Abstract
Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: Any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.
| Original language | English |
|---|---|
| Pages (from-to) | 3130-3141 |
| Number of pages | 12 |
| Journal | Diabetes |
| Volume | 66 |
| Issue number | 12 |
| DOIs | |
| State | Published - 1 Dec 2017 |
| Externally published | Yes |
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In: Diabetes, Vol. 66, No. 12, 01.12.2017, p. 3130-3141.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Genetically determined plasma lipid levels and risk of diabetic retinopathy
T2 - A mendelian randomization study
AU - Sobrin, Lucia
AU - Chong, Yong He
AU - Fan, Qiao
AU - Gan, Alfred
AU - Stanwyck, Lynn K.
AU - Kaidonis, Georgia
AU - Craig, Jamie E.
AU - Kim, Jihye
AU - Liao, Wen Ling
AU - Huang, Yu Chuen
AU - Lee, Wen Jane
AU - Hung, Yi Jen
AU - Guo, Xiuqing
AU - Hai, Yang
AU - Ipp, Eli
AU - Pollack, Samuela
AU - Hancock, Heather
AU - Price, Alkes
AU - Penman, Alan
AU - Mitchell, Paul
AU - Liew, Gerald
AU - Smith, Albert V.
AU - Gudnason, Vilmundur
AU - Tan, Gavin
AU - Klein, Barbara E.K.
AU - Kuo, Jane
AU - Li, Xiaohui
AU - Christiansen, Mark W.
AU - Psaty, Bruce M.
AU - Sandow, Kevin
AU - Jensen, Richard A.
AU - Klein, Ronald
AU - Cotch, Mary Frances
AU - Wang, Jie Jin
AU - Jia, Yucheng
AU - Chen, Ching J.
AU - Ida Chen, Yii Der
AU - Rotter, Jerome I.
AU - Tsai, Fuu Jen
AU - Hanis, Craig L.
AU - Burdon, Kathryn P.
AU - Wong, Tien Yin
AU - Cheng, Ching Yu
N1 - Funding Information: The Jackson Heart Study (JHS) is supported and conducted in collaboration with Jackson State University (HHSN268201300049C, HHSN268201300050C), Tougaloo College (HHSN268201300048C), and the University of Mississippi Medical Center (HHSN268201300046C, HHSN268201300047C) contracts from the NHLBI and the National Institute on Minority Health and Health Disparities. The authors also wish to thank the staffs and participants of the JHS. The views expressed in the manuscript are those of the authors and do not necessarily represent the views of the NHLBI, the NIH, or the U.S. Department of Health and Human Services. Funding Information: The Australian Genetics of Diabetic Retinopathy Study (AUST) was supported by the National Health and Medical Research Council of Australia (NHMRC) (595918) and the Ophthalmic Research Institute of Australia. K.P.B. is supported by a Senior Research Fellowship from the NHMRC, and J.E.C. is supported by a Practitioner Fellowship from the NHMRC. Funding Information: The Cardiovascular Health Study (CHS) was supported by the NIH National Heart, Lung, and Blood Institute (NHLBI) (HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC75150, U01HL080295, U01HL130114) and the CHARGE infrastructure grant HL105756, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by the National Institute on Aging (R01AG023629). A full list of principal CHS investigators and institutions can be found at https://chs-nhlbi.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Funding Information: The Age, Gene/Environment Susceptibility–Reykjavik Study (AGES Reykjavik) was supported by the U.S. National Institutes of Health (NIH) through the Intramural Research Program of the National Institute on Aging (ZIAAG007380) and the National Eye Institute (ZIAEY00401, N01-AG-1-2100), Hjartavernd (the Icelandic Heart Association), the Althingi (Icelandic Parliament), and the University of Iceland Research Fund. The authors are indebted to the staff at the Icelandic Heart Association and to the AGES Reykjavik participants who volunteered their time and allowed us to contribute their data to this international project. The funders had no role in collection, management, analysis, or interpretation of data nor were funders involved in the preparation, writing, or approval of the article or the decision to submit the article for publication. Funding Information: Acknowledgments and Funding. The authors acknowledge the support from the following organizations for this research: Research to Prevent Blindness, Inc. (Career Development Grant, Special Scholar Award), National Eye Institute (EY16335, EY22302), Massachusetts Lions Eye Research Fund, Alcon Research Institute (Young Investigator Award), American Diabetes Association (1-11-CT-51), and Harvard Catalyst (Faculty Fellowship Award). Funding Information: The study of Genetic Center, China Medical University Hospital, Taiwan, was supported by research grants from Academia Sinica, Taiwan (Biosignature Project). The funding organization had no role in the design or conduct of this research. Funding Information: The Singapore Epidemiology of Eye Diseases (SEED) study was supported by the National Medical Research Council, Singapore (0796/2003, 1176/2008, 1149/2008, STaR/0003/2008, 1249/2010, CG/SERI/2010, CIRG/1371/2013, CIRG/1417/2015) and Biomedical Research Council, Singapore (08/1/35/19/550, 09/1/35/19/616). C.-Y.C is supported by an award from National Medical Research Council (CSA/033/2012). The funding organization had no role in the design or conduct of this research. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. L.S., Y.H.C., L.K.S., and C.-Y.C. contributed to the writing of the manuscript. Q.F., A.G., G.K., J.E.C., J.Ki., W.-L.L., Y.-C.H., W.-J.L., Y.-J.H., X.G., Y.H., E.I., S.P., H.H., A.Pr., A.Pe., P.M., G.L., A.V.S., V.G., G.T., B.E.K.K., J.Ku., X.L., M.W.C., B.M.P., K.S., Asian Genetic Epidemiology Network Consortium, R.A.J., R.K., M.F.C., J.J.W., Y.J., C.J.C., Y.-D.I.C., J.I.R., F.-J.T., C.L.H., K.P.B., and T.Y.W. reviewed and edited the manuscript. All authors collected and researched data. L.S., Y.H.C., Q.F., A.G., L.K.S., G.K., J.E.C., J.Ki., W.-L.L., Y.-C.H., W.-J.L., Y.-J.H., X.G., Y.H., E.I., S.P., A.Pr., P.M., G.L., A.V.S., V.G., G.T., B.E.K.K., J.Ku., X.L., M.W.C., B.M.P., K.S., Asian Genetic Epidemiology Network Consortium, R.A.J., R.K., M.F.C., J.J.W., Y.J., Y.-D.I.C., J.I.R., F.-J.T., C.L.H., K.P.B., T.Y.W., and C.-Y.C. performed the analysis. C.-Y.C. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Funding Information: The Blue Mountains Eye Study (BMES) was supported by the NHMRC, Canberra, Australia (NHMRC project grants 974159, 211069, 302068, 529923 [Centre for Clinical Research Excellence in Translational Clinical Research in Eye Diseases]). The BMES GWAS and genotyping costs was supported by NHMRC, Canberra, Australia (NHMRC project grants 512423, 475604, 529912), and the Wellcome Trust as part of Wellcome Trust Case Control Consortium 2 (085475/B/08/Z, 085475/08/Z). Funding Information: The Multi-Ethnic Study of Atherosclerosis (MESA) and the MESA SNP Health Association Resource (SHARe) project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by NHLBI contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, CA) and the Broad Institute (Boston, MA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Publisher Copyright: © 2017 by the American Diabetes Association.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: Any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.
AB - Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: Any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.
UR - http://www.scopus.com/inward/record.url?scp=85035343574&partnerID=8YFLogxK
U2 - 10.2337/db17-0398
DO - 10.2337/db17-0398
M3 - Article
C2 - 28951389
AN - SCOPUS:85035343574
SN - 0012-1797
VL - 66
SP - 3130
EP - 3141
JO - Diabetes
JF - Diabetes
IS - 12
ER -