Evaluating the causal relationship between human blood metabolites and gastroesophageal reflux disease

Table 1 Supplementary and sensitivity analyses for causality from blood metabolites on gastroesophageal reflux disease

Metabolites	n	MR analysis			Heterogeneity		Pleiotropy
		Method	OR (95%CI)	P value	Q	P value	Intercept	P value
Amino acid
Tryptophan	162	ME	0.72 (0.37-1.40)	0.34	160	0.58	0.002	0.07
		WM	1.42 (1.11-1.82)	0.006
Kynurenine	33	ME	1.19 (0.78-1.81)	0.44	31	0.88	0.002	0.96
		WM	1.16 (0.90-1.48)	0.24
Levulinate (4-oxovalerate)	52	ME	0.96 (0.73-1.27)	0.80	50	0.94	0.002	0.15
		WM	0.86 (0.67-1.09)	0.20
Indoleacetate	16	ME	0.79 (0.60-1.05)	0.13	14	0.74	0.003	0.72
		WM	0.83 (0.67-1.04)	0.11
Cofactors and Vitamin
Ascorbate (Vitamin C)	12	ME	1.06 (0.89-1.25)	0.54	10	0.48	0.006	0.94
		WM	1.05 (0.98-1.13)	0.17
Lipid
Stearate (18:0)	31	ME	0.82 (0.51-1.32)	0.43	29	0.49	0.003	0.51
		WM	0.78 (0.60-1.01)	0.06
1-linoleoylglycerophosphoethanolamine	13	ME	1.16 (0.80-1.68)	0.44	11	0.85	0.004	0.99
		WM	1.24 (1.03-1.50)	0.03
1-stearoylglycerol (1-monostearin)	20	ME	1.42 (0.62-3.25)	0.42	18	0.49	0.006	0.90
		WM	1.16 (0.90-1.50)	0.25
1-palmitoylglycerol (1-monopalmitin)	11	ME	0.88 (0.48-1.60)	0.68	9	0.89	0.005	0.27
		WM	1.09 (0.83-1.43)	0.54
7-alpha-hydroxy-3-oxo-4-cholestenoate (7-Hoca)	11	ME	1.12 (0.52-2.41)	0.78	9	0.36	0.006	0.23
		WM	0.70 (0.48-1.01)	0.06
Butyrylcarnitine	39	ME	1.06 (0.99-1.15)	0.11	37	0.30	0.002	0.26
		WM	1.07 (1.00-1.14)	0.04
2-palmitoylglycerophosphocholine*	21	ME	0.91 (0.72-1.14)	0.41	19	0.76	0.002	0.50
		WM	0.97 (0.79-1.20)	0.80
10-nonadecenoate (19:1n9)	7	ME	0.95 (0.60-1.50)	0.83	5	0.52	0.006	0.19
		WM	1.27 (1.00-1.61)	0.05
1-stearoylglycerophosphocholine	9	ME	1.55 (0.85-2.83)	0.20	7	0.87	0.006	0.53
		WM	1.30 (1.01-1.67)	0.04
Adrenate (22:4n6)	11	ME	0.75 (0.50-1.12)	0.19	9	0.20	0.005	0.66
		WM	0.74 (0.60-0.91)	0.004
Nucleotide
Guanosine	11	ME	1.31 (1.06-1.64)	0.04	9	0.99	0.005	0.16
		WM	1.16 (1.05-1.29)	0.005
Xenobiotics
p-acetamidophenylglucuronide	32	ME	1.00 (0.99-1.00)	0.41	30	0.25	0.004	0.60
		WM	1.00 (0.99-1.00)	0.75
Unknow
X-09108	9	ME	1.31 (0.72-2.37)	0.41	7	0.71	0.005	0.61
		WM	1.31 (0.89-1.93)	0.17
X-11247	18	ME	0.92 (0.78-1.10)	0.37	16	0.68	0.004	0.82
		WM	0.91 (0.83-0.99)	0.03
X-11452	5	ME	1.02 (0.67-1.56)	0.93	3	0.45	0.008	0.58
		WM	1.15 (0.97-1.36)	0.10
X-11787	33	ME	0.84 (0.64-1.12)	0.25	31	0.94	0.002	0.84
		WM	0.89 (0.72-1.11)	0.31
X-12007	18	ME	1.10 (1.03-1.17)	0.01	16	0.68	0.003	0.39
		WM	1.07 (1.01-1.13)	0.02
X-12063	21	ME	1.06 (0.98-1.16)	0.16
		WM	1.10 (1.03-1.17)	0.004	19	0.30	0.002	0.60
X-12456	21	ME	1.26 (1.07-1.49)	0.01	19	0.86	0.003	0.09
		WM	1.10 (0.99-1.22)	0.07
X-12786	12	ME	0.95 (0.78-1.14)	0.58	10	0.87	0.003	0.48
		WM	0.91 (0.80-1.05)	0.20

MR: Mendelian randomization; ME: MR-egger; WM: Weighted median; CI: Confidence interval; OR: Odd ratio.

Table 2 Genetic predictors of butyrylcarnitine and their association with GERD

SNP	Gene	CHR	A1	A2	Butyrylcarnitine			GERD
					Beta	SE	P value	Beta	SE	P value
rs10849832	OASL	12	C	T	0.0499	0.0067	1.06E-13	0.0106	0.0083	0.2040
rs10849846	P2RX7	12	C	T	0.0511	0.0097	1.34E-07	0.0079	0.0115	0.4916
rs11065202	CABP1	12	C	T	-0.1297	0.004	1.00E-200	-0.0087	0.0049	0.0751
rs11065208	MLEC	12	A	G	-0.0683	0.0106	1.17E-10	-0.0075	0.0134	0.5745
rs11065270	SPPL3	12	C	T	0.0603	0.0069	1.65E-18	0.0198	0.0091	0.0298
rs1109732	RP11-210L7.1	12	A	G	-0.0606	0.014	1.47E-05	-0.0004	0.0187	0.9848
rs1171617	SLC16A9	10	T	G	0.0358	0.0047	1.61E-14	0.0049	0.0057	0.3849
rs1186055	P2RX7	12	C	A	-0.0344	0.0043	1.30E-15	-0.0042	0.0054	0.4358
rs12025912	KIF17	1	C	T	0.0228	0.0053	1.76E-05	-0.0005	0.0069	0.9418
rs12255141	VTI1A	10	A	G	-0.0272	0.0062	1.15E-05	-0.0093	0.0081	0.2478
rs12257526	GRID1	10	C	T	0.0248	0.0058	1.74E-05	0.0105	0.0074	0.1580
rs12368199	OASL	12	A	G	0.1211	0.0052	1.67E-121	0.0062	0.0067	0.3564
rs12562686	RP11-410C4.4	1	A	C	-0.036	0.0084	1.74E-05	-0.0014	0.0103	0.8883
rs1336584	CTA-21C21.1	1	C	T	-0.018	0.0042	1.91E-05	-0.0079	0.0049	0.1064
rs1469231	NECAP1P1	7	A	G	-0.0188	0.0043	1.00E-05	-0.0098	0.0053	0.0653
rs1557852	RNA5SP192	5	G	A	-0.0181	0.0042	1.53E-05	-0.0067	0.0051	0.1904
rs17050084	AC007131.2	2	C	T	-0.0413	0.0096	1.90E-05	-0.0270	0.0123	0.0274
rs17507671	RNU4-1	12	C	T	-0.0512	0.0096	1.03E-07	0.0036	0.0108	0.7423
rs17686203	WAC	10	C	T	-0.0518	0.0118	1.06E-05	0.0118	0.0142	0.4093
rs1873745	C8orf37-AS1	8	A	G	-0.0195	0.0044	1.01E-05	-0.0098	0.0059	0.0972
rs1955919	LINC01765	1	A	G	-0.0467	0.0106	1.13E-05	-0.0253	0.0123	0.0389
rs1957910	PRKCH	14	A	G	0.0376	0.0088	1.96E-05	-0.0046	0.0093	0.6255
rs208294	-	-	-	-	0.0315	0.0036	1.08E-18	0.0058	0.0048	0.2293
rs2631693	FSIP1	15	C	G	-0.0233	0.0053	1.14E-05	-0.0085	0.0071	0.2302
rs273914	SLC22A4	5	T	A	0.0236	0.0041	1.17E-08	0.0016	0.0050	0.7519
rs278136	CIT	12	C	T	-0.0259	0.0043	1.96E-09	0.0040	0.0057	0.4776
rs3767512	CACNA1S	1	A	G	0.0625	0.0146	1.91E-05	0.0252	0.0177	0.1544
rs3817190	CAMKK2	12	A	T	0.0249	0.0047	1.14E-07	-0.0008	0.0049	0.8770
rs4146382	AC019050.1	2	C	T	-0.0186	0.0043	1.25E-05	-0.0001	0.0052	0.9912
rs4766962	COX6A1	12	A	T	0.0516	0.0043	1.70E-33	0.0078	0.0051	0.1238
rs4767937	SPPL3	12	C	G	0.1052	0.0035	1.00E-200	0.0142	0.0048	0.0032
rs4870883	FER1L6	8	A	T	-0.0262	0.006	1.41E-05	0.0057	0.0053	0.2824
rs4943508	LINC01048	13	C	T	0.0153	0.0035	1.38E-05	0.0098	0.0048	0.0431
rs646454	SGO1-AS1	3	T	C	0.0257	0.0059	1.17E-05	-0.0079	0.0074	0.2851
rs6468765	KB-1410C5.3	8	C	T	0.0156	0.0035	1.02E-05	-0.0078	0.0049	0.1082
rs6496996	RN7SL599P	15	A	G	0.0197	0.0045	1.05E-05	0.0035	0.0060	0.5583
rs7295193	TMEM117	12	C	T	-0.0288	0.0067	1.58E-05	0.0115	0.0088	0.1884
rs7303401	HNF1A-AS1	12	A	T	-0.0692	0.006	1.38E-30	-0.0106	0.0077	0.1678
rs7954772	SLC38A4	12	A	T	0.0182	0.0042	1.22E-05	-0.0009	0.0050	0.8617
rs7979473	HNF1A	12	G	A	0.0184	0.0042	1.20E-05	0.0078	0.0050	0.1184

GERD: Gastroesophageal reflux disease; SNP: Single nucleotide polymorphism; CHR: Chromosome.