Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene
Aims/hypothesis Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic...
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| Veröffentlicht in: | Diabetologia 2015-10, Vol.58 (10), p.2288-2297 |
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| creator | Burdon, Kathryn P. Fogarty, Rhys D. Shen, Weiyong Abhary, Sotoodeh Kaidonis, Georgia Appukuttan, Binoy Hewitt, Alex W. Sharma, Shiwani Daniell, Mark Essex, Rohan W. Chang, John H. Klebe, Sonja Lake, Stewart R. Pal, Bishwanath Jenkins, Alicia Govindarjan, Gowthaman Sundaresan, Periasamy Lamoureux, Ecosse L. Ramasamy, Kim Pefkianaki, Maria Hykin, Philip G. Petrovsky, Nikolai Brown, Matthew A. Gillies, Mark C. Craig, Jamie E. |
| description | Aims/hypothesis
Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study.
Methods
Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (
n
= 336) with diabetic controls with no retinopathy (
n
= 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene
GRB2
by immunohistochemistry and quantitative western blot.
Results
The top ranked variant was rs3805931 with
p
= 2.66 × 10
−7
, but no association was found in the replication cohort. Only rs9896052 (
p
= 6.55 × 10
−5
) was associated with sight-threatening diabetic retinopathy in both the type 2
(p
= 0.035) and the type 1 (
p =
0.041) replication cohorts, as well as in the Indian cohort (
p
= 0.016). The study-wide meta-analysis reached genome-wide significance (
p
= 4.15 × 10
−8
). The
GRB2
gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina.
Conclusions/interpretation
Genetic variation near
GRB2
on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular
GRB2
is upregulated during retinal stress and neovascularisation. |
| doi_str_mv | 10.1007/s00125-015-3697-2 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1768587616</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1768587616</sourcerecordid><originalsourceid>FETCH-LOGICAL-c518t-6a1ec7bbb51e83add94b213326db2e3387c119aa778667d30882bba4615cdda83</originalsourceid><addsrcrecordid>eNqNkc2KFDEUhYM4OO3oA7iRAjdu4uQmlZ9a6qCtMDAgCu6KpHK7K0N3qk1SM_QL-NxWdbeiA4Kb3JDznRMuh5AXwN4AY_oyMwZcUgaSCtVoyh-RBdSCU1Zz85gsZpmCUd_OydOcbxljQtbqCTnnCowRmi3IjyXGYYv0PnisbM5DF2wJQ6xyGf2-Wg2pymHdF1r6hLZgDHFd-WAdltBVaTrjsLOl30_3O7Sb_FfIfSh9tcZ4gO9sOj1HtKkqPVbLz-_4QX9GzlaTGZ-f5gX5-uH9l6uP9Ppm-enq7TXtJJhClQXstHNOAhphvW9qx0EIrrzjKITRHUBjrdZGKe0FM4Y7Z2sFsvPeGnFBXh9zd2n4PmIu7TbkDjcbG3EYcwtaGWm0AvUfKIhGCsn5hL56gN4OY4rTIjPFNa-bAwVHqktDzglX7S6FrU37Flg799ke-2ynPtu5z3b2vDwlj26L_rfjV4ETwI9AnqS4xvTH1_9M_QlhR6xJ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1712724922</pqid></control><display><type>article</type><title>Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene</title><source>MEDLINE</source><source>Springer Nature - Complete Springer Journals</source><creator>Burdon, Kathryn P. ; Fogarty, Rhys D. ; Shen, Weiyong ; Abhary, Sotoodeh ; Kaidonis, Georgia ; Appukuttan, Binoy ; Hewitt, Alex W. ; Sharma, Shiwani ; Daniell, Mark ; Essex, Rohan W. ; Chang, John H. ; Klebe, Sonja ; Lake, Stewart R. ; Pal, Bishwanath ; Jenkins, Alicia ; Govindarjan, Gowthaman ; Sundaresan, Periasamy ; Lamoureux, Ecosse L. ; Ramasamy, Kim ; Pefkianaki, Maria ; Hykin, Philip G. ; Petrovsky, Nikolai ; Brown, Matthew A. ; Gillies, Mark C. ; Craig, Jamie E.</creator><creatorcontrib>Burdon, Kathryn P. ; Fogarty, Rhys D. ; Shen, Weiyong ; Abhary, Sotoodeh ; Kaidonis, Georgia ; Appukuttan, Binoy ; Hewitt, Alex W. ; Sharma, Shiwani ; Daniell, Mark ; Essex, Rohan W. ; Chang, John H. ; Klebe, Sonja ; Lake, Stewart R. ; Pal, Bishwanath ; Jenkins, Alicia ; Govindarjan, Gowthaman ; Sundaresan, Periasamy ; Lamoureux, Ecosse L. ; Ramasamy, Kim ; Pefkianaki, Maria ; Hykin, Philip G. ; Petrovsky, Nikolai ; Brown, Matthew A. ; Gillies, Mark C. ; Craig, Jamie E.</creatorcontrib><description>Aims/hypothesis
Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study.
Methods
Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (
n
= 336) with diabetic controls with no retinopathy (
n
= 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene
GRB2
by immunohistochemistry and quantitative western blot.
Results
The top ranked variant was rs3805931 with
p
= 2.66 × 10
−7
, but no association was found in the replication cohort. Only rs9896052 (
p
= 6.55 × 10
−5
) was associated with sight-threatening diabetic retinopathy in both the type 2
(p
= 0.035) and the type 1 (
p =
0.041) replication cohorts, as well as in the Indian cohort (
p
= 0.016). The study-wide meta-analysis reached genome-wide significance (
p
= 4.15 × 10
−8
). The
GRB2
gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina.
Conclusions/interpretation
Genetic variation near
GRB2
on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular
GRB2
is upregulated during retinal stress and neovascularisation.</description><identifier>ISSN: 0012-186X</identifier><identifier>EISSN: 1432-0428</identifier><identifier>DOI: 10.1007/s00125-015-3697-2</identifier><identifier>PMID: 26188370</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Animals ; Australia ; Diabetes ; Diabetes Mellitus, Type 2 - genetics ; Diabetic retinopathy ; Diabetic Retinopathy - genetics ; Genes ; Genetic Predisposition to Disease ; Genetic Variation ; Genome-Wide Association Study ; Genomes ; GRB2 Adaptor Protein - genetics ; Health risk assessment ; Hospitals ; Human Physiology ; Humans ; Internal Medicine ; Medical research ; Medicine ; Medicine & Public Health ; Metabolic Diseases ; Mice ; Ophthalmology ; Polymorphism, Single Nucleotide ; Retina ; Risk factors</subject><ispartof>Diabetologia, 2015-10, Vol.58 (10), p.2288-2297</ispartof><rights>Springer-Verlag Berlin Heidelberg 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c518t-6a1ec7bbb51e83add94b213326db2e3387c119aa778667d30882bba4615cdda83</citedby><cites>FETCH-LOGICAL-c518t-6a1ec7bbb51e83add94b213326db2e3387c119aa778667d30882bba4615cdda83</cites><orcidid>0000-0001-8217-1249</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00125-015-3697-2$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00125-015-3697-2$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26188370$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Burdon, Kathryn P.</creatorcontrib><creatorcontrib>Fogarty, Rhys D.</creatorcontrib><creatorcontrib>Shen, Weiyong</creatorcontrib><creatorcontrib>Abhary, Sotoodeh</creatorcontrib><creatorcontrib>Kaidonis, Georgia</creatorcontrib><creatorcontrib>Appukuttan, Binoy</creatorcontrib><creatorcontrib>Hewitt, Alex W.</creatorcontrib><creatorcontrib>Sharma, Shiwani</creatorcontrib><creatorcontrib>Daniell, Mark</creatorcontrib><creatorcontrib>Essex, Rohan W.</creatorcontrib><creatorcontrib>Chang, John H.</creatorcontrib><creatorcontrib>Klebe, Sonja</creatorcontrib><creatorcontrib>Lake, Stewart R.</creatorcontrib><creatorcontrib>Pal, Bishwanath</creatorcontrib><creatorcontrib>Jenkins, Alicia</creatorcontrib><creatorcontrib>Govindarjan, Gowthaman</creatorcontrib><creatorcontrib>Sundaresan, Periasamy</creatorcontrib><creatorcontrib>Lamoureux, Ecosse L.</creatorcontrib><creatorcontrib>Ramasamy, Kim</creatorcontrib><creatorcontrib>Pefkianaki, Maria</creatorcontrib><creatorcontrib>Hykin, Philip G.</creatorcontrib><creatorcontrib>Petrovsky, Nikolai</creatorcontrib><creatorcontrib>Brown, Matthew A.</creatorcontrib><creatorcontrib>Gillies, Mark C.</creatorcontrib><creatorcontrib>Craig, Jamie E.</creatorcontrib><title>Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene</title><title>Diabetologia</title><addtitle>Diabetologia</addtitle><addtitle>Diabetologia</addtitle><description>Aims/hypothesis
Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study.
Methods
Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (
n
= 336) with diabetic controls with no retinopathy (
n
= 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene
GRB2
by immunohistochemistry and quantitative western blot.
Results
The top ranked variant was rs3805931 with
p
= 2.66 × 10
−7
, but no association was found in the replication cohort. Only rs9896052 (
p
= 6.55 × 10
−5
) was associated with sight-threatening diabetic retinopathy in both the type 2
(p
= 0.035) and the type 1 (
p =
0.041) replication cohorts, as well as in the Indian cohort (
p
= 0.016). The study-wide meta-analysis reached genome-wide significance (
p
= 4.15 × 10
−8
). The
GRB2
gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina.
Conclusions/interpretation
Genetic variation near
GRB2
on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular
GRB2
is upregulated during retinal stress and neovascularisation.</description><subject>Animals</subject><subject>Australia</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Type 2 - genetics</subject><subject>Diabetic retinopathy</subject><subject>Diabetic Retinopathy - genetics</subject><subject>Genes</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetic Variation</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>GRB2 Adaptor Protein - genetics</subject><subject>Health risk assessment</subject><subject>Hospitals</subject><subject>Human Physiology</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolic Diseases</subject><subject>Mice</subject><subject>Ophthalmology</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Retina</subject><subject>Risk factors</subject><issn>0012-186X</issn><issn>1432-0428</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqNkc2KFDEUhYM4OO3oA7iRAjdu4uQmlZ9a6qCtMDAgCu6KpHK7K0N3qk1SM_QL-NxWdbeiA4Kb3JDznRMuh5AXwN4AY_oyMwZcUgaSCtVoyh-RBdSCU1Zz85gsZpmCUd_OydOcbxljQtbqCTnnCowRmi3IjyXGYYv0PnisbM5DF2wJQ6xyGf2-Wg2pymHdF1r6hLZgDHFd-WAdltBVaTrjsLOl30_3O7Sb_FfIfSh9tcZ4gO9sOj1HtKkqPVbLz-_4QX9GzlaTGZ-f5gX5-uH9l6uP9Ppm-enq7TXtJJhClQXstHNOAhphvW9qx0EIrrzjKITRHUBjrdZGKe0FM4Y7Z2sFsvPeGnFBXh9zd2n4PmIu7TbkDjcbG3EYcwtaGWm0AvUfKIhGCsn5hL56gN4OY4rTIjPFNa-bAwVHqktDzglX7S6FrU37Flg799ke-2ynPtu5z3b2vDwlj26L_rfjV4ETwI9AnqS4xvTH1_9M_QlhR6xJ</recordid><startdate>20151001</startdate><enddate>20151001</enddate><creator>Burdon, Kathryn P.</creator><creator>Fogarty, Rhys D.</creator><creator>Shen, Weiyong</creator><creator>Abhary, Sotoodeh</creator><creator>Kaidonis, Georgia</creator><creator>Appukuttan, Binoy</creator><creator>Hewitt, Alex W.</creator><creator>Sharma, Shiwani</creator><creator>Daniell, Mark</creator><creator>Essex, Rohan W.</creator><creator>Chang, John H.</creator><creator>Klebe, Sonja</creator><creator>Lake, Stewart R.</creator><creator>Pal, Bishwanath</creator><creator>Jenkins, Alicia</creator><creator>Govindarjan, Gowthaman</creator><creator>Sundaresan, Periasamy</creator><creator>Lamoureux, Ecosse L.</creator><creator>Ramasamy, Kim</creator><creator>Pefkianaki, Maria</creator><creator>Hykin, Philip G.</creator><creator>Petrovsky, Nikolai</creator><creator>Brown, Matthew A.</creator><creator>Gillies, Mark C.</creator><creator>Craig, Jamie E.</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</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>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><orcidid>https://orcid.org/0000-0001-8217-1249</orcidid></search><sort><creationdate>20151001</creationdate><title>Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene</title><author>Burdon, Kathryn P. ; Fogarty, Rhys D. ; Shen, Weiyong ; Abhary, Sotoodeh ; Kaidonis, Georgia ; Appukuttan, Binoy ; Hewitt, Alex W. ; Sharma, Shiwani ; Daniell, Mark ; Essex, Rohan W. ; Chang, John H. ; Klebe, Sonja ; Lake, Stewart R. ; Pal, Bishwanath ; Jenkins, Alicia ; Govindarjan, Gowthaman ; Sundaresan, Periasamy ; Lamoureux, Ecosse L. ; Ramasamy, Kim ; Pefkianaki, Maria ; Hykin, Philip G. ; Petrovsky, Nikolai ; Brown, Matthew A. ; Gillies, Mark C. ; Craig, Jamie E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c518t-6a1ec7bbb51e83add94b213326db2e3387c119aa778667d30882bba4615cdda83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Australia</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Type 2 - genetics</topic><topic>Diabetic retinopathy</topic><topic>Diabetic Retinopathy - genetics</topic><topic>Genes</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetic Variation</topic><topic>Genome-Wide Association Study</topic><topic>Genomes</topic><topic>GRB2 Adaptor Protein - genetics</topic><topic>Health risk assessment</topic><topic>Hospitals</topic><topic>Human Physiology</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metabolic Diseases</topic><topic>Mice</topic><topic>Ophthalmology</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Retina</topic><topic>Risk factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Burdon, Kathryn P.</creatorcontrib><creatorcontrib>Fogarty, Rhys D.</creatorcontrib><creatorcontrib>Shen, Weiyong</creatorcontrib><creatorcontrib>Abhary, Sotoodeh</creatorcontrib><creatorcontrib>Kaidonis, Georgia</creatorcontrib><creatorcontrib>Appukuttan, Binoy</creatorcontrib><creatorcontrib>Hewitt, Alex W.</creatorcontrib><creatorcontrib>Sharma, Shiwani</creatorcontrib><creatorcontrib>Daniell, Mark</creatorcontrib><creatorcontrib>Essex, Rohan W.</creatorcontrib><creatorcontrib>Chang, John H.</creatorcontrib><creatorcontrib>Klebe, Sonja</creatorcontrib><creatorcontrib>Lake, Stewart R.</creatorcontrib><creatorcontrib>Pal, Bishwanath</creatorcontrib><creatorcontrib>Jenkins, Alicia</creatorcontrib><creatorcontrib>Govindarjan, Gowthaman</creatorcontrib><creatorcontrib>Sundaresan, Periasamy</creatorcontrib><creatorcontrib>Lamoureux, Ecosse L.</creatorcontrib><creatorcontrib>Ramasamy, Kim</creatorcontrib><creatorcontrib>Pefkianaki, Maria</creatorcontrib><creatorcontrib>Hykin, Philip G.</creatorcontrib><creatorcontrib>Petrovsky, Nikolai</creatorcontrib><creatorcontrib>Brown, Matthew A.</creatorcontrib><creatorcontrib>Gillies, Mark C.</creatorcontrib><creatorcontrib>Craig, Jamie E.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology 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>Public Health Database</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</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical 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>MEDLINE - Academic</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Diabetologia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Burdon, Kathryn P.</au><au>Fogarty, Rhys D.</au><au>Shen, Weiyong</au><au>Abhary, Sotoodeh</au><au>Kaidonis, Georgia</au><au>Appukuttan, Binoy</au><au>Hewitt, Alex W.</au><au>Sharma, Shiwani</au><au>Daniell, Mark</au><au>Essex, Rohan W.</au><au>Chang, John H.</au><au>Klebe, Sonja</au><au>Lake, Stewart R.</au><au>Pal, Bishwanath</au><au>Jenkins, Alicia</au><au>Govindarjan, Gowthaman</au><au>Sundaresan, Periasamy</au><au>Lamoureux, Ecosse L.</au><au>Ramasamy, Kim</au><au>Pefkianaki, Maria</au><au>Hykin, Philip G.</au><au>Petrovsky, Nikolai</au><au>Brown, Matthew A.</au><au>Gillies, Mark C.</au><au>Craig, Jamie E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene</atitle><jtitle>Diabetologia</jtitle><stitle>Diabetologia</stitle><addtitle>Diabetologia</addtitle><date>2015-10-01</date><risdate>2015</risdate><volume>58</volume><issue>10</issue><spage>2288</spage><epage>2297</epage><pages>2288-2297</pages><issn>0012-186X</issn><eissn>1432-0428</eissn><abstract>Aims/hypothesis
Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study.
Methods
Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (
n
= 336) with diabetic controls with no retinopathy (
n
= 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene
GRB2
by immunohistochemistry and quantitative western blot.
Results
The top ranked variant was rs3805931 with
p
= 2.66 × 10
−7
, but no association was found in the replication cohort. Only rs9896052 (
p
= 6.55 × 10
−5
) was associated with sight-threatening diabetic retinopathy in both the type 2
(p
= 0.035) and the type 1 (
p =
0.041) replication cohorts, as well as in the Indian cohort (
p
= 0.016). The study-wide meta-analysis reached genome-wide significance (
p
= 4.15 × 10
−8
). The
GRB2
gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina.
Conclusions/interpretation
Genetic variation near
GRB2
on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular
GRB2
is upregulated during retinal stress and neovascularisation.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>26188370</pmid><doi>10.1007/s00125-015-3697-2</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0001-8217-1249</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0012-186X |
| ispartof | Diabetologia, 2015-10, Vol.58 (10), p.2288-2297 |
| issn | 0012-186X 1432-0428 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1768587616 |
| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | Animals Australia Diabetes Diabetes Mellitus, Type 2 - genetics Diabetic retinopathy Diabetic Retinopathy - genetics Genes Genetic Predisposition to Disease Genetic Variation Genome-Wide Association Study Genomes GRB2 Adaptor Protein - genetics Health risk assessment Hospitals Human Physiology Humans Internal Medicine Medical research Medicine Medicine & Public Health Metabolic Diseases Mice Ophthalmology Polymorphism, Single Nucleotide Retina Risk factors |
| title | Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T18%3A09%3A20IST&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=Genome-wide%20association%20study%20for%20sight-threatening%20diabetic%20retinopathy%20reveals%20association%20with%20genetic%20variation%20near%20the%20GRB2%20gene&rft.jtitle=Diabetologia&rft.au=Burdon,%20Kathryn%20P.&rft.date=2015-10-01&rft.volume=58&rft.issue=10&rft.spage=2288&rft.epage=2297&rft.pages=2288-2297&rft.issn=0012-186X&rft.eissn=1432-0428&rft_id=info:doi/10.1007/s00125-015-3697-2&rft_dat=%3Cproquest_cross%3E1768587616%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1712724922&rft_id=info:pmid/26188370&rfr_iscdi=true |