Causal effect of lipoprotein(a) level on chronic kidney disease of European ancestry: a two-sample Mendelian randomization study

Figures & data

Figure 1. Design framework of the MR analysis between Lp(a) and CKD. This analysis is consistent with the hypothesis that genetic variants (SNPs) are significantly associated with Lp(a) but not with confounding factors and that SNPs are not directly related to CKD risk. MR, Mendelian randomization; SNP, single-nucleotide polymorphism; Lp(a), lipoprotein (a); CKD, chronic kidney disease.

Table 1. Overview of the datasets used for analyses.

Exposure/outcome (data source)	Contributing studies	Ancestry	Sample size (cases / controls)
Lipoprotein(a)	PROCARDIS consortium	European	6,487 (3,145/3,352)
	Copenhagen city heart study (CCHS)	European	7,808 (1,943/5,865)
	Copenhagen general population study (CGPS-CIHDS)	European	17,120 (7,740/9,380)
	European prospective investigation into cancer and nutrition-cardiovascular disease study (EPIC-CVD)	European	20,780 (9,810/10,970)
Chronic kidney disease	Chronic kidney disease genetics consortium (CKDgen)	European	480,698 (41,395/43,9403)

Table 2. Characteristics of included eight SNPs associated with Lp(a) level.

SNP	Locus	Genomic coordinate	EA/OA	EAF	SNP-Lp(a) association			SNP-CKD association
					β	SE	P value	β	SE	P value
rs10455872	LPA	chr6:161010118	G/A	0.07	1.18	0.04	3.6E-166	0.050	0.033	0.1302
rs3798220	LPA	chr6:160961137	C/T	0.02	1.27	0.08	5.9E-51	0.038	0.048	0.4227
rs11751605	LPA	chr6:160963230	C/T	0.16	0.5	0.04	5.9E-28	0.022	0.019	0.2495
rs10945682	LPA	chr6:161069941	G/A	0.64	0.32	0.04	1.8E-17	0.020	0.013	0.1333
rs6919346	LPA	chr6:160960359	C/T	0.83	0.43	0.05	1.6E-16	−0.010	0.017	0.5596
rs3127596	LPA	chr6:160953035	G/A	0.3	0.30	0.04	1.5E-14	0.023	0.018	0.1871
rs3798221	LPA	chr6:160998148	G/T	0.81	0.28	0.05	2.0E-9	0.021	0.019	0.2761
rs6415084	LPA	chr6:160980330	T/C	0.49	0.22	0.04	2.7E-9	0.008	0.013	0.5270

Genomic coordinates refer to hg19 (human genome build 37).

SNP, single nucleotide polymorphism; EA, effect allele; OA, other allele; EAF, effect allele frequency; Lp(a), lipoprotein(a); CKD, chronic kidney disease; SE, standard error.

Figure 2. Causal role of genetically predicted Lp(a) level on CKD. (A) Causal estimate of each individual SNP to CKD in fixed-effect IVW analysis. The Y-axis indicates each individual SNP, the X-axis indicates the genetic association with CKD of each SNP. The black dots and lines represent the causal estimates with 95% CI of individual SNP. The red dots and lines represent the overall effect of summarized SNPs using MR egger [estimated β = 0.028, 95% CI (−0.028, 0.085), p = 0.325] and IVW method [estimated β = 0.038, 95% CI (0.009, 0.067), p = 0.010]. (B) Scatter plot of the association of each SNP with Lp(a) and CKD. The points represented the causal estimates of each individual SNP with Lpa (X-axis) and CKD (Y-axis). The line indicated the estimate of effect of Lp(a) and CKD using fixed-IVW method. CKD, chronic kidney disease; CI, confidence interval; IVW, inverse variance weighted; Lp(a), lipoprotein(a); MR, Mendelian randomization; SE, standard error; SNP, single nucleotide polymorphism.

Table 3. Association of Lp(a) levels with CKD risk using various methods.

Method	OR	LCI	UCI	P value
Fixed-effect IVW	1.039	1.009	1.069	0.010*
Random-effect IVW	1.039	1.009	1.069	0.010*
Weighted median	1.044	1.006	1.082	0.022*
Simple median	1.044	1.006	1.083	0.023*
Maximum likelihood	1.039	1.009	1.069	0.010*
MR-Egger	1.028	0.972	1.089	0.325

Lp(a), lipoprotein(a); CKD, chronic kidney disease; OR, odds ratio; LCI, lower confidence interval; UCI, upper confidence interval; IVW, inverse variance-weighted; MR, Mendelian randomization.

*p < 0.05.

Table 4. MR-Egger intercept test results of association between Lp(a) and CKD.

Method	Estimate	LCI	UCI	P value
MR-Egger intercept	0.005	−0.002	0.029	0.703

Lp(a), lipoprotein(a); CKD, chronic kidney disease; LCI, lower confidence interval; UCI, upper confidence interval; MR, Mendelian randomization.

Table 5. Heterogeneity test results of association between Lp(a) and CKD.

Method	Q	Q_df	Q_P value
IVW	3.515	7	0.834
MR-Egger	3.370	6	0.761

Lp(a), lipoprotein(a); CKD, chronic kidney disease; IVW, inverse variance-weighted; MR, Mendelian randomization.

Table 6. Association of CKD with Lp(a) using various methods.

Method	OR	LCI	UCI	P value
Random-effect IVW	1.154	0.845	1.576	0.367
Fixed-effect IVW	1.154	1.137	1.172	<0.001*
Weighted median	1.015	0.993	1.039	0.182
Simple median	1.020	0.994	1.046	0.137
Maximum likelihood	2.328	1.436	3.770	0.001*
MR-Egger	1.147	0.507	2.591	0.743

CKD, chronic kidney disease; Lp(a), lipoprotein(a); OR, odds ratio; LCI, lower confidence interval; UCI, upper confidence interval; IVW, inverse variance-weighted; MR, Mendelian randomization.

*p < 0.05.

Data availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.