Exon 2 variants (rs3811046 and rs3811047) of the IL37 gene are associated with susceptibility to systemic lupus erythematosus

Figures & data

Table 1. Baseline clinical and laboratory data for SLE patients and healthy control women.

Variable; median (IQR) or n (%)		SLE; n = 120	HCW; n = 120	р-value
Age; year		32.0 (26.0–42.5)	34.0 (28.0–41.5)	0.143
Age group; n (%)	≤40	82 (68.3)	89 (74.2)	0.318
	>40	38 (31.7)	31 (25.8)
Disease duration; year		4.0 (2.0–6.0)	NA
Disease duration group	1–2	36 (30.0)
	3–4	35 (29.2)
	5–6	20 (16.7)
	>6	29 (24.2)
BMI; kg/m^2		28.6 (25.0–31.7)	NA
BMI group	Normal-weight	28 (23.3)
	Overweight/obese	92 (76.7)
SLEDAI		8.0 (6.0–10.0)	NA
SLEDAI group	Mild/moderate	103 (85.8)
	Active	17 (14.2)
Lupus nephritis group	Present	28 (23.3)	NA
	Absent	92 (76.7)
ANA; AU/mL		7 (4–34)	NA
Anti-dsDNA; U/mL		5 (3–9)	NA
C3; mg/dL		70 (46–95)	NA
C4; mg/dL		20 (14–24)	NA
BUN; mg/dL		26 (19–36)	NA
SCR; mg/dL		0.60 (0.50–1.00)	NA
RPG; mg/dL		92 (83–104)	NA
Hb; g/dL		11 (10–12)	NA
WBC; × 10^9/L		8 (5–9)	NA
Platelets; × 10^9/L		267 (206–323)	NA

SLE: Systemic lupus erythematosus; HCW: Healthy control women; IQR: Interquartile range; BMI: Body mass index; SLEDAI: SLE disease activity index; ANA: Anti-nuclear antibody; Anti-dsDNA: Anti-double stranded DNA; C3: Complement component 3; C4: Complement component 4; BUE: Blood urea nitrogen; SCR: Serum creatinine; RPG: Random plasma glucose; Hb: Hemoglobin; WBC: White blood cell; p: Mann-Whitney test probability; NA: Not applicable.

Figure 1. [a] Box-whisker plot of serum IL-37 levels in SLE patients and healthy control women (HCW). The horizontal line inside the box indicates the median. Whiskers indicate interquartile range (IQR). Black circles indicate outliers. Mann-Whitney U test was used to assess significant difference (***p < 0.001). [b] Receiver operating characteristic (ROC) curve analysis of IL-37 in SLE patients versus HCW. AUC: area under the curve; CI: confidence interval; p: probability.

Table 2. Serum interleukin-37 levels stratified by characteristics of SLE patients.

Group		IL-37 level; ng/L		р-value
		Median	IQR; 25–75%
Age; year	≤40	34.9	28.7–46.2	0.311
	>40	33.9	26.7–40.1
Disease duration; year	1–2	37.8	27.2–45.6	0.902
	3–4	34.0	30.0–52.0
	5–6	35.2	24.4–46.8
	>6	33.9	26.7–40.1
BMI	NW	38.3	28.5–46.7	0.354
	O/O	34.0	27.7–44.7
SLEDAI	M/M	34.0	26.1–43.6	0.049
	Active	40.1	32.2–52.4
Lupus nephritis	Present	38.0	29.1–45.6	0.413
	Absent	34.0	26.4–45.7

BMI: Body mass index; NW: Normal weight; O/O: Overweight/obese; SLEDAI: Systemic lupus erythematosus disease activity index; M/M: Mild/moderate; IQR: Interquartile range; p: Mann-Whitney test or Kruskal-Wallis test probability (significant p-value is indicated in bold).

Table 3. Association analysis of IL37 gene SNPs rs3811046 and rs3811047 with SLE risk.

SNP allele/genotype/haplotype	SLE; n = 120		HCW; n = 120		OR (95% CI)	p-value (pc)
	n	%	n	%
rs3811046
G	106	44.2	81	33.8	Reference
T	134	55.8	159	66.2	0.64 (0.45–0.93)	0.025 (0.075)
GG	29	24.2	17	14.2	Reference
GT	48	40.0	47	39.2	0.60 (0.29–1.23)	0.207
TT	43	35.8	56	46.6	0.45 (0.22–0.92)	0.033 (0.099)
p-HWE	0.039		0.174
rs3811047
A	117	48.7	55	22.9	Reference
G	123	51.2	185	77.1	0.31 (0.21–0.46)	<0.001 (<0.001)
AA	40	33.4	9	7.5	Reference
AG	37	30.8	37	30.8	0.22 (0.10–0.52)	<0.001 (<0.001)
GG	43	35.8	74	61.7	0.13 (0.06–0.29)	<0.001 (<0.001)
p-HWE	0.001		0.163
rs3811046–rs3811047
T-A	62	25.8	29	12.0	2.53 (1.56–4.11)	<0.001 (<0.001)
T-G	72	30.0	130	54.1	0.36 (0.25–0.53)	<0.001 (<0.001)
G-A	55	22.9	26	10.8	2.45 (1.47–4.06)	<0.001 (<0.001)
G-G	51	21.2	55	22.9	0.91 (0.59–1.40)	0.741

SNP: Single nucleotide polymorphism; SLE: Systemic lupus erythematosus; HCW: Healthy control women; OR: Odds ratio; CI: Confidence interval; HWE: Hardy-Weinberg equilibrium; p: Two-tailed probability; pc: Bonferroni correction probability. Significant p-value is indicated in bold.

Figure 2. Two-locus linkage disequilibrium (LD) plot for the IL37 gene variants rs3811046 G/T and rs3811047 A/G showing the LD coefficient (D’; 0.13; left) and correlation coefficient (R²; 0.01; right).

Table 4. Relationship of IL37 gene variants rs3811046 and rs3811047 to disease activity and lupus nephritis.

Allele/ genotype	SLEDAI		р-value	Lupus nephritis		р-value
	M/M; n = 103	Active; n = 17		Present; n = 28	Absent; n = 92
	n (%)	n (%)		n (%)	n (%)
rs3811046
G	95 (46.1)	11 (32.4)	0.142	23 (41.1)	83 (45.1)	0.646
T	111 (53.9)	23 (67.6)		33 (58.9)	101 (54.9)
GG	28 (27.2)	1 (5.9)	0.155	5 (17.9)	24 (26.1)	0.613
GT	39 (37.8)	9 (52.9)		13 (46.4)	35 (38.0)
TT	36 (35.0)	7 (41.2)		10 (35.7)	33 (35.9)
rs3811047
A	102 (49.5)	15 (44.1)	0.584	21 (37.5)	96 (52.2)	0.067
G	104 (50.5)	19 (55.9)		35 (62.5)	88 (47.8)
AA	35 (34.0)	5 (29.4)	0.877	6 (21.4)	34 (37.0)	0.257
AG	32 (31.0)	5 (29.4)		9 (32.1)	28 (30.4)
GG	36 (35.0)	7 (41.2)		13 (46.4)	30 (32.6)

SLEDAI: Systemic lupus erythematosus disease activity index; M/M: Mild/moderate; p: Two-tailed Fisher’s exact probability.

Figure 3. Box-whisker plot of serum IL-37 levels in SLE patients plus healthy control women stratified by genotypes of IL37 SNPs rs3811046 and rs3811047. The horizontal line inside the box indicates the median. Whiskers indicate interquartile range (IQR). Black circles indicate outliers. Mann-Whitney U test was used to assess significant difference (ns: not significant).