Candidate Gene Association Study for Diabetic Retinopathy in Persons with Type 2 Diabetes

The Candidate Gene Association Resource (CARe)

Lucia Sobrin, Todd Green, Xueling Sim, Richard A. Jensen, E. Shyong Tai, Wan Ting Tay, Jie Jin Wang, Paul Mitchell, Niina Sandholm, Yiyuan Liu, Kustaa Hietala, Sudha K. Iyengar, Matthew Brooks, Monika Buraczynska, Natalie Van Zuydam, Albert V. Smith, Vilmundur Gudnason, Alex S. F. Doney, Andrew D. Morris, Graham P. Leese & 17 others Colin N. A. Palmer, Anand Swaroop, Herman A. Taylor, James G. Wilson, Alan Penman, Ching J. Chen, Per-Henrik Groop, Seang-Mei Saw, Tin Aung, Barbara E. Klein, Jerome I. Rotter, David S. Siscovick, Mary Frances Cotch, Ronald Klein, Mark J. Daly, Tien Y. Wong, Wellcome Trust Case Control Consor, Family Invest Nephropathy Diabet-E

    Research output: Contribution to journalArticle

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    Abstract

    PURPOSE. To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe).

    METHODS. Persons with T2D who were enrolled in the study (n = 2691) had fundus photography and genotyping of single nucleotide polymorphisms (SNPs) in 2000 candidate genes. Two case definitions were investigated: Early Treatment Diabetic Retinopathy Study (ETDRS) grades >= 14 and >= 30. The chi(2) analyses for each CARe cohort were combined by Cochran-Mantel- Haenszel (CMH) pooling of odds ratios (ORs) and corrected for multiple hypothesis testing. Logistic regression was performed with adjustment for other DR risk factors. Results from replication in independent cohorts were analyzed with CMH meta-analysis methods.

    RESULTS. Among 39 genes previously associated with DR, DN, or T2D, three SNPs in P-selectin (SELP) were associated with DR. The strongest association was to rs6128 (OR = 0.43, P = 0.0001, after Bonferroni correction). These associations remained significant after adjustment for DR risk factors. Among other genes examined, several variants were associated with DR with significant P values, including rs6856425 tagging alpha-Liduronidase (IDUA) (P = 2.1 X 10(-5), after Bonferroni correction). However, replication in independent cohorts did not reveal study-wide significant effects. The P values after replication were 0.55 and 0.10 for rs6128 and rs6856425, respectively.

    CONCLUSIONS. Genes associated with DN, T2D, and vascular diseases do not appear to be consistently associated with DR. A few genetic variants associated with DR, particularly those in SELP and near IDUA, should be investigated in additional DR cohorts. (Invest Ophthalmol Vis Sci. 2011;52:7593-7602) DOI:10.1167/iovs.11-7510

    Original languageEnglish
    Pages (from-to)7593-7602
    Number of pages10
    JournalInvestigative Ophthalmology & Visual Science
    Volume52
    Issue number10
    DOIs
    Publication statusPublished - Sep 2011

    Keywords

    • GENOME-WIDE ASSOCIATION
    • CORONARY-ARTERY-DISEASE
    • COMMON VARIANTS
    • RISK-FACTORS
    • ERYTHROPOIETIN GENE
    • LINKAGE ANALYSES
    • BLOOD-PRESSURE
    • UNITED-STATES
    • FTO GENE
    • COMPLICATIONS

    Cite this

    Sobrin, L., Green, T., Sim, X., Jensen, R. A., Tai, E. S., Tay, W. T., ... Wellcome Trust Case Control Consor, Family Invest Nephropathy Diabet-E (2011). Candidate Gene Association Study for Diabetic Retinopathy in Persons with Type 2 Diabetes: The Candidate Gene Association Resource (CARe). Investigative Ophthalmology & Visual Science, 52(10), 7593-7602. https://doi.org/10.1167/iovs.11-7510
    Sobrin, Lucia ; Green, Todd ; Sim, Xueling ; Jensen, Richard A. ; Tai, E. Shyong ; Tay, Wan Ting ; Wang, Jie Jin ; Mitchell, Paul ; Sandholm, Niina ; Liu, Yiyuan ; Hietala, Kustaa ; Iyengar, Sudha K. ; Brooks, Matthew ; Buraczynska, Monika ; Van Zuydam, Natalie ; Smith, Albert V. ; Gudnason, Vilmundur ; Doney, Alex S. F. ; Morris, Andrew D. ; Leese, Graham P. ; Palmer, Colin N. A. ; Swaroop, Anand ; Taylor, Herman A. ; Wilson, James G. ; Penman, Alan ; Chen, Ching J. ; Groop, Per-Henrik ; Saw, Seang-Mei ; Aung, Tin ; Klein, Barbara E. ; Rotter, Jerome I. ; Siscovick, David S. ; Cotch, Mary Frances ; Klein, Ronald ; Daly, Mark J. ; Wong, Tien Y. ; Wellcome Trust Case Control Consor, Family Invest Nephropathy Diabet-E. / Candidate Gene Association Study for Diabetic Retinopathy in Persons with Type 2 Diabetes : The Candidate Gene Association Resource (CARe). In: Investigative Ophthalmology & Visual Science. 2011 ; Vol. 52, No. 10. pp. 7593-7602.
    @article{1bbc31c76430404fbc9679441f00362d,
    title = "Candidate Gene Association Study for Diabetic Retinopathy in Persons with Type 2 Diabetes: The Candidate Gene Association Resource (CARe)",
    abstract = "PURPOSE. To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe).METHODS. Persons with T2D who were enrolled in the study (n = 2691) had fundus photography and genotyping of single nucleotide polymorphisms (SNPs) in 2000 candidate genes. Two case definitions were investigated: Early Treatment Diabetic Retinopathy Study (ETDRS) grades >= 14 and >= 30. The chi(2) analyses for each CARe cohort were combined by Cochran-Mantel- Haenszel (CMH) pooling of odds ratios (ORs) and corrected for multiple hypothesis testing. Logistic regression was performed with adjustment for other DR risk factors. Results from replication in independent cohorts were analyzed with CMH meta-analysis methods.RESULTS. Among 39 genes previously associated with DR, DN, or T2D, three SNPs in P-selectin (SELP) were associated with DR. The strongest association was to rs6128 (OR = 0.43, P = 0.0001, after Bonferroni correction). These associations remained significant after adjustment for DR risk factors. Among other genes examined, several variants were associated with DR with significant P values, including rs6856425 tagging alpha-Liduronidase (IDUA) (P = 2.1 X 10(-5), after Bonferroni correction). However, replication in independent cohorts did not reveal study-wide significant effects. The P values after replication were 0.55 and 0.10 for rs6128 and rs6856425, respectively.CONCLUSIONS. Genes associated with DN, T2D, and vascular diseases do not appear to be consistently associated with DR. A few genetic variants associated with DR, particularly those in SELP and near IDUA, should be investigated in additional DR cohorts. (Invest Ophthalmol Vis Sci. 2011;52:7593-7602) DOI:10.1167/iovs.11-7510",
    keywords = "GENOME-WIDE ASSOCIATION, CORONARY-ARTERY-DISEASE, COMMON VARIANTS, RISK-FACTORS, ERYTHROPOIETIN GENE, LINKAGE ANALYSES, BLOOD-PRESSURE, UNITED-STATES, FTO GENE, COMPLICATIONS",
    author = "Lucia Sobrin and Todd Green and Xueling Sim and Jensen, {Richard A.} and Tai, {E. Shyong} and Tay, {Wan Ting} and Wang, {Jie Jin} and Paul Mitchell and Niina Sandholm and Yiyuan Liu and Kustaa Hietala and Iyengar, {Sudha K.} and Matthew Brooks and Monika Buraczynska and {Van Zuydam}, Natalie and Smith, {Albert V.} and Vilmundur Gudnason and Doney, {Alex S. F.} and Morris, {Andrew D.} and Leese, {Graham P.} and Palmer, {Colin N. A.} and Anand Swaroop and Taylor, {Herman A.} and Wilson, {James G.} and Alan Penman and Chen, {Ching J.} and Per-Henrik Groop and Seang-Mei Saw and Tin Aung and Klein, {Barbara E.} and Rotter, {Jerome I.} and Siscovick, {David S.} and Cotch, {Mary Frances} and Ronald Klein and Daly, {Mark J.} and Wong, {Tien Y.} and {Wellcome Trust Case Control Consor, Family Invest Nephropathy Diabet-E}",
    year = "2011",
    month = "9",
    doi = "10.1167/iovs.11-7510",
    language = "English",
    volume = "52",
    pages = "7593--7602",
    journal = "Investigative Ophthalmology & Visual Science",
    issn = "0146-0404",
    publisher = "Association for Research in Vision and Ophthalmology",
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    Sobrin, L, Green, T, Sim, X, Jensen, RA, Tai, ES, Tay, WT, Wang, JJ, Mitchell, P, Sandholm, N, Liu, Y, Hietala, K, Iyengar, SK, Brooks, M, Buraczynska, M, Van Zuydam, N, Smith, AV, Gudnason, V, Doney, ASF, Morris, AD, Leese, GP, Palmer, CNA, Swaroop, A, Taylor, HA, Wilson, JG, Penman, A, Chen, CJ, Groop, P-H, Saw, S-M, Aung, T, Klein, BE, Rotter, JI, Siscovick, DS, Cotch, MF, Klein, R, Daly, MJ, Wong, TY & Wellcome Trust Case Control Consor, Family Invest Nephropathy Diabet-E 2011, 'Candidate Gene Association Study for Diabetic Retinopathy in Persons with Type 2 Diabetes: The Candidate Gene Association Resource (CARe)', Investigative Ophthalmology & Visual Science, vol. 52, no. 10, pp. 7593-7602. https://doi.org/10.1167/iovs.11-7510

    Candidate Gene Association Study for Diabetic Retinopathy in Persons with Type 2 Diabetes : The Candidate Gene Association Resource (CARe). / Sobrin, Lucia; Green, Todd; Sim, Xueling; Jensen, Richard A.; Tai, E. Shyong; Tay, Wan Ting; Wang, Jie Jin; Mitchell, Paul; Sandholm, Niina; Liu, Yiyuan; Hietala, Kustaa; Iyengar, Sudha K.; Brooks, Matthew; Buraczynska, Monika; Van Zuydam, Natalie; Smith, Albert V.; Gudnason, Vilmundur; Doney, Alex S. F.; Morris, Andrew D.; Leese, Graham P.; Palmer, Colin N. A.; Swaroop, Anand; Taylor, Herman A.; Wilson, James G.; Penman, Alan; Chen, Ching J.; Groop, Per-Henrik; Saw, Seang-Mei; Aung, Tin; Klein, Barbara E.; Rotter, Jerome I.; Siscovick, David S.; Cotch, Mary Frances; Klein, Ronald; Daly, Mark J.; Wong, Tien Y.; Wellcome Trust Case Control Consor, Family Invest Nephropathy Diabet-E.

    In: Investigative Ophthalmology & Visual Science, Vol. 52, No. 10, 09.2011, p. 7593-7602.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Candidate Gene Association Study for Diabetic Retinopathy in Persons with Type 2 Diabetes

    T2 - The Candidate Gene Association Resource (CARe)

    AU - Sobrin, Lucia

    AU - Green, Todd

    AU - Sim, Xueling

    AU - Jensen, Richard A.

    AU - Tai, E. Shyong

    AU - Tay, Wan Ting

    AU - Wang, Jie Jin

    AU - Mitchell, Paul

    AU - Sandholm, Niina

    AU - Liu, Yiyuan

    AU - Hietala, Kustaa

    AU - Iyengar, Sudha K.

    AU - Brooks, Matthew

    AU - Buraczynska, Monika

    AU - Van Zuydam, Natalie

    AU - Smith, Albert V.

    AU - Gudnason, Vilmundur

    AU - Doney, Alex S. F.

    AU - Morris, Andrew D.

    AU - Leese, Graham P.

    AU - Palmer, Colin N. A.

    AU - Swaroop, Anand

    AU - Taylor, Herman A.

    AU - Wilson, James G.

    AU - Penman, Alan

    AU - Chen, Ching J.

    AU - Groop, Per-Henrik

    AU - Saw, Seang-Mei

    AU - Aung, Tin

    AU - Klein, Barbara E.

    AU - Rotter, Jerome I.

    AU - Siscovick, David S.

    AU - Cotch, Mary Frances

    AU - Klein, Ronald

    AU - Daly, Mark J.

    AU - Wong, Tien Y.

    AU - Wellcome Trust Case Control Consor, Family Invest Nephropathy Diabet-E

    PY - 2011/9

    Y1 - 2011/9

    N2 - PURPOSE. To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe).METHODS. Persons with T2D who were enrolled in the study (n = 2691) had fundus photography and genotyping of single nucleotide polymorphisms (SNPs) in 2000 candidate genes. Two case definitions were investigated: Early Treatment Diabetic Retinopathy Study (ETDRS) grades >= 14 and >= 30. The chi(2) analyses for each CARe cohort were combined by Cochran-Mantel- Haenszel (CMH) pooling of odds ratios (ORs) and corrected for multiple hypothesis testing. Logistic regression was performed with adjustment for other DR risk factors. Results from replication in independent cohorts were analyzed with CMH meta-analysis methods.RESULTS. Among 39 genes previously associated with DR, DN, or T2D, three SNPs in P-selectin (SELP) were associated with DR. The strongest association was to rs6128 (OR = 0.43, P = 0.0001, after Bonferroni correction). These associations remained significant after adjustment for DR risk factors. Among other genes examined, several variants were associated with DR with significant P values, including rs6856425 tagging alpha-Liduronidase (IDUA) (P = 2.1 X 10(-5), after Bonferroni correction). However, replication in independent cohorts did not reveal study-wide significant effects. The P values after replication were 0.55 and 0.10 for rs6128 and rs6856425, respectively.CONCLUSIONS. Genes associated with DN, T2D, and vascular diseases do not appear to be consistently associated with DR. A few genetic variants associated with DR, particularly those in SELP and near IDUA, should be investigated in additional DR cohorts. (Invest Ophthalmol Vis Sci. 2011;52:7593-7602) DOI:10.1167/iovs.11-7510

    AB - PURPOSE. To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe).METHODS. Persons with T2D who were enrolled in the study (n = 2691) had fundus photography and genotyping of single nucleotide polymorphisms (SNPs) in 2000 candidate genes. Two case definitions were investigated: Early Treatment Diabetic Retinopathy Study (ETDRS) grades >= 14 and >= 30. The chi(2) analyses for each CARe cohort were combined by Cochran-Mantel- Haenszel (CMH) pooling of odds ratios (ORs) and corrected for multiple hypothesis testing. Logistic regression was performed with adjustment for other DR risk factors. Results from replication in independent cohorts were analyzed with CMH meta-analysis methods.RESULTS. Among 39 genes previously associated with DR, DN, or T2D, three SNPs in P-selectin (SELP) were associated with DR. The strongest association was to rs6128 (OR = 0.43, P = 0.0001, after Bonferroni correction). These associations remained significant after adjustment for DR risk factors. Among other genes examined, several variants were associated with DR with significant P values, including rs6856425 tagging alpha-Liduronidase (IDUA) (P = 2.1 X 10(-5), after Bonferroni correction). However, replication in independent cohorts did not reveal study-wide significant effects. The P values after replication were 0.55 and 0.10 for rs6128 and rs6856425, respectively.CONCLUSIONS. Genes associated with DN, T2D, and vascular diseases do not appear to be consistently associated with DR. A few genetic variants associated with DR, particularly those in SELP and near IDUA, should be investigated in additional DR cohorts. (Invest Ophthalmol Vis Sci. 2011;52:7593-7602) DOI:10.1167/iovs.11-7510

    KW - GENOME-WIDE ASSOCIATION

    KW - CORONARY-ARTERY-DISEASE

    KW - COMMON VARIANTS

    KW - RISK-FACTORS

    KW - ERYTHROPOIETIN GENE

    KW - LINKAGE ANALYSES

    KW - BLOOD-PRESSURE

    KW - UNITED-STATES

    KW - FTO GENE

    KW - COMPLICATIONS

    U2 - 10.1167/iovs.11-7510

    DO - 10.1167/iovs.11-7510

    M3 - Article

    VL - 52

    SP - 7593

    EP - 7602

    JO - Investigative Ophthalmology & Visual Science

    JF - Investigative Ophthalmology & Visual Science

    SN - 0146-0404

    IS - 10

    ER -