proposed role of lipid metabolism in insulin secretion. These data suggest that
RXRγ may contribute to disordered lipid metabolism in members of familial T2DM kindreds, but this gene is unlikely to explain the linkage of T2DM with this region.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>12175776</pmid><doi>10.1016/S1096-7192(02)00016-1</doi><tpages>9</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1096-7192 |
| ispartof | Molecular genetics and metabolism, 2002-05, Vol.76 (1), p.14-22 |
| issn | 1096-7192 1096-7206 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_72010523 |
| source | Elsevier |
| subjects | Blood Glucose - metabolism Cholesterol, HDL - blood Diabetes Mellitus, Type 2 - blood Diabetes Mellitus, Type 2 - genetics Fatty Acids, Nonesterified - blood Free fatty acids Glucose tolerance Haplotypes Humans Insulin - blood Linkage Disequilibrium Lipid metabolism Mutation Polymorphism Polymorphism, Single Nucleotide Receptors, Retinoic Acid - genetics Retinoid X receptor Retinoid X Receptors Sequence Analysis, DNA Transcription Factors - genetics Triglycerides Triglycerides - blood Type 2 diabetes |
| title | Mutation screening and association of human retinoid X receptor γ variation with lipid levels in familial type 2 diabetes |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-08T12%3A48%3A37IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Mutation%20screening%20and%20association%20of%20human%20retinoid%20X%20receptor%20%CE%B3%20variation%20with%20lipid%20levels%20in%20familial%20type%202%20diabetes&rft.jtitle=Molecular%20genetics%20and%20metabolism&rft.au=Wang,%20Hua&rft.date=2002-05-01&rft.volume=76&rft.issue=1&rft.spage=14&rft.epage=22&rft.pages=14-22&rft.issn=1096-7192&rft.eissn=1096-7206&rft_id=info:doi/10.1016/S1096-7192(02)00016-1&rft_dat=%3Cproquest_cross%3E72010523%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c361t-6574b9ec3ff58ae8bb397cf94340a3503da0878f4cffcc3c6d3efde7c5ebeb523%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=72010523&rft_id=info:pmid/12175776&rfr_iscdi=true |