Association of genetic variants for plasma LRG1 with rapid decline in kidney function in patients with type 2 diabetes

2021 ◽  
Author(s):  
Resham Lal Gurung ◽  
Rajkumar Dorajoo ◽  
M Yiamunaa ◽  
Jian-Jun Liu ◽  
Sharon Li Ting Pek ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glomerular Filtration ◽  
Kidney Function ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Causal Effect ◽  
Mendelian Randomisation ◽  
Rapid Decline ◽  
A Genome

Abstract Context Elevated levels of plasma Leucine Rich α-2-Glycoprotein 1 (LRG1), a component of TGF-ß signalling, are associated with development and progression of chronic kidney disease in patients with type 2 diabetes (T2D). However, whether this relationship is causal is uncertain. Objectives To identify genetic variants associated with plasma LRG1 levels and determine whether genetically predicted plasma LRG1 contributes to a rapid decline in kidney function (RDKF) in patients with T2D. Design and participants We performed a genome-wide association study (GWAS) of plasma LRG1 among 3,694 T2D individuals [1,881(983 Chinese, 420 Malay and 478 Indian) discovery from SMART2D cohort and 1,813 (Chinese) validation from DN cohort]. One- sample Mendelian randomization analysis was performed among 1,337 T2D Chinese participants with preserved glomerular filtration function (baseline estimated glomerular filtration rate (eGFR) >60ml/min/1.73m 2). RDKF was defined as an eGFR decline of 3 mL/min/1.73 m 2/year or greater. Results We identified rs4806985 variant near LRG1 locus robustly associated with plasma LRG1 levels (MetaP=6.66x10 -16). Among 1,337 participants, 344 (26%) developed RDKF and the rs4806985 variant was associated with higher odds of RDKF (meta odds ratio =1.23, P=0.030 adjusted for age and sex). Mendelian randomisation analysis provided evidence for a potential causal effect of plasma LRG1 on kidney function decline in T2D (P<0.05). Conclusion We demonstrate that genetically influenced plasma LRG1 increases the risk of RDKF in T2D patients suggesting plasma LRG1 as a potential treatment target. However, further studies are warranted to elucidate underlying pathways to provide insight into DKD prevention.

scholarly journals A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants

Science ◽  
2007 ◽  
Vol 316 (5829) ◽  
pp. 1341-1345 ◽  
Author(s):  
L. J. Scott ◽  
K. L. Mohlke ◽  
L. L. Bonnycastle ◽  
C. J. Willer ◽  
Y. Li ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

scholarly journals PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study

2017 ◽  
Vol 5 (2) ◽  
pp. 97-105 ◽  
Author(s):  
Amand F Schmidt ◽  
Daniel I Swerdlow ◽  
Michael V Holmes ◽  
Riyaz S Patel ◽  
Zammy Fairhurst-Hunter ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Variants ◽  
Mendelian Randomisation

scholarly journals A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

Diabetes ◽  
2018 ◽  
Vol 67 (7) ◽  
pp. 1414-1427 ◽  
Author(s):  
Natalie R. van Zuydam ◽  
Emma Ahlqvist ◽  
Niina Sandholm ◽  
Harshal Deshmukh ◽  
N. William Rayner ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Kidney Disease ◽  
Association Study ◽  
Diabetic Kidney Disease ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Diabetic Kidney ◽  
Genome Wide ◽  
A Genome

Abstract P072: Circulating Phylloquinone Concentrations and Type 2 Diabetes Incidence: A Mendelian Randomization Study

Circulation ◽  
2018 ◽  
Vol 137 (suppl_1) ◽  
Author(s):  
Sharon Remmelzwaal ◽  
Sabine Zwakenberg ◽  
Joline Beulens ◽  
Edith Feskens ◽  
Sarah Booth ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Relation ◽  
Genetic Risk Score ◽  
Diabetes Incidence ◽  
A Genome ◽  
Weighted Genetic Risk Score

Introduction: This study aims to investigate the causal relation of genetically conferred circulating phylloquinone levels and the risk of type 2 diabetes (T2D) via a Mendelian Randomization approach. Methods: We used data from the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study comprising 10,071 diabetes cases and 13,309 subcohort members from eight European countries. We calculated a weighted genetic risk score (wGRS) including four SNPs (rs2192574, rs6862071, rs4645543 and rs2108622) likely to be related to circulating phylloquinone levels from a genome wide association study. Inverse-variance weighted (IVW) analysis was used to obtain a Hazard Ratio (HR) for the unconfounded relation between circulating phylloquinone levels and T2D incidence. All analyses were adjusted for sex, center, principal components of ancestry, genetic platform, triglycerides and hours fasting. Furthermore, we assessed the robustness of our results with a MR Egger analyses. In follow-up analyses, we have included data from the Diabetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, increasing our dataset to 21,571 participants with diabetes. Results: The median follow-up time was 10.9 years. In IVW analysis, genetically conferred higher circulating phylloquinone levels were associated with a reduced risk of T2D with a HR of 0.87 (0.78;0.97) for every ln-nmol/L increase in circulating phylloquinone. The MR Egger method resulted in a HR of 0.88 (0.72;1.08).Adding DIAGRAM data resulted in a summary odds ratio of 0.90 (0.81;1.00). Conclusion: Our study suggests that the association between higher circulating phylloquinone levels and lower T2D incidence may be causal.

scholarly journals A Genome-Wide Association Study Confirms Previously Reported Loci for Type 2 Diabetes in Han Chinese

PLoS ONE ◽  
2011 ◽  
Vol 6 (7) ◽  
pp. e22353 ◽  
Author(s):  
Bin Cui ◽  
Xiaolin Zhu ◽  
Min Xu ◽  
Ting Guo ◽  
Dalong Zhu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Han Chinese ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

scholarly journals Pharmacogenetics of Oral Antidiabetic Drugs

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Matthijs L. Becker ◽  
Ewan R. Pearson ◽  
Ivan Tkáč
Keyword(s):  
Type 2 Diabetes ◽  
Genome Wide Association Study ◽  
Antidiabetic Drugs ◽  
Gene Variants ◽  
Oral Antidiabetic Drugs ◽  
Oral Antidiabetic ◽  
Genome Wide ◽  
A Genome ◽  
Register Studies

Oral antidiabetic drugs (OADs) are used for more than a half-century in the treatment of type 2 diabetes. Only in the last five years, intensive research has been conducted in the pharmacogenetics of these drugs based mainly on the retrospective register studies, but only a handful of associations detected in these studies were replicated. The gene variants inCYP2C9,ABCC8/KCNJ11, andTCF7L2were associated with the effect of sulfonylureas.CYP2C9encodes sulfonylurea metabolizing cytochrome P450 isoenzyme 2C9,ABCC8andKCNJ11genes encode proteins constituting ATP-sensitive K+channel which is a therapeutic target for sulfonylureas, andTCF7L2is a gene with the strongest association with type 2 diabetes.SLC22A1,SLC47A1, andATMgene variants were repeatedly associated with the response to metformin.SLC22A1andSLC47A1encode metformin transporters OCT1 and MATE1, respectively. The function of a gene variant nearATMgene identified by a genome-wide association study is not elucidated so far. The first variant associated with the response to gliptins is a polymorphism in the proximity ofCTRB1/2gene which encodes chymotrypsinogen. Establishment of diabetes pharmacogenetics consortia and reduction in costs of genomics might lead to some significant clinical breakthroughs in this field in a near future.

P2486The association between genetic variant ZNF259 and decreased kidney function in the diabetic patients

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Pereira ◽  
M Mendonca ◽  
J Monteiro ◽  
J Sousa ◽  
F Mendonca ◽  
...  
Keyword(s):  
Risk Factors ◽  
Type 2 Diabetes ◽  
Renal Failure ◽  
Logistic Regression ◽  
Risk Factor ◽  
Kidney Function ◽  
Genetic Variants ◽  
Diabetic Patients ◽  
Cross Sectional

Abstract Type 2 Diabetes (T2D) is a risk factor for dysregulation of glomerular filtration rate (GFR) and albuminuria. However, it remains unclear whether this association is only causal. Genetic variants are inherited independent of potential confounding factors and represent a lifetime exposure. Aim Investigate whether the reduction of GFR is a direct consequence of T2D or there are other genetic mechanisms involved in the pathophysiology of the evolution to chronic kidney disease. Methods Cross-sectional study with a total of 2579 individuals was performed, of which 735 patients had T2D. Subjects were classified as `'diabetic” if they were taking oral anti-diabetic medication or insulin or if their fasting plasma glucose was higher than 7.0 mmol/l or 126 mg/dl. Within the diabetic group, we considered those with (n=63) and without (n=627) decreased GFR. GFR was calculated through the Cockcroft and Gault formula and decreased GFR was defined as GFR<60 ml/min/1.73m2. Twenty-four genetic variants associated with T2D, metabolic syndrome, dyslipidemia and hypertension were investigated for its impact on GFR, namely: MTHFR 677 and 1298; MTHFD1L; PON 55, 192 and 108; ATIR A/C; AGT M235T; ACE I/D; TCF7L2; SLC30A8; MC4R; ADIPOQ; FTO; TAS2R50; HNF4A; IGF2BP2; PPARG; PCSK9; KIF6; ZNF259; LPA; APOE; PSRS1. Risk factors for decreased GFR were also evaluated (essential hypertension, glycaemia >120 mg/ml, dyslipidemia, alcohol consumption, CAD diagnosis). A logistic regression was performed firstly with the risk factors solely; and secondly adding the genetic variants in order to evaluate the independent predictors of progression to renal failure in T2D. Results After the first multivariate logistic regression with all the risk factors for decreased GFR, only CAD remained in the equation, showing to be an independent risk factor for progression to renal failure, in T2D (OR=4.17; 95% CI: 1.64–10.59; p=0.003). In the second logistic regression, including risk factors and the genetic variants, only ZNF259 rs964184 showed an independent and significant association with the risk of decreased GFR (OR=3.03; 95% CI: 1.06–8.70; p=0.039). Conclusion This study shows that the variant ZNF259 rs964184 is associated with decreased kidney function, independently of other risk factors. This finding needs further investigation to clarify the genetic mechanism behind the association of rs964184 with decreased GFR, in Type 2 diabetes.

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