Recent advances in the application of Mendelian randomization to chronic kidney disease

Figures & data

Figure 1. Comparison of Mendelian randomization methods with those of controlled trials.

Table 1. Blood biochemistry factors and renal function.

	Exposure		Sample	Outcome	Effect size	p value
Ahmad et al. [18]	circulating copper levels	total of 12,385 CKD patients and 104,780 control participants of European descent		CKD	OR=1.17 (1.04, 1.32)	9.00E-03
Mazidi et al. [17]	blood lead levels of type 2 diabetes	fasting glucose ≥ 126 mg/dl, antidiabetic drug treatment, or by self-reported history; 5433 individuals from UK and Australian populations		CKD	β = −0.03416	1.32E-02
Zhou et al. [19]	high serum calcium	337,535 UK Biobank participants		urinary calculus	OR =3.5 (per 1 mg/dl) CI (1.3–9.2)	1.10E-02
Fu et al. [20]	Selenium	circulating selenium levels (n = 5477) and toenail selenium levels (n = 4162) in the European population		eGFR	β = −0.0042 CI (−0.0053, −0.0031)	2.19E-13
Zhao et al. [21]	Genetically predicted bioavailable testosterone	179,916 white British men (6016 CKD patients) and 212,079 white British women		CKD (Men)	OR=1.14 (1.02, 1.28)	2.50E-02
Xiong et al. [24]	1-SD increase of tHcy	480,698 participants: 41,395 patients and 439,303 control participants). Mainly European		CKD	OR = 1.32 (1.06, 1.64)	5.00E-02
Zhao et al. [22]	levels of sex hormone-binding globulin (SHBG)	179,916 white British men (6016 patients with CKD)		CKD (Men)	OR=0.78 CI (0.65, 0.93)	1.00E-02
Kim et al. [16]	fasting glucose	5909 participants without diabetes and CKD from the Korean Genome Epidemiology Study		CKD	OR=0.99 CI (0.977, 1.002)	9.80E-02

CKD (eGFR < 60 mL/min/1.73 m²).

Table 2. Chronic heart disease and CKD.

	Exposure	Sample	Outcome	Effect size	p value
Yoshikawa et al. [31]	per doubling odds ratio of atrial fibrillation/flutter	567,460 participants of European ancestry	CKD	OR = 9.39 (2.39, 37.0)	1.00E-03
Liu et al. [27]	diastolic blood pressure		CKD	OR = 1.35 (1.10, 1.65)	4.00E-03
Geurts et al. [30]	CKD		atrial fibrillation	OR = 1.1 (1.04,1.17)	1.97E-03

Figure 2. Mendelian randomization-confirmed factors affecting kidney function. Red lines indicate factors detrimental to kidney function; blue lines indicate factors beneficial to kidney function.

Table 3. Lifestyle factor and renal function data.

	Exposure	Sample	Outcome	Effect size	p value
Zhang et al. [41]	tea consumption	European ancestry (n = 117,165; 12,385 European)	CKD	OR = 0.803 (0.692, 0.932)	4.00E-03
Mazidi et al. [38]	PUFAs intake	n = 8866 adults of European descent	CKD	β = 0.3791	8.13E-01
Mazidi et al. [42]	coffee intake	18,436 participants	CKD	β = −0.019	7.18E-01
Kennedy et al. [40]	Coffee consumption	117,165	CKD G3-G5	OR = 0.84 (0.72, 0.98)	3.00E-02
Park et al. [34]	Positive affect	567,460 individuals of European ancestry	CKD	OR = 0.69 (0.52, 0.91)	8.00E-03
Park et al. [39]	Relative fat intake	567,460 individuals of European ancestry	CKD	OR = 1.94 (1.39, 2.71)	1.07E-04
Park et al. [36]	Short sleep	321,260 White British individuals, CKD stage 3-5	CKD	OR = 1.80 (1.25, 2.60)	2.00E-03
Park et al. [43]	alcohol use	337,138 participants of white British ancestry (CKD stage ≥ 3)	CKD	OR = 1.00 (0.97, 1.04)	9.90E-01
Park et al. [34]	overall activity	567 460 individuals of European ancestry	CKD	OR = 0.49 (0.32, 0.75)	1.00E-03
Park et al. [35]	Education attainment > 17 years	321 260 Individuals of white British ancestry	CKD	OR = 0.932 (0.874, 0.994)	3.10E-02

Table 4. Obesity factors and renal function.

	Exposure	Sample	Outcome	Effect size	P value
Lanktree et al. [46]	a 17-mg/dL higher HDL cholesterol concentration		CKD	OR = 0.85 CI (0.77, 0.93)	1.00E-03
Ye et al. [45]	1-SD increment in BMI	11,384 Chinese adults	CKD	OR: 2.58; 95% CI (1.39, 4.79)	3.00E-03
Wu et al. [47]	adiponectin	39,883 participants: 29,347 European whites, and 10,536 non-European individuals	CKD	OR = 0.71 CI (0.57–0.89)	2.00E-03

Ahmad S, Ärnlöv J, Larsson SC. Genetically predicted circulating copper and risk of chronic kidney disease: a Mendelian randomization study. Nutrients. 2022;14(3):509. doi:10.3390/nu14030509.

 PubMed Web of Science ®Google Scholar

Mazidi M, Kirwan R, Davies IG. Genetically determined blood lead is associated with reduced renal function amongst individuals with type 2 diabetes mellitus: insight from Mendelian randomisation. J Mol Med. 2022;100(1):125–134. doi:10.1007/s00109-021-02152-5.

 PubMed Web of Science ®Google Scholar

Zhou A, Morris HA, Hyppönen E. Health effects associated with serum calcium concentrations: evidence from MR-PheWAS analysis in UK biobank. Osteoporos Int. 2019;30(11):2343–2348. doi:10.1007/s00198-019-05118-z.

 PubMed Web of Science ®Google Scholar

Fu S, Zhang L, Ma F, et al. Effects of selenium on chronic kidney disease: a Mendelian randomization study. Nutrients. 2022;14(21):4458. doi:10.3390/nu14214458.

 PubMed Web of Science ®Google Scholar

Zhao JV, Schooling CM. The role of testosterone in chronic kidney disease and kidney function in men and women: a bi-directional Mendelian randomization study in the UK biobank. BMC Med. 2020;18(1):122. doi:10.1186/s12916-020-01594-x.

 PubMed Web of Science ®Google Scholar

Xiong Y, Zhang Y, Zhang F, et al. Genetic evidence supporting the causal role of homocysteine in chronic kidney disease: a Mendelian randomization study. Front Nutr. 2022;9:843534. doi:10.3389/fnut.2022.843534.

 PubMed Web of Science ®Google Scholar

Zhao JV, Schooling CM. Sex-specific associations of sex hormone binding globulin with CKD and kidney function: a univariable and multivariable Mendelian randomization study in the UK biobank. J Am Soc Nephrol. 2021;32(3):686–694. doi:10.1681/ASN.2020050659.

 PubMed Web of Science ®Google Scholar

Kim H, Park S, Kwon SH, et al. Impaired fasting glucose and development of chronic kidney disease in non-diabetic population: a Mendelian randomization study. BMJ Open Diabetes Res Care. 2020;8(1):e001395. doi:10.1136/bmjdrc-2020-001395.

 PubMed Web of Science ®Google Scholar

Yoshikawa M, Asaba K, Nakayama T. Causal effect of atrial fibrillation/flutter on chronic kidney disease: a bidirectional two-sample Mendelian randomization study. PLOS One. 2021;16(12):e0261020. doi:10.1371/journal.pone.0261020.

 PubMed Web of Science ®Google Scholar

Liu HM, Hu Q, Zhang Q, et al. Causal effects of genetically predicted cardiovascular risk factors on chronic kidney disease: a two-sample Mendelian randomization study. Front Genet. 2019;10:415. doi:10.3389/fgene.2019.00415.

 PubMed Web of Science ®Google Scholar

Geurts S, van der Burgh AC, Bos MM, et al. Disentangling the association between kidney function and atrial fibrillation: a bidirectional Mendelian randomization study. Int J Cardiol. 2022;355:15–22. doi:10.1016/j.ijcard.2022.03.004.

 PubMed Web of Science ®Google Scholar

Zhang Y, Xiong Y, Shen S, et al. Causal association between tea consumption and kidney function: a Mendelian randomization study. Front Nutr. 2022;9:801591. doi:10.3389/fnut.2022.801591.

 PubMedGoogle Scholar

Mazidi M, Kengne AP, Siervo M, et al. Association of dietary intakes and genetically determined serum concentrations of Mono and poly unsaturated fatty acids on chronic kidney disease: insights from dietary analysis and Mendelian randomization. Nutrients. 2022;14(6):1231. doi:10.3390/nu14061231.

 PubMed Web of Science ®Google Scholar

Mazidi M, Mikhailidis DP, Dehghan A, et al. The association between coffee and caffeine consumption and renal function: insight from individual-level data, Mendelian randomization, and meta-analysis. Arch Med Sci. 2022; 18(4):900–911. doi:10.5114/aoms/144905.

 PubMed Web of Science ®Google Scholar

Kennedy OJ, Pirastu N, Poole R, et al. Coffee consumption and kidney function: a Mendelian randomization study. Am J Kidney Dis. 2020;75(5):753–761. doi:10.1053/j.ajkd.2019.08.025.

 PubMed Web of Science ®Google Scholar

Park S, Lee S, Kim Y, et al. Causal effects of physical activity or sedentary behaviors on kidney function: an integrated population-scale observational analysis and Mendelian randomization study. Nephrol Dial Transplant. 2022;37(6):1059–1068. doi:10.1093/ndt/gfab153.

 PubMed Web of Science ®Google Scholar

Park S, Lee S, Kim Y, et al. Causal effects of relative fat, protein, and carbohydrate intake on chronic kidney disease: a Mendelian randomization study. Am J Clin Nutr. 2021;113(4):1023–1031. doi:10.1093/ajcn/nqaa379.

 PubMed Web of Science ®Google Scholar

Park S, Lee S, Kim Y, et al. Short or long sleep duration and CKD: a Mendelian randomization study. J Am Soc Nephrol. 2020;31(12):2937–2947. doi:10.1681/ASN.2020050666.

 PubMed Web of Science ®Google Scholar

Park S, Lee S, Kim Y, et al. Causal effect of alcohol use on the risk of end-stage kidney disease and related comorbidities: a Mendelian randomization study. Kidney Res Clin Pract. 2021;40(2):282–293. doi:10.23876/j.krcp.20.186.

 PubMed Web of Science ®Google Scholar

Park S, Lee S, Kim Y, et al. Causal effects of education on chronic kidney disease: a Mendelian randomization study. Clin Kidney J. 2020;14(8):1932–1938. doi:10.1093/ckj/sfaa240.

 PubMed Web of Science ®Google Scholar

Lanktree MB, Thériault S, Walsh M, et al. HDL cholesterol, LDL cholesterol, and triglycerides as risk factors for CKD: a Mendelian randomization study. Am J Kidney Dis. 2018;71(2):166–172. doi:10.1053/j.ajkd.2017.06.011.

 PubMed Web of Science ®Google Scholar

Ye C, Kong L, Zhao Z, et al. Causal associations of obesity with chronic kidney disease and arterial stiffness: a Mendelian randomization study. J Clin Endocrinol Metab. 2022;107(2):e825–e835. doi:10.1210/clinem/dgab633.

 PubMed Web of Science ®Google Scholar

Wu R, Luo P, Luo M, et al. Genetically predicted adiponectin causally reduces the risk of chronic kidney disease, a bilateral and multivariable Mendelian randomization study. Front Genet. 2022;13:920510. doi:10.3389/fgene.2022.920510.

 PubMed Web of Science ®Google Scholar