Is High-Density Lipoprotein Cholesterol Causally Related to Kidney Function? Evidence From Genetic Epidemiological Studies.
A recent observational study with almost 2 million men reported an association between low high-density lipoprotein (HDL) cholesterol and worse kidney function. The causality of this association would be strongly supported if genetic variants associated with HDL cholesterol were also associated with kidney function.



We used 68 genetic variants (single-nucleotide polymorphisms [SNPs]) associated with HDL cholesterol in genome-wide association studies including >188 000 subjects and tested their association with estimated glomerular filtration rate (eGFR) using summary statistics from another genome-wide association studies meta-analysis of kidney function including ≤133 413 subjects. Fourteen of the 68 SNPs (21%) had a P value <0.05 compared with the 5% expected by chance (Binomial test P=5.8×10-6). After Bonferroni correction, 6 SNPs were still significantly associated with eGFR. The genetic variants with the strongest associations with HDL cholesterol concentrations were not the same as those with the strongest association with kidney function and vice versa. An evaluation of pleiotropy indicated that the effects of the HDL-associated SNPs on eGFR were not mediated by HDL cholesterol. In addition, we performed a Mendelian randomization analysis. This analysis revealed a positive but nonsignificant causal effect of HDL cholesterol-increasing variants on eGFR.



In summary, our findings indicate that HDL cholesterol does not causally influence eGFR and propose pleiotropic effects on eGFR for some HDL cholesterol-associated SNPs. This may cause the observed association by mechanisms other than the mere HDL cholesterol concentration.
From the Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Austria (S.C., S.F., C.L., F.K.); and Division of Genetic Epidemiology, Institute for Medical Biometry and Statistics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany (A.K.).
Stefan
S
Coassin
From the Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Austria (S.C., S.F., C.L., F.K.); and Division of Genetic Epidemiology, Institute for Medical Biometry and Statistics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany (A.K.).
Salome
S
Friedel
From the Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Austria (S.C., S.F., C.L., F.K.); and Division of Genetic Epidemiology, Institute for Medical Biometry and Statistics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany (A.K.).
Anna
A
Köttgen
From the Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Austria (S.C., S.F., C.L., F.K.); and Division of Genetic Epidemiology, Institute for Medical Biometry and Statistics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany (A.K.). florian.kronenberg@i-med.ac.at claudia.lamina@i-med.ac.at.
Claudia
C
Lamina
From the Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Austria (S.C., S.F., C.L., F.K.); and Division of Genetic Epidemiology, Institute for Medical Biometry and Statistics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany (A.K.). florian.kronenberg@i-med.ac.at claudia.lamina@i-med.ac.at.
Florian
F
Kronenberg
D015415:Biomarkers / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood*; D030541:Databases, Genetic; D050171:Dyslipidemias / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005919:Glomerular Filtration Rate / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000503:physiopathology*; D007674:Kidney Diseases / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D057182:Mendelian Randomization Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors
D015415:Biomarkers; D008076:Cholesterol, HDL
HDL cholesterol; Mendelian randomization analysis; atherosclerosis; dyslipidemia; genetic association study; kidney
Nat Cell Biol. 2011 Apr;13(4):423-33
21423178
Nat Genet. 2013 Nov;45(11):1274-83
24097068
Lancet. 2015 Aug 1;386(9992):412-4
26047976
J Am Soc Nephrol. 2016 Nov;27(11):3253-3265
27486138
Nat Genet. 2013 Nov;45(11):1345-52
24097064
Circ J. 2013;77(10):2432-48
24067275
Int J Epidemiol. 2011 Jun;40(3):740-52
20813862
Hum Mol Genet. 2012 Dec 15;21(24):5329-43
22962313
Hypertension. 1995 Oct;26(4):670-5
7558229
Am J Epidemiol. 2013 Oct 1;178(7):1177-84
23863760
Diabetes Care. 2012 Nov;35(11):2201-6
22891258
Nature. 2010 Aug 5;466(7307):707-13
20686565
Nat Commun. 2016 Jan 21;7:10023
26831199
Transl Res. 2016 Jul;173:30-57
26972566
J Am Soc Nephrol. 2006 Feb;17(2):528-36
16382017
Circulation. 2003 Dec 2;108(22):2751-6
14638544
Kidney Int. 2000 Jul;58(1):293-301
10886574
J Am Soc Nephrol. 2003 Aug;14(8):2084-91
12874462
Lancet. 2012 Aug 11;380(9841):572-80
22607825
J Intern Med. 2011 Aug;270(2):128-31
21575086
Kidney Int. 2016 Apr;89(4):747-9
26994572
Kidney Int. 2002 Nov;62(5):1524-38
12371953
JAMA. 2009 Nov 11;302(18):1993-2000
19903920
Nat Rev Nephrol. 2016 Jan;12(1):37-47
26568191
Genet Epidemiol. 2013 Nov;37(7):658-65
24114802
J Intern Med. 2011 Aug;270(2):136-46
21443680
J Lipid Res. 2000 Sep;41(9):1495-508
10974057
Kidney Int. 2016 Apr;89(4):886-96
26924057
Kidney Int Suppl. 2005 Dec;(99):S87-93
16336584