Gene variants of osteoprotegerin, estrogen-, calcitonin- and vitamin D-receptor genes and serum markers of bone metabolism in patients with Gaucher disease type 1

Figures & data

Table 1 Patients’ characteristics, compared to controls

Characteristics	Patients	Controls (group 2)	P-value
Age (years)	40 (26–51)	39 (28–48)	0.429
Sex (M/F)	19/31	19/31	1
Body mass index (kg/m^2)	24.47±3.72	24.09±4.23	0.196
Age at diagnosis (years)	32.2 (20.4–40.4)
Duration of treatment (years)	6.7 (1.27–8.75)

Table 2 Patients’ characteristics, according to splenic status, genotype of the glucocerebrosidase gene, and specific bone parameters

Splenectomy: n (%)	21/50 (42)	With splenectomy (a) (n=21)	Without splenectomy (b) (n=29)	P (a,b)
Genotype: n (%)
N409S/N409S	13 (26)	2/21 (9.5)	11/29 (37.9)	0.047
N409S/L444P	10 (20)	5/21 (23.8)	5/29 (17.2)	0.723
N409/other alleles	27 (54)	14/21 (66.6)	13/29 (44.4)	0.157
Pathological fractures: n (%)	14/50 (28)	11/21 (52.3)	3/29 (10.3)	0.001
Bone crises: n (%)	4/50 (8)	4/21 (19.0)	0/29	0.025
BMD (Z score L1–L4)
Before ERT	−1.81 (−2.62; −0.84)	−2.07 (−2.87; −1.20)	−1.69 (−2.5; −0.69)	0.14
Last visit	−0.5 (−1.1; −0.1)	−0.8 (−1; −0.1)	−0.5 (−1.1; −0.4)	0.46
Delta Z	1.3 (0.73; 2.12)	1.43 (0.78; 2.21)	1.2 (0.6; 2.1)	0.65
Avascular necrosis: n (%)	14/50 (28)	11/21 (52.3)	3/29 (10.3)	0.001
Severity score for bone disease^Citation25	4.44±1.86	5.64±1.91	3.39±1.20	0.011

Note: Quantitative variables were expressed as means and standard deviations if they followed a normal distribution or as medians and quartiles otherwise. Bold values indicate statistically significant values, P<0.05.

Abbreviations: BMD, bone mineral density; ERT, enzyme replacement therapy.

Figure 1 Improvement of BMD under ERT in patients with Gaucher disease type 1.

Abbreviations: BMD, bone mineral density; ERT, enzyme replacement therapy.

Table 3 Distribution of gene variants (alleles) with implications in bone metabolism in patients, stratified according to splenic status and controls

Gene	Gene variant/rs identification	Patients				Control group 1, (n=117, 234 alleles) (B)	P A,B OR (95% CI)	HWE (P)
		Total (n=50, 100 alleles) (A)	With splenectomy (a) (n=21, 42 alleles)	Without splenectomy (b) (n=29, 58 alleles)	P (a,b) OR (95% CI)
TNFRSF11B (OPG)	c.9C>G rs2073618	53G/47C	21G/21C	32G/26C	1 0.96 (0.4–2.29)	141G/93C	0.228 0.81 (0.49–1.33)	0.095
ESR1	c.453-351A>G rs9340799	44G/56A	19G/23A	25G/33A	0.841 0.92 (0.38–2.21)	107G/127A	0.810 1.07 (0.65–1.77)	0.0002*
	c.453–397T>C rs2234693	51C/49T	17C/25T	34C/24T	0.104 0.48 (0.2–1.16)	106C/128T	0.282 1.31 (0.8–2.15)	1
CALCR	c.1340T>C rs1801197	26C/74T	12C/30T	14C/44T	0.649 1.25 (0.46–3.39)	71C/163T	0.510 0.81 (0.46–1.4)	0.064
VDR	c.1024+283G>A rs1544410	66A/34G	28A/14G	38A/20G	1 0.95 (0.37–2.38)	140A/94G	0.223 0.73 (0.43–1.23)	1

Notes: Bold values indicate statistically significant values, P<0.05.

* Bonferroni correction for statistically significant results, corrected for the analyses in the two groups, separately for each gene variant.

Abbreviations: CALCR, calcitonin receptor gene; ESR1, estrogen receptor-α gene; HWE, Hardy–Weinberg equilibrium; OPG, osteoprotegerin gene; OR, odds ratio; rs, reference single nucleotide polymorphisms cluster; VDR, vitamin D receptor gene.

Table 4 Comparison between the bone densities (Z score) of patients before start of ERT (Z pre-ERT), at the moment of evaluation (Z under ERT), and the Z score increase under ERT (delta Z), depending on the analyzed gene variants of the osteoprotegerin, estrogen receptor 1, calcitonin receptor, and vitamin D receptor genes

TNFRSF11B (OPG) (c.9C>G; rs2073618)
	GG (n=17)	GC (n=19)	CC (n=14)	P(GG,GC)	P(GG,CC)	P(GC,CC)
Z pre-ERT	−1.8 (−2.2; −0.73)	−1.9 (−2.48; −0.59)	−2.69 (−3.09; −2.29)	0.98	0.32	0.35
Z under ERT	−0.1 (−0.95; 0.03)	−0.8 (−1.1; 0.1)	−0.3 (−0,4; 0.3)	0.88	0.99	0.18
Delta Z	1.11 (1.95; 2.70)	1.10 (0.6; 1.7)	2.89 (2.54; 3.04)	0.991	0.093	0.003*
ESR1 (c.453–351A>G; rs 9340799)
	AA (n=9)	AG (n=38)	GG (n=3)	P(AA,AG)	P(AA,GG)	P(AG,GG)
Z pre-ERT	−2.10 (−2.65; −1.75)	−1.86 (−2.57; −0.85)	−3.28 (−3.56; −2.99)	0.88	0.30	0.17
Z under ERT	0.0 (−1.00; 0.05)	−0.75 (−1.10; 0.12)	−0.40 (−0.45; −0.35)	0.98	0.6	0.38
Delta Z	1.70 (0.74; 2.00)	1.18 (0.76; 1.78)	2.88 (2.54; 3.21)	0.95	0.31	0.15
ESR1 (c.453–397T>C; rs 2234693)
	CC (n=13)	CT (n=25)	TT (n=12)	P(CC,CT)	P(CC,TT)	P(CT,TT)
Z pre-ERT	−1.81 (−2.62; −0.27)	−2.08 (−2.57; −1.59)	−1.40 (−2.71; −0.28)	0.90	1.00	0.81
Z under ERT	−0.10 (−0.95; 0.25)	−0.65 (−1.02; 0.18)	−0.90 (−1.50; −0.35)	0.89	0.41	0.60
Delta Z	1.27 (0.67; 1.75)	1.42 (0.97; 2.52)	0.85 (−0.35; 1.58)	0.68	0.53	0.30
CALCR (c.1340T>C; rs 1801197)
	CC (n=6)	CT (n=14)	TT (n=30)	P(CC,CT)	P(CC,TT)	P(CT,TT)
Z pre-ERT	−0.89 (−1.38; −0.59)	−1.7 (−2.83; −1.4)	−2.16 (−2.65; −1.50)	0.240	0.041*	0.998
Z under ERT	−0.25 (−0.73; 1.12)	−0.30 (−0.90; 0.20)	−0.80 (−1.15; 0.05)	0.89	0.40	0.62
Delta Z	0.88 (0.18; 1.83)	1.60 (1.10; 2.59)	1.16 (0.73; 2.03)	0.67	0.93	0.60
VDR (c.1024+283G>A; rs1544410)
	GG (n=6)	GA (n=22)	AA (n=22)	P(GG,GA)	P(GG,AA)	P(GA,AA)
Z pre-ERT	−1.85 (−2.61; −1.05)	−1.47 (−1.81; −0.45)	−2.60 (−2.83; −2.07)	0.734	0.689	0.033*
Z under ERT	−0.65 (−0.8; −0.12)	−0.40 (−1.10; 0.28)	−0.60 (−1.30; 0.00)	0.970	0.870	0.750
Delta Z	1.94 (1.05; 2.95)	1.13 (0.50; 1.54)	1.70 (0.80; 2.63)	0.580	0.990	0.120

Notes: Values are given as medians and interquartile ranges. Bold values indicate statistically significant values, P<0.05. All P-values for each genotype were corrected for multiple testing;

* Bonferroni correction was added for statistically significant P-values (corrected for the three variables that were assessed per each genotype).

Abbreviations: CALCR, calcitonin receptor gene; delta Z, difference between Z score at present and Z score before the start of ERT; ERT, enzyme replacement therapy; ESR1, estrogen receptor α gene; TNFRSF11B (OPG), osteoprotegerin gene; VDR, vitamin D receptor gene.

Table 5 Distribution of the genotypes of the c.1024+283 G>A variant of VDR gene in patients with Gaucher disease, stratified according to BMD before ERT and to splenic status

BMD	n	Genotypes: n (%)				P-value
		GG		GA	AA
All patients (n=50)
OP	17	2/17 (11.7)		1/17 (5.8)	14/17 (82.3)	0.006*	}0.001
O	18	2/18 (11.1)		11/18 (61.1)	5/18 (27.8)
N	15	2/15 (13.3)		10/1 (66.6)	3/15 (20)
Total	50	6 (12)		22 (44)	22 (44)
Patients with splenectomy (n=2l)
OP	8	2/8 (25)		0/8 (0)	6/8 (75)	0.011*	}0.06#
O	8	1/8 (12.5)		5/8 (62.5)	2/8 (25)
N	5	0/5 (0)		3/5 (60)	2/5 (40)
Total	21	3 (14.2)		8 (38.1)	10 (47.6)
Patients without splenectomy (n=29)
OP	9		0/9 (0)	1/9 (11.1)	8/9 (88.8)	0.03*	}0.006#
O	10		1/10 (10)	6/10 (60)	3/10 (30)
N	10		2/10 (20)	7/10 (70)	1/10 (10)
Total	29		3 (10.3)	14 (48.3)	12 (41.3)

Notes: Bold values indicate statistically significant values, P<0.05.

* Bonferroni-corrected P-value for BMD subgroup analysis (P × 3);

# Bonferroni-corrected P-value for splenectomy subgroup analysis (P × 2).

Abbreviations: BMD, bone mineral density; ERT, enzyme replacement therapy; N, normal BMD; O, osteopenia; OP, osteoporosis.

Table 6 Biomarkers of bone metabolism and subclinical inflammation

	Patients (A)	Control group 2 (B)	P-value (A,B)	Patients with splenectomy (a)	Patients without splenectomy (b)	P-value (a,b)
Calcium (mmol/L)	2.46 (2.36; 2.53)	2.43 (2.34; 2.50)	0.085	2.49 (2.36–2.56)	2.45 (2.38–2.49)	0.36
Phosphate (mg/dL)	3.8 (3.6; 4.2)	3.9 (3.6; 4.1)	0.897	4 (3.7–4.4)	3.8 (3.5–4.2)	0.447
Total alkaline phosphatase (U/L)	59 (49–68)	63 (52; 80)	0.056	69 (55–79)	54 (45–62)	0.002
Parathormone intact (pg/mL)	44.2 (35.8; 55.7)	44.3 (36.9; 58.2)	0.942	48.1 (33.9–60.1)	44.2 (38.1–53.1)	0.569
25-hydroxy-vitamin D (ng/mL)	24.6 (18.8; 28.3)	19.8 (17.6; 28.4)	0.208	22.3 (18.4–26.2)	24.6 (20.4–29.5)	0.219
OC (ng/mL)	16.8 (13.1; 21.9)	20.6 (17.3; 24.7)	0.011	16.8 (13.8–24)	16.8 (13.1–21.5)	0.609
P1NP (µL/L)	59 (42; 73)	56 (42; 76)	0.886	65 (46–79)	52 (42–63)	0.135
OPG (pmol/L)	4.7±2.8	6.2±2.7	0.009	5.6±2.9	4.1±2.5	0.068
Total soluble RANKL (pg/mL)	49,250 (20,317; 1,06,000)	54,910 (14,510–79,125)	0.976	65,590 (23,200–99,500)	46,950 (19,700–1,34,000)	0.953
C-terminal telopeptide of type 1 collagen (ß-CTX, ß-CrossLaps) (pg/mL)	390 (273; 518)	318 (256; 364)	0.009	423 (240–518)	390 (276–555)	0.922
Sclerostin (pmol/L)	35 (29; 43)	32 (27; 47)	0.956	36 (32–46)	34 (29–39)	0.201
hsCRP (mg/L)	1.34 (0.49; 2.53)	1.2 (0.5; 1.52)	0.134	1.59 (0.74–2.53)	1.09 (0.45–2.44)	0.345
IL-6 (pg/mL)	2 (2–3)	2 (2–2)	0.008	2 (2–3)	2 (2–2)	0.7
Iron (µg/dL)	107.1±43.5	109.1±32.5	0.607	115 (90–147)	93 (70–130)	0.075
Ferritin (ng/mL)	251 (72; 476)	36 (20; 106)	<0.001	252 (165–689)	181 (44–383)	0.13
Transferrin (g/L)	2.52 (2.27; 2.8)	2.82 (2.49; 2.91)	0.140	2.48 (2.31–2.79)	2.55 (2.26–2.83)	0.665
Transferrin saturation (%)	26.6 (22.5; 42.1)	26.3 (23.3; 40.2)	0.802	32.9 (24.9–44)	23.9 (19.9–36.4)	0.046

Note: Quantitative variables were expressed as means and standard deviations if they followed a normal distribution or as medians and quartiles otherwise. Bold values indicate statistically significant values, P<0.05.

Abbreviations: hsCRP, high-sensitive C-reactive protein; IL-6, interleukin-6; OC, osteocalcin; OPG, osteoprotegerin; P1NP, N-terminal propeptide of type 1 collagen.

CoxTMAertsJMBelmatougNManagement of non-neuronopathic Gaucher disease with special reference to pregnancy, splenectomy, bisphosphonate therapy, use of biomarkers and bone disease monitoringJ Inherit Metab Dis200831331933618509745

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