Serum bilirubin concentration is modified by UGT1A1 haplotypes and influences risk of type-2 diabetes in the Norfolk Island genetic isolate
Located in the Pacific Ocean between Australia and New Zealand, the unique population isolate of Norfolk Island has been shown to exhibit increased prevalence of metabolic disorders (type-2 diabetes, cardiovascular disease) compared to mainland Australia. We investigated this well-established geneti...
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| Veröffentlicht in: | BMC genetics 2015-12, Vol.16 (1), p.136-136, Article 136 |
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| description | Located in the Pacific Ocean between Australia and New Zealand, the unique population isolate of Norfolk Island has been shown to exhibit increased prevalence of metabolic disorders (type-2 diabetes, cardiovascular disease) compared to mainland Australia. We investigated this well-established genetic isolate, utilising its unique genomic structure to increase the ability to detect related genetic markers. A pedigree-based genome-wide association study of 16 routinely collected blood-based clinical traits in 382 Norfolk Island individuals was performed.
A striking association peak was located at chromosome 2q37.1 for both total bilirubin and direct bilirubin, with 29 SNPs reaching statistical significance (P |
| doi_str_mv | 10.1186/s12863-015-0291-z |
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A striking association peak was located at chromosome 2q37.1 for both total bilirubin and direct bilirubin, with 29 SNPs reaching statistical significance (P < 1.84 × 10(-7)). Strong linkage disequilibrium was observed across a 200 kb region spanning the UDP-glucuronosyltransferase family, including UGT1A1, an enzyme known to metabolise bilirubin. Given the epidemiological literature suggesting negative association between CVD-risk and serum bilirubin we further explored potential associations using stepwise multivariate regression, revealing significant association between direct bilirubin concentration and type-2 diabetes risk. In the Norfolk Island cohort increased direct bilirubin was associated with a 28% reduction in type-2 diabetes risk (OR: 0.72, 95% CI: 0.57-0.91, P = 0.005). When adjusted for genotypic effects the overall model was validated, with the adjusted model predicting a 30% reduction in type-2 diabetes risk with increasing direct bilirubin concentrations (OR: 0.70, 95% CI: 0.53-0.89, P = 0.0001).
In summary, a pedigree-based GWAS of blood-based clinical traits in the Norfolk Island population has identified variants within the UDPGT family directly associated with serum bilirubin levels, which is in turn implicated with reduced risk of developing type-2 diabetes within this population.</description><identifier>ISSN: 1471-2156</identifier><identifier>EISSN: 1471-2156</identifier><identifier>DOI: 10.1186/s12863-015-0291-z</identifier><identifier>PMID: 26628212</identifier><language>eng</language><publisher>England: BioMed Central Ltd</publisher><subject>Alleles ; Base Sequence ; Bilirubin - blood ; Cardiovascular disease ; Cardiovascular diseases ; Cardiovascular Diseases - complications ; Cardiovascular Diseases - genetics ; Chromosomes ; Chromosomes, Human, Pair 2 - genetics ; Comparative analysis ; Development and progression ; Diabetes ; Diabetes Mellitus, Type 2 - blood ; Diabetes Mellitus, Type 2 - enzymology ; Diabetes Mellitus, Type 2 - genetics ; Enzymes ; Epidemiology ; Genes, Recessive ; Genetic aspects ; Genetic markers ; Genetic Predisposition to Disease ; Genetic research ; Genome-Wide Association Study ; Genomes ; Genomics ; Glucuronosyltransferase - genetics ; Haplotypes - genetics ; Humans ; Inheritance Patterns - genetics ; Linkage Disequilibrium ; Medical research ; Medicine, Experimental ; Melanesia ; Metabolic Syndrome - complications ; Metabolic Syndrome - genetics ; Metabolism ; Molecular Sequence Annotation ; Molecular Sequence Data ; Polymorphism, Single Nucleotide - genetics ; Risk Factors ; Type 2 diabetes</subject><ispartof>BMC genetics, 2015-12, Vol.16 (1), p.136-136, Article 136</ispartof><rights>COPYRIGHT 2015 BioMed Central Ltd.</rights><rights>Copyright BioMed Central 2015</rights><rights>Benton et al. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c562t-c9d02cd2dcd720027a065ff3d395c9be6b2d8394875e2bc82319cdd5fbf7f8393</citedby><cites>FETCH-LOGICAL-c562t-c9d02cd2dcd720027a065ff3d395c9be6b2d8394875e2bc82319cdd5fbf7f8393</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667444/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667444/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27922,27923,53789,53791</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26628212$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Benton, M C</creatorcontrib><creatorcontrib>Lea, R A</creatorcontrib><creatorcontrib>Macartney-Coxson, D</creatorcontrib><creatorcontrib>Bellis, C</creatorcontrib><creatorcontrib>Carless, M A</creatorcontrib><creatorcontrib>Curran, J E</creatorcontrib><creatorcontrib>Hanna, M</creatorcontrib><creatorcontrib>Eccles, D</creatorcontrib><creatorcontrib>Chambers, G K</creatorcontrib><creatorcontrib>Blangero, J</creatorcontrib><creatorcontrib>Griffiths, L R</creatorcontrib><title>Serum bilirubin concentration is modified by UGT1A1 haplotypes and influences risk of type-2 diabetes in the Norfolk Island genetic isolate</title><title>BMC genetics</title><addtitle>BMC Genet</addtitle><description>Located in the Pacific Ocean between Australia and New Zealand, the unique population isolate of Norfolk Island has been shown to exhibit increased prevalence of metabolic disorders (type-2 diabetes, cardiovascular disease) compared to mainland Australia. We investigated this well-established genetic isolate, utilising its unique genomic structure to increase the ability to detect related genetic markers. A pedigree-based genome-wide association study of 16 routinely collected blood-based clinical traits in 382 Norfolk Island individuals was performed.
A striking association peak was located at chromosome 2q37.1 for both total bilirubin and direct bilirubin, with 29 SNPs reaching statistical significance (P < 1.84 × 10(-7)). Strong linkage disequilibrium was observed across a 200 kb region spanning the UDP-glucuronosyltransferase family, including UGT1A1, an enzyme known to metabolise bilirubin. Given the epidemiological literature suggesting negative association between CVD-risk and serum bilirubin we further explored potential associations using stepwise multivariate regression, revealing significant association between direct bilirubin concentration and type-2 diabetes risk. In the Norfolk Island cohort increased direct bilirubin was associated with a 28% reduction in type-2 diabetes risk (OR: 0.72, 95% CI: 0.57-0.91, P = 0.005). When adjusted for genotypic effects the overall model was validated, with the adjusted model predicting a 30% reduction in type-2 diabetes risk with increasing direct bilirubin concentrations (OR: 0.70, 95% CI: 0.53-0.89, P = 0.0001).
In summary, a pedigree-based GWAS of blood-based clinical traits in the Norfolk Island population has identified variants within the UDPGT family directly associated with serum bilirubin levels, which is in turn implicated with reduced risk of developing type-2 diabetes within this population.</description><subject>Alleles</subject><subject>Base Sequence</subject><subject>Bilirubin - blood</subject><subject>Cardiovascular disease</subject><subject>Cardiovascular diseases</subject><subject>Cardiovascular Diseases - complications</subject><subject>Cardiovascular Diseases - genetics</subject><subject>Chromosomes</subject><subject>Chromosomes, Human, Pair 2 - genetics</subject><subject>Comparative analysis</subject><subject>Development and progression</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Type 2 - blood</subject><subject>Diabetes Mellitus, Type 2 - enzymology</subject><subject>Diabetes Mellitus, Type 2 - genetics</subject><subject>Enzymes</subject><subject>Epidemiology</subject><subject>Genes, Recessive</subject><subject>Genetic aspects</subject><subject>Genetic markers</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetic research</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Glucuronosyltransferase - genetics</subject><subject>Haplotypes - genetics</subject><subject>Humans</subject><subject>Inheritance Patterns - genetics</subject><subject>Linkage Disequilibrium</subject><subject>Medical research</subject><subject>Medicine, Experimental</subject><subject>Melanesia</subject><subject>Metabolic Syndrome - complications</subject><subject>Metabolic Syndrome - genetics</subject><subject>Metabolism</subject><subject>Molecular Sequence Annotation</subject><subject>Molecular Sequence Data</subject><subject>Polymorphism, Single Nucleotide - genetics</subject><subject>Risk Factors</subject><subject>Type 2 diabetes</subject><issn>1471-2156</issn><issn>1471-2156</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNksFu1DAURSMEoqXwAWyQJTawSLEdx042SKMKykgVlWjL1nLs5xm3STzYDmL6C_w0jqaUDmKBsnDkd-613_MtipcEHxPS8HeR0IZXJSZ1iWlLyttHxSFhgpSU1Pzxg_-D4lmM1xgT0VD2tDignNOGEnpY_LyAMA2oc70LU-dGpP2oYUxBJedH5CIavHHWgUHdFl2dXpIFQWu16X3abiAiNRrkRttPkGURBRdvkLdoLpYUGac6SHk_G6c1oM8-WN_foGXsZ-EKRkhO51N8rxI8L55Y1Ud4cbceFVcfP1yefCrPzk-XJ4uzUtecplK3BlNtqNFGUIypUJjX1lamamvddsA7apqqZY2ogXa6oRVptTG17aywuVAdFe93vpupG8Ds2u3lJrhBha30ysn9yujWcuW_S8a5YIxlgzd3BsF_myAmObiooc9NgZ-iJKJqGtJUtM7o67_Qaz-FMbeXKdHWFW4F_0OtVA8yz9Pnc_VsKheMt5hzxuZ7H_-Dyp-BweV3A-vy_p7g7Z4gMwl-pJWaYpTLiy__z55_3WfJjtXBxxjA3s-OYDknU-6SKXMy5ZxMeZs1rx4O_V7xO4rVL0SX3jc</recordid><startdate>20151202</startdate><enddate>20151202</enddate><creator>Benton, M C</creator><creator>Lea, R A</creator><creator>Macartney-Coxson, D</creator><creator>Bellis, C</creator><creator>Carless, M A</creator><creator>Curran, J E</creator><creator>Hanna, M</creator><creator>Eccles, D</creator><creator>Chambers, G K</creator><creator>Blangero, J</creator><creator>Griffiths, L R</creator><general>BioMed Central Ltd</general><general>BioMed Central</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20151202</creationdate><title>Serum bilirubin concentration is modified by UGT1A1 haplotypes and influences risk of type-2 diabetes in the Norfolk Island genetic isolate</title><author>Benton, M C ; Lea, R A ; Macartney-Coxson, D ; Bellis, C ; Carless, M A ; Curran, J E ; Hanna, M ; Eccles, D ; Chambers, G K ; Blangero, J ; Griffiths, L R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c562t-c9d02cd2dcd720027a065ff3d395c9be6b2d8394875e2bc82319cdd5fbf7f8393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Alleles</topic><topic>Base Sequence</topic><topic>Bilirubin - blood</topic><topic>Cardiovascular disease</topic><topic>Cardiovascular diseases</topic><topic>Cardiovascular Diseases - complications</topic><topic>Cardiovascular Diseases - genetics</topic><topic>Chromosomes</topic><topic>Chromosomes, Human, Pair 2 - genetics</topic><topic>Comparative analysis</topic><topic>Development and progression</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Type 2 - blood</topic><topic>Diabetes Mellitus, Type 2 - enzymology</topic><topic>Diabetes Mellitus, Type 2 - genetics</topic><topic>Enzymes</topic><topic>Epidemiology</topic><topic>Genes, Recessive</topic><topic>Genetic aspects</topic><topic>Genetic markers</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetic research</topic><topic>Genome-Wide Association Study</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Glucuronosyltransferase - genetics</topic><topic>Haplotypes - genetics</topic><topic>Humans</topic><topic>Inheritance Patterns - genetics</topic><topic>Linkage Disequilibrium</topic><topic>Medical research</topic><topic>Medicine, Experimental</topic><topic>Melanesia</topic><topic>Metabolic Syndrome - complications</topic><topic>Metabolic Syndrome - genetics</topic><topic>Metabolism</topic><topic>Molecular Sequence Annotation</topic><topic>Molecular Sequence Data</topic><topic>Polymorphism, Single Nucleotide - genetics</topic><topic>Risk Factors</topic><topic>Type 2 diabetes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Benton, M C</creatorcontrib><creatorcontrib>Lea, R A</creatorcontrib><creatorcontrib>Macartney-Coxson, D</creatorcontrib><creatorcontrib>Bellis, C</creatorcontrib><creatorcontrib>Carless, M A</creatorcontrib><creatorcontrib>Curran, J E</creatorcontrib><creatorcontrib>Hanna, M</creatorcontrib><creatorcontrib>Eccles, D</creatorcontrib><creatorcontrib>Chambers, G K</creatorcontrib><creatorcontrib>Blangero, J</creatorcontrib><creatorcontrib>Griffiths, L R</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>BMC genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Benton, M C</au><au>Lea, R A</au><au>Macartney-Coxson, D</au><au>Bellis, C</au><au>Carless, M A</au><au>Curran, J E</au><au>Hanna, M</au><au>Eccles, D</au><au>Chambers, G K</au><au>Blangero, J</au><au>Griffiths, L R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Serum bilirubin concentration is modified by UGT1A1 haplotypes and influences risk of type-2 diabetes in the Norfolk Island genetic isolate</atitle><jtitle>BMC genetics</jtitle><addtitle>BMC Genet</addtitle><date>2015-12-02</date><risdate>2015</risdate><volume>16</volume><issue>1</issue><spage>136</spage><epage>136</epage><pages>136-136</pages><artnum>136</artnum><issn>1471-2156</issn><eissn>1471-2156</eissn><abstract>Located in the Pacific Ocean between Australia and New Zealand, the unique population isolate of Norfolk Island has been shown to exhibit increased prevalence of metabolic disorders (type-2 diabetes, cardiovascular disease) compared to mainland Australia. We investigated this well-established genetic isolate, utilising its unique genomic structure to increase the ability to detect related genetic markers. A pedigree-based genome-wide association study of 16 routinely collected blood-based clinical traits in 382 Norfolk Island individuals was performed.
A striking association peak was located at chromosome 2q37.1 for both total bilirubin and direct bilirubin, with 29 SNPs reaching statistical significance (P < 1.84 × 10(-7)). Strong linkage disequilibrium was observed across a 200 kb region spanning the UDP-glucuronosyltransferase family, including UGT1A1, an enzyme known to metabolise bilirubin. Given the epidemiological literature suggesting negative association between CVD-risk and serum bilirubin we further explored potential associations using stepwise multivariate regression, revealing significant association between direct bilirubin concentration and type-2 diabetes risk. In the Norfolk Island cohort increased direct bilirubin was associated with a 28% reduction in type-2 diabetes risk (OR: 0.72, 95% CI: 0.57-0.91, P = 0.005). When adjusted for genotypic effects the overall model was validated, with the adjusted model predicting a 30% reduction in type-2 diabetes risk with increasing direct bilirubin concentrations (OR: 0.70, 95% CI: 0.53-0.89, P = 0.0001).
In summary, a pedigree-based GWAS of blood-based clinical traits in the Norfolk Island population has identified variants within the UDPGT family directly associated with serum bilirubin levels, which is in turn implicated with reduced risk of developing type-2 diabetes within this population.</abstract><cop>England</cop><pub>BioMed Central Ltd</pub><pmid>26628212</pmid><doi>10.1186/s12863-015-0291-z</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Alleles Base Sequence Bilirubin - blood Cardiovascular disease Cardiovascular diseases Cardiovascular Diseases - complications Cardiovascular Diseases - genetics Chromosomes Chromosomes, Human, Pair 2 - genetics Comparative analysis Development and progression Diabetes Diabetes Mellitus, Type 2 - blood Diabetes Mellitus, Type 2 - enzymology Diabetes Mellitus, Type 2 - genetics Enzymes Epidemiology Genes, Recessive Genetic aspects Genetic markers Genetic Predisposition to Disease Genetic research Genome-Wide Association Study Genomes Genomics Glucuronosyltransferase - genetics Haplotypes - genetics Humans Inheritance Patterns - genetics Linkage Disequilibrium Medical research Medicine, Experimental Melanesia Metabolic Syndrome - complications Metabolic Syndrome - genetics Metabolism Molecular Sequence Annotation Molecular Sequence Data Polymorphism, Single Nucleotide - genetics Risk Factors Type 2 diabetes |
| title | Serum bilirubin concentration is modified by UGT1A1 haplotypes and influences risk of type-2 diabetes in the Norfolk Island genetic isolate |
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