Cuproptosis-Related Gene – SLC31A1, FDX1 and ATP7B – Polymorphisms are Associated with Risk of Lung Cancer

Figures & data

Table 1 The Demographic Characteristics of the Participants

Characteristics	Case (n=650)	Control (n=650)	χ^2/t	p
Sex (%)			0.030	0.862
Male	418 (64.3)	415 (63.8)
Female	232 (35.7)	235 (36.2)
Age			0.688	0.337
Mean ±SD	56.91±10.17	56.36±10.26
Smoking (%)			0.030	0.862
Yes	415 (63.8)	412 (63.4)
No	235 (36.2)	238 (36.6)
Pathological types
Adenocarcinoma	300 (46.2)
Squamous cell carcinoma	203 (31.2)
Small cell lung cancer	122 (18.8)
Others	25 (3.8)

Table 2 Basic Information and Predicted Functions of Candidate SNPs

SNP	Gene	Position	Allele	Region	Predicted Functions
rs2233914	SLC31A1	chr9:113221260	G>A	2kB Upstream Variant	Promoter histone marks, DNAse, Motifs changed, eQTLhits
rs10981694	SLC31A1	chr9:113224129	T>G	Intron Variant	DNAse, Motifs changed, Selected eQTLhits
rs10488764	FDX1	chr11:110460907	G>A	Intron Variant	Motifs changed, eQTLhits
rs1061472	ATP7B	chr13:51950352	T>C	Missense Variant	Lys832Arg
rs9535826	ATP7B	chr13:51991990	T>G	Intron Variant	Enhancer histone marks, Motifs changed, eQTLhits
rs9535828	ATP7B	chr13:51999286	G>A	Intron Variant	Promoter/Enhancer histone marks, DNAse, Motifs changed, eQTLhits

Abbreviations: SNP, single-nucleotide polymorphism; eQTL, expression quantitative trait locus.

Table 3 The MAF and HWE of Candidate SNPs Between Lung Cancer Cases and Healthy Controls

SNP	Gene	MAF-Case	MAF-Control	HWE p	OR (95% CI)	p
rs2233914	SLC31A1	0.35	0.33	0.86	1.075(0.914–1.264)	0.385
rs10981694	SLC31A1	0.24	0.17	0.22	1.455(1.201–1.763)	0.00012*
rs10488764	FDX1	0.30	0.23	0.57	1.483(1.244–1.768)	0.00001*
rs1061472	ATP7B	0.41	0.40	0.46	1.066(0.911–1.247)	0.424
rs9535826	ATP7B	0.32	0.40	0.19	0.714(0.608–0.838)	0.00004*
rs9535828	ATP7B	0.34	0.43	0.75	0.679(0.579–0.796)	0.00001*

Note: *Bonferroni multiple adjustment was applied, with p ≤ 0.008.

Abbreviations: SNP, single-nucleotide polymorphism; MAF, minor allele frequency; HWE, Hardy–Weinberg equilibrium.

Table 4 Genotype Frequency Distributions Between Lung Cancer Cases and Healthy Controls

Model	Genotype	Control	Case	OR (95% CI)	p
rs2233914	GG	290 (44.6%)	269 (41.4%)	1	0.47
	GA	287 (44.1%)	308 (47.4%)	1.15 (0.92–1.46)
	AA	73 (11.2%)	73 (11.2%)	1.08 (0.75–1.55)
rs10981694	TT	438 (67.4%)	377 (58%)	1	0.0005*
	TG	197 (30.3%)	240 (36.9%)	1.44 (1.12–1.84)
	GG	15 (2.3%)	33 (5.1%)	2.57 (1.37–4.82)
rs10488764	GG	392 (60.3%)	318 (48.9%)	1	<0.0001*
	GA	222 (34.1%)	271 (41.7%)	1.52 (1.21–1.92)
	AA	36 (5.5%)	61 (9.4%)	2.15 (1.39–3.34)
rs1061472	TT	242 (37.2%)	226 (34.8%)	1	0.67
	TC	302 (46.5%)	314 (48.3%)	1.11 (0.87–1.42)
	CC	106 (16.3%)	110 (16.9%)	1.10 (0.80–1.53)
rs9535826	TT	224 (34.5%)	291 (44.8%)	1	0.0002*
	TG	329 (50.6%)	296 (45.5%)	0.69 (0.55–0.88)
	GG	97 (14.9%)	63 (9.7%)	0.50 (0.35–0.72)
rs9535828	GG	207 (31.9%)	285 (43.9%)	1	<0.0001*
	GA	324 (49.9%)	287 (44.1%)	0.49 (0.37–0.64)
	AA	119 (18.3%)	78 (12%)	0.30 (0.20–0.45)

Note: *Bonferroni multiple adjustment was applied, with p ≤ 0.008.

Abbreviations: SNP, single-nucleotide polymorphism; OR, odds ratio; CI, confidence interval.

Table 5 Association Between SNPs and Risk of Lung Cancer in Genetic Models

SNP	Model	Genotype	Control	Case	OR (95% CI)	p
rs2233914	Dominant	GG	290 (44.6%)	269 (41.4%)	1	0.250
		GA-AA	360 (55.4%)	381 (58.6%)	1.14 (0.91–1.42)
	Recessive	GG-GA	577 (88.8%)	577 (88.8%)	1	1.000
		AA	73 (11.2%)	73 (11.2%)	1.00 (0.71–1.41)
	Log-additive	—	—	—	1.08 (0.91–1.27)	0.390
rs10981694	Dominant	TT	438 (67.4%)	377 (58%)	1	0.0005*
		TG-GG	212 (32.6%)	273 (42%)	1.52 (1.20–1.93)
	Recessive	TT-TG	635 (97.7%)	617 (94.9%)	1	0.0085*
		GG	15 (2.3%)	33 (5.1%)	2.24 (1.20–4.16)
	Log-additive	—	—	—	1.50 (1.22–1.84)	0.0001*
rs10488764	Dominant	GG	392 (60.3%)	318 (48.9%)	1	<0.0001*
		GA-AA	258 (39.7%)	332 (51.1%)	1.61 (1.29–2.01)
	Recessive	GG-GA	614 (94.5%)	589 (90.6%)	1	0.006*
		AA	36 (5.5%)	61 (9.4%)	1.81 (1.18–2.78)
	Log-additive	—	—	—	1.49 (1.25–1.78)	<0.0001*
rs1061472	Dominant	TT	242 (37.2%)	226 (34.8%)	1	0.370
		TC-CC	408 (62.8%)	424 (65.2%)	1.11 (0.88–1.39)
	Recessive	TT-TC	544 (83.7%)	540 (83.1%)	1	0.790
		CC	106 (16.3%)	110 (16.9%)	1.04 (0.78–1.39)
	Log-additive	—	—	—	1.06 (0.91–1.24)	0.450
rs9535826	Dominant	TT	224 (34.5%)	291 (44.8%)	1	0.0002*
		TG-GG	426 (65.5%)	359 (55.2%)	0.65 (0.52–0.81)
	Recessive	TT-TG	553 (85.1%)	587 (90.3%)	1	0.0043*
		GG	97 (14.9%)	63 (9.7%)	0.61 (0.44–0.86)
	Log-additive	—	—	—	0.70 (0.60–0.83)	<0.0001*
rs9535828	Dominant	GG	207 (31.9%)	285 (43.9%)	1	<0.0001*
		GA-AA	443 (68.2%)	365 (56.1%)	0.46 (0.35–0.60)
	Recessive	GG-GA	531 (81.7%)	572 (88%)	1	0.0002*
		AA	119 (18.3%)	78 (12%)	0.53 (0.38–0.74)
	Log-additive	—	—	—	0.54 (0.44–0.65)	<0.0001*

Note: *Bonferroni multiple adjustment was applied, with p ≤ 0.008.

Abbreviations: SNP, single-nucleotide polymorphism; OR, odds ratio; CI, confidence interval.

Table 6 Association Between rs10981694, rs10488764, rs9535826 and rs9535828 and Risk of Lung Cancer in Smokers and Nonsmokers

SNP	Model	Genotype	Smokers		Nonsmokers
			OR (95% CI)	p	OR (95% CI)	p
rs10981694	Dominant	TT	1	0.057	1	0.0016*
		TG-GG	1.45 (1.02–2.08)		1.86 (1.26–2.73)
	Recessive	TT-TG	1	0.040	1	0.048
		GG	1.99 (0.92–4.31)		2.72 (0.95–7.77)
	Log-additive	—	1.42 (1.06–1.90)	0.018	1.79 (1.27–2.52)	0.0006*
rs10488764	Dominant	GG	1	0.010	1	0.0034*
		GA-AA	1.61 (1.21–2.14)		1.75 (1.20–2.55)
	Recessive	GG-GA	1	0.240	1	0.0039*
		AA	1.39 (0.80–2.41)		2.68 (1.33–5.40)
	Log-additive	—	1.44 (1.14–1.81)	0.002*	1.66 (1.24–2.21)	0.0005*
rs9535826	Dominant	TT	1	0.028	1	0.0008*
		TG-GG	0.73 (0.55–0.97)		0.52 (0.36–0.77)
	Recessive	TT-TG	1	0.064	1	0.027
		GG	0.66 (0.43–1.03)		0.55 (0.32–0.94)
	Log-additive	—	0.76 (0.62–0.94)	0.012	0.61 (0.47–0.81)	0.0004*
rs9535828	Dominant	GG	1	<0.0001*	1	0.100
		GA-AA	0.27 (0.18–0.40)		0.72 (0.49–1.06)
	Recessive	GG-GA	1	0.004*	1	0.0087*
		AA	0.50 (0.32–0.81)		0.53 (0.32–0.86)
	Log-additive	—	0.32 (0.24–0.45)	<0.0001	0.72 (0.55–0.93)	0.011

Note: *Bonferroni multiple adjustment was applied, with p ≤ 0.008.

Abbreviations: SNP, single-nucleotide polymorphism; OR, odds ratio; CI, confidence interval.

Table 7 Association Between rs10981694, rs10488764, rs9535826 and rs9535828 and Risk of Different Pathological Types of Lung Cancer

SNP	Model	Genotype	Adenocarcinoma		Squamous Cell Carcinoma		Small Cell Lung Cancer
			OR (95% CI)	p	OR (95% CI)	p	OR (95% CI)	p
rs10981694	Dominant	TT	1	0.048	1	0.0001*	1	0.024
		TG-GG	1.35 (1.00–1.81)		2.06 (1.44–2.96)		1.67 (1.07–2.59)
	Recessive	TT-TG	1	0.027	1	0.07	1	0.015
		GG	2.31 (1.11–4.83)		2.21 (0.96–5.09)		3.26 (1.34–7.93)
	Log-additive	—	1.37 (1.07–1.77)	0.014	1.86 (1.38–2.53)	0.0001*	1.70 (1.18–2.46)	0.005*
rs10488764	Dominant	GG	1	0.0021*	1	0.0098	1	0.0006*
		GA-AA	1.55 (1.17–2.05)		1.53 (1.11–2.12)		2.00 (1.34–2.96)
	Recessive	GG-GA	1	0.22	1	0.0006*	1	0.058
		AA	1.42 (0.82–2.45)		2.70 (1.56–4.68)		1.97 (1.01–3.85)
	Log-additive	—	1.40 (1.12–1.75)	0.003*	1.56 (1.22–2.00)	0.0005*	1.72 (1.27–2.31)	0.0005*
rs9535826	Dominant	TT	1	0.0013*	1	0.18	1	0.0048*
		TG-GG	0.63 (0.47–0.83)		0.80 (0.57–1.11)		0.56 (0.38–0.84)
	Recessive	TT-TG	1	0.006*	1	0.29	1	0.015
		GG	0.54 (0.34–0.85)		0.77 (0.47–1.26)		0.44 (0.22–0.91)
	Log-additive	—	0.67 (0.54–0.83)	0.0002*	0.83 (0.65–1.06)	0.13	0.60 (0.44–0.82)	0.0011*
rs9535828	Dominant	GG	1	<0.0001*	1	0.0022*	1	<0.0001*
		GA-AA	0.46 (0.33–0.64)		0.52 (0.34–0.79)		0.36 (0.22–0.59)
	Recessive	GG-GA	1	0.0041*	1	0.0035*	1	0.049
		AA	0.55 (0.36–0.84)		0.48 (0.28–0.80)		0.53 (0.27–1.03)
	Log-additive	—	0.55 (0.43–0.71)	<0.0001*	0.52 (0.38–0.72)	<0.0001*	0.46 (0.31–0.67)	<0.0001*

Note: *Bonferroni multiple adjustment was applied, with p ≤ 0.008.

Abbreviations: SNP, single-nucleotide polymorphism; OR, odds ratio; CI, confidence interval.