Pharmacogenetic analysis of cinacalcet response in secondary hyperparathyroidism patients

Figures & data

Table 1 Demographic characteristics at baseline for included subjects (n=70)

Characteristics	Total (N=70)* (%)	Grouped by cinacalcet response (N=68)** (%)		P-value
		Responders (n=53)	Nonresponders (n=15)
Male sex, n (%)	32 (45.7)	27 (50.9)	4 (26.7)	0.096
Age, years, median (range)	50 (21–75)	49 (21–75)	52 (24–71)	0.325
BMI, kg/cm^2, median (range)	22.37 (16.01–31.45)	22.08 (16.01–31.00)	23.29 (17.76–27.38)	0.206
Cause of CKD, n (%)
DM	12 (17.2)	7 (13.2)	4 (26.7)	0.680
HTN	10 (14.3)	7 (13.2)	2 (13.3)	1.000
GN	28 (40.0)	22 (41.5)	6 (40.0)	0.916
Others	20 (28.6)	17 (32.1)	3 (20.0)	0.762
Mode of dialysis, n (%)
HD	19 (27.1)	11 (20.8)	7 (46.7)	0.093
PD	40 (57.1)	33 (62.3)	6 (40.0)	0.124
Both	11 (15.7)	9 (17.0)	2 (13.3)	1.000
Dialysis duration, median (range)	97 (38–195)	77.5 (15–300)	97 (38–195)	0.363
Use of phosphate binder/calcium supplement, n (%)	62 (88.6)	48 (90.6)	14 (93.3)	1.000
Lab values, median (range)
iPTH (pg/mL)*	620 (300–1,493)	622 (300–1,493)	601 (316–1,183)	0.375
Albumin corrected calcium (mg/dL)	9.84 (7.4–13.52)	9.72 (7.40–13.52)	10.50 (9.18–11.88)	0.001
Phosphorus (mg/dL)	5.85 (3.40–12.80)	5.70 (3.50–12.80)	6.00 (3.40–7.50)	0.673
Ca × P (mg^2/dL^2)	58.35 (32.41–94.72)	57.01 (32.41–94.72)	61.80 (37.38–71.10)	0.787
ALP (IU/L)	106 (41–393)	100 (41–381)	124 (61–762)	0.252
Hb (g/dL)	10.50 (7.00–14.60)	10.70 (7.00–14.00)	10.10 (7.70–14.60)	0.107
Albumin (g/dL)	3.80 (2.40–11.50)	3.80 (2.40–5.10)	3.90 (3.10–4.40)	0.953
Serum creatinine (mg/dL)	11.69 (4.30–20.66)	12.03 (4.30–20.66)	10.85 (4.35–18.12)	0.248
GFR (mL/min/1.73 m^2)	3.80 (2.10–15.7)	3.80 (2.50–13.30)	3.80 (2.10–15.70)	0.842
Comorbidity related with CKD-MBD, n (%)
Osteoporosis	6 (8.6)	5 (9.4)	1 (6.7)	1.000
Osteopenia	22 (31.4)	18 (34.0)	3 (20.0)	0.361
Fracture	11 (15.7)	7 (13.2)	4 (26.7)	0.243
PTH hyperplasia or adenoma	15 (21.4)	12 (22.6)	3 (20.0)	0.726
HTN	51 (72.9)	39 (73.6)	10 (66.7)	0.745
IHD, HF, AF, LVH	25 (35.7)	16 (30.2)	8 (53.3)	0.666
Comorbidity related with neoplasm	13 (18.6)	7 (13.2)	5 (33.3)	0.442

Notes:

* A total of 70 patients were included in the final analysis.

** A total of 68 patients who had available iPTH level were included in the cinacalcet response analysis. Significant results are marked in bold.

Abbreviations: AF, atrial fibrillation; ALP, alkaline phosphatase; BMI, body mass index; CKD, chronic kidney disease; CKD-MBD, chronic kidney disease-mineral bone disease; DM, diabetes mellitus; GFR, glomerular filtration rate; Hb, hemoglobin; HF, heart failure; HTN, hypertension; GN, glomerulonephritis; HD, hemodialysis; IHD, ischemic heart disease; iPTH, intact parathyroid hormone; LVH, left ventricular hypertrophy; PD, peritoneal dialysis; PTH, parathyroid hormone.

Table 2 Comparison of biochemical parameter percent changes between baseline and 3-month treatment with cinacalcet (n=68)

Parameter	Responders Median (range) (%)	Nonresponders Median (range) (%)	P-value*
ΔPTH (pg/mL)	−42.29 (−97.41–[−9.23])	6.16 (0.90–45.25)	<0.001
ΔCalcium (mg/dL)	−5.75 (−25.67–15.81)	−7.13 (−19.09–1.67)	0.182
ΔPhosphorus (mg/dL)	−9.84 (−69.23–69.43)	−8.42 (−33.33–72.43)	0.170
ΔCa × P (mg^2/dL^2)	−14.70 (−71.13–68.70)	−8.84 (−36.99–43.70)	0.296
ΔALP (IU/L)	1.60 (−28.48–146.58)	10.71 (−29.26–93.89)	0.211

Notes: The 3-month treatment value for biochemical parameters is defined as the mean value during baseline to 3-month treatment.

* Descriptive P-values were obtained from the independent-samples t-test or Mann–Whitney U-test. Significant results are marked in bold.

Abbreviations: ALP, alkaline phosphatase; PTH, parathyroid hormone.

Table 3 The loci and minor allele frequency (MAF) information of the 24 SNPs in CASR, VDR, FGFR1, KL, RGS14, SLC34A1, ALPL, NR4A2, and PTHLH genes

Gene/SNP	Chromosome position	Alleles	SNP location	Observed MAF/expected MAF	HWE test (P-value)
CASR
rs1042636	3:122284922	A/G	Exon	0.458/0.2065	0.59
rs2221266	3:122277969	C/T	Intron	0.410/0.4619	0.97
rs10190	3:122286389	C/T	3′UTR	0.387/0.4669	0.81
rs1802757	3:122286284	C/T	3′UTR	0.359/0.1983	0.43
VDR
rs7975232	12:47845054	A/C	Intron	0.160/0.4846	0.87
rs2228570	12:47879112	C/T	Exon	0.382/0.3285	0.80
rs1544410	12:47846052	A/G	Intron	0.063/0.2959	0.57
rs11574129	12:47843520	T/C	3′UTR	0.099/0.0385	0.08
rs3847987	12:47844285	G/T	3′UTR	0.106/0.1288	0.13
rs739837	12:47844438	C/A	3′UTR	0.176/0.4942	0.67
rs9729	12:47842840	C/A	3′UTR	0.169/0.4902	0.71
FGFR1
rs13317	8:38411996	C/T	3′UTR	0.345/0.2250	0.06
KL
rs1207568	13:33016046	C/T	Exon	0.160/0.1601	0.11
RGS14
rs4074995	5:177370342	A/G	Intron	0.236/0.1895	0.20
SLC34A1*
rs3812035	5:177390142	A/C	3′UTR	0.255/0.387	0.01
ALPL
rs1697421	1:21496799	A/G	Exon	0.458/0.3776	0.50
rs3200254	1:21568242	C/T	Exon	0.424/0.2670	0.66
rs2242420	1:21578036	C/T	3′UTR	0.155/0.1172	0.47
rs2242421	1:21578081	A/G	3′UTR	0.345/0.2220	0.46
rs1697405	1:21577713	G/A	3′UTR	0.268/0.3367	0.43
rs1697406	1:21577774	A/G	3′UTR	0.148/0.1318	0.49
NR4A2
rs12803	2:156329935	G/A	3′UTR	0.2863/0.169	0.45
PTHLH
rs2796	12:27963178	A/G	3′UTR	0.127/0.0727	0.76
rs6253	12:27963008	A/G	3′UTR	0.394/0.3243	0.09
rs6245	12:27963124	A/G	3′UTR	0.085/0.0629	0.40

Note:

* Hardy–Weinberg Equilibrium (HWE) test was not satisfied and SLC34A1 rs3812035 excluded for our analysis. Significant results are marked in bold.

Abbreviations: UTR, untranslated region; SNP, single nucleotide polymorphism; MAF, minor allele frequency.

Table 4 Comparisons of genotypes and allele frequencies between responders versus nonresponders group

Gene/SNP	Genotype frequency (%)			Minor allele frequency (%)
	Responders (n=53)	Nonresponders (n=15)	P-value	Responders (n=53)	Nonresponders (n=15)	P-value
	AA/AB/BB	AA/AB/BB		B	B
CASR
rs1042636 (A/G)	15.1/50.9/34.0	40/53.3/6.7	0.036	59.4	33.3	0.075
rs2221266 (C/T)	41.5/45.3/13.2	13.3/53.3/33.3	0.086	35.8	60.0	0.111
rs10190# (C/T)	42.3/44.2/13.5	15.4/61.5/23.1	0.190	35.6	53.8	0.149
rs1802757# (C/T)	44.2/48.1/7.7	15.4/61.5/23.1	0.086	31.7	53.8	0.085
VDR
rs7975232 (G/T)	66.0/28.3/3.8	80/20/0	0.336	17.9	10	0.292
rs2228570 (C/T)	37.7/47.2/15.1	33.3/60.0/6.7	0.585	38.7	36.7	0.920
rs1544410 (A/G)	84.9/15.1/0	93.3/6.7/0	0.672	7.5	3.3	1.000
rs11574129# (T/C)	82.7/13.5/3.8	84.6/15.4/0	0.574	10.5	7.7	1.000
rs3847987# (G/T)	78.8/15.4/3.8	84.6/15.4/0	0.706	11.5	7.7	0.672
rs739837# (C/A)	61.5/32.7/3.8	76.9/23.1/0	0.762	20.2	11.5	1.000
rs9729# (C/A)	63.5/30.8/3.8	76.9/23.1/0	0.769	19.2	11.5	1.000
FGFR1
rs13317 (G/A)	47.2/39.6/13.2	46.7/20.0/33.3	0.313	33.0	43.3	0.865
KL
rs1207568 (C/T)	66.0/32.1/1.9	66.7/33.3/0	0.865	17.0	20.0	0.852
RGS14
rs4074995 (A/G)	50.9/30.2/11.3 (F:7.6)	60.0/33.3/6.7	0.828	26.4	23.3	1.000
ALPL
rs1697421 (A/G)	34.0/41.5/24.5	6.7/46.7/26.7	0.491	45.3	50.0	0.666
rs3200254 (C/T)	30.2/45.3/24.5	26.7/53.3/6.7 (F:13.3)	0.837	47.2	33.3	0.818
rs2242420# (C/T)	65.4/32.7/1.9	76.9/23.1/0	0.880	18.3	11.5	1.000
rs2242421# (A/G)	42.3/42.3/15.4	46.2/38.5/15.4	0.964	36.5	34.6	0.955
rs1697405# (G/A)	51.9/42.3/5.8	46.2/38.5/7.7	0.920	26.9	26.9	1.000
rs1697406# (A/G)	67.3/30.8/1.9	69.2/23.1/0 (F:7.7)	0.858	17.3	11.5	1.000
NR4A2
rs12803 (G/A)	69.2/28.8/1.9	61.5/38.5/0	0.721	16.3	19.2	0.704
PTHLH
rs2796# (A/G)	73.1/25.0/1.9	84.6/15.4/0	0.589	14.4	7.7	0.672
rs6253# (A/G)	32.7/51.9/15.4	23.1/76.9/0	0.296	41.3	38.5	0.656
rs6245# (A/G)	80.8/19.2/0	92.3/7.7/0	0.439	9.6	3.8	1.000

Notes: Significant result is marked with bold type. F means failure rate (%) to genotype analysis.

# SNPs are located in 3′ untranslated region and analyzed in 65 patients (responder: 52, nonresponder: 13).

Abbreviations: AA, homozygote major allele; AB, heterozygote allele; BB, homozygote minor allele; SNP, single nucleotide polymorphism.

Table 5 Association of PTH regulation by cinacalcet with SNPs of CASR, VDR, FGFR1, KL, ALPL, RGS14, NR4A2, and PTHLH

Gene/SNP	Genotype model*			Dominant model**	Recessive model**
	BB	AB	AA	BB + AB vs AA	BB vs AB + AA
	OR (95% CI)	OR (95% CI)	OR	OR (95% CI)	OR (95% CI)
CASR
rs1042636 (A/G)	0.074 (0.008–0.721) P=0.025	0.395 (0.106–1.479) P=0.168	1	0.267 (0.074–0.957) P=0.035	0.139 (0.017–1.142) P=0.050
rs2221266 (C/T)	5.500 (0.839–36.059) P=0.076	3.826 (0.730–20.044) P=0.112	1	4.613 (0.945–22.526) P=0.065	2.813 (0.758–10.431) P=0.142
rs10190 (C/T)	5.500 (0.741–40.803) P=0.095	4.304 (0.730–20.044) P=0.112	1	4.033 (0.811–20.056) P=0.109	1.929 (0.423–8.784) P=0.405
rs1802757 (C/T)	8.625 (1.077–69.075) P=0.042	3.680 (0.707–19.156) P=0.122	1	4.362 (0.878–21.669) P=0.056	3.600 (0.695–18.646) P=0.136
VDR
rs7975232 (G/T)		0.365 (0.073–1.823) P=0.219	1	0.324 (0.065–1.607) P=0.200
rs2228570 (C/T)	0.500 (0.050–4.978) P=0.554	1.440 (0.416–4.983) P=0.565	1	1.212 (0.362–4.059) P=0.755	0.402 (0.046–3.497) P=0.672
rs1544410 (A/G)		0.402 (0.046–3.497) P=0.409	1	0.402 (0.046–3.497) P=0.672
rs11574129 (T/C)		0.438 (0.050–3.853) P=0.456	1	0.350 (0.041–3.015) P=0.439
rs3847987 (G/T)		0.741 (0.141–3.905) P=0.723	1	0.606 (0.118–3.121) P=0.717
rs739837 (C/A)		0.917 (0.245–3.433) P=0.897	1	0.815 (0.220–3.021) P=1.000
rs9729 (C/A)		1.007 (0.268–3.791) P=0.991	1	0.889 (0.239–3.307) P=1.000
FGFR1
rs13317 (C/T)	1.500 (0.355–6.347) P=0.582	0.429 (0.100–1.828) P=0.252	1	0.724 (0.229–2.286) P=0.581	2.045 (0.520–8.044) P=0.442
KL
rs1207568 (C/T)		1.029 (0.304–3.486) P=0.963	1	0.972 (0.289–3.276) P=0.964
RGS14
rs4074995 (A/G)	0.500 (0.053–4.732) P=0.546	0.938 (0.267–3.292) P=0.920	1	0.818 (0.252–2.653) P=0.738	0.512 (0.057–4.626) P=1.000
ALPL
rs1697421 (A/G)	1.821 (0.266–12.473) P=0.541	2.705 (0.497–14.718) P=0.250	1	2.361 (0.465–11.979) P=0.484	0.929 (0.220–3.928) P=1
rs3200254 (C/T)	0.667 (0.104–4.261) P=0.668	1.120 (0.282–4.449) P=0.872	1	0.973 (0.261–3.627) P=1.000	0.621 (0.121–3.197) P=0.718
rs2242420 (C/T)		0.972 (0.260–3.632) P=0.967	1	0.915 (0.246–3.400) P=1.000
rs2242421 (A/G)	0.917 (0.153–5.508) P=0.924	0.833 (0.221–3.138) P=0.788	1	0.856 (0.252–2.902) P=0.802	1.000 (0.186–5.390) P=1.000
rs1697405 (G/A)	1.500 (0.132–17.037) P=0.744	1.227 (0.347–4.343) P=0.751	1	1.080 (0.308–3.791) P=0.904	1.485 (0.141–15.659) P=0.574
rs1697406 (A/G)		1.200 (0.313–4.596) P=0.790	1	0.686 (0.164–2.866) P=0.739
NR4A2
rs12803 (G/A)		1.500 (0.422–5.338) P=0.531	1	1.250 (0.361–4.327) P=0.724
PTHLH
rs2796 (A/G)		0.487 (0.096–2.472) P=0.385	1	0.452 (0.090–2.280) P=0.488
rs6253 (A/G)		1.286 (0.341–4.853) P=0.711	1	1.000 (0.268–3.732) P=1.000
rs6245 (A/G)		0.350 (0.041–3.015) P=0.339	1	0.350 (0.041–3.015) P=0.439

Notes: Significant results are marked in bold type.

* Logistic regression analysis.

** Chi-square analysis.

Abbreviations: AA, homozygote major allele; AB, heterozygote; BB, homozygote minor allele; CI, confidence interval; OR, odds ratio; PTH, parathyroid hormone; SNP, single nucleotide polymorphism.

Table 6 Association of PTH regulation by cinacalcet with CASR, VDR, and ALPL haplotypes

Gene/SNP	Haplotype	Haplotype frequency (%)	Case/control frequencies (%)	OR (95% CI)	P-value
CASR
rs1042636 (A/G)	GCC	0.529	33.3/58.5	0.355 (0.151–0.832)	0.015
rs1802757 (C/T)	ATT	0.375	57.3/31.9	2.769 (1.208–6.347)	0.014
rs10190 (C/T)	ACC	0.064	8.5/5.8	1.786 (0.420–7.597)	0.423
	ACT	0.032	0.9/3.8	–	0.575
VDR
rs9729 (C/A)	CTGCG	0.815	88.5/79.8	1.940 (0.531–7.081)	0.404
rs11574129 (T/C)	ACTAT	0.092	7.7/9.6	0.783 (0.161–3.814)	1
rs3847987 (G/T)	ATGAT	0.068	3.8/7.6	0.480 (0.057–4.019)	0.686
rs739837 (C/A)
rs7975232 (G/T)
ALPL
rs1697406 (A/G)	GCG	0.638	65.4/63.5	1.088 (0.442–2.678)	0.855
rs2242420 (C/T)	GCA	0.192	23.1/18.3	1.342 (0.475–3.794)	0.578
rs2242421 (A/G)	ATA	0.162	11.5/17.3	0.623 (0.169–2.300)	0.567

Note: Significant results are marked in bold type.

Abbreviations: CI, confidence interval; OR, odds ratio; PTH, parathyroid hormone; SNP, single nucleotide polymorphism.

Figure 1 The haplotype blocks of the three studied genes: (A) CASR, (B) VDR, and (C) ALPL.

Notes: The numbers indicate the extent of linkage equilibrium based on D′ value between two SNPs calculated with Haploview 4.2. Only CASR haplotype of GCC (odds ratio [OR]: 0.355 [0.151–0.832], P=0.015) and ATT (OR: 2.769 [1.208–6.347], P=0.014) showed the significance D′ represents the linkage disequilibrium of one haplotype.
Abbreviation: SNPs, single nucleotide polymorphisms.

Table S1 The primer sets and melting temperature (Tm) used for the SNaPshot assay

Gene	rs number	Strand	Primer sequence		Tm
CASR	rs1042636	Forward	Forward primer	CAGATGCAAGCAGAAGGT	55
			Reverse primer	CAAAGCTCTGTGAACTGGA
			Genotyping primer	GCCTCAGAAGAAYKCCATGGCSCAC
	rs2221266	Reverse	Forward primer	CTGTTTACCCCTGTTGGAT	55
			Reverse primer	TCCATTGTGTGCTACGTTT
			Genotyping primer	GTGTGCTACGTTTGAGGTAAT
	rs10190	Reverse	Forward primer	CCAAGAAAGATCCACCCTCA	55
			Reverse primer	TGGGCTAGGCAGTACAATCTG
			Genotyping primer	atccacataagagctctgaggggaa
	rs1802757	Forward	Forward primer	CCAAGAAAGATCCACCCTCA	55
			Reverse primer	TGGGCTAGGCAGTACAATCTG
			Genotyping primer	ggagccagMgagacaRaccggggtt
VDR	rs7975232	Forward	Forward primer	aagtcactggagggcttt	55
			Reverse primer	TTAGCTTCATGCTGCACTC
			Genotyping primer	TGGTGGGATTGAGCAGTGAGG
	rs2228570	Reverse	Forward primer	gatgcaacatctgaaacca	55
			Reverse primer	AGCCTTCACAGGTCATAGC
			Genotyping primer	agggaagtgctggccRccattKcctcc
	rs1544410	Forward	Forward primer	CTACTTTGCTGGTTTGCAG	55
			Reverse primer	ATTGCCTCCAAAATCAATC
			Genotyping primer	TTCCTGGRGCCACAGACAGRCCTGC
	rs11574129	Forward	Forward primer	TGTTCACCCACAGGGCTAA	55
			Reverse primer	CACAGCTTCCAGGAGTTGG
			Genotyping primer	GAGTGATACAACTTCAAGTGCATGC
	rs3847987	Reverse	Forward primer	CACCCAGCCCATTCTCTCT	55
			Reverse primer	GGGAAGAAAACCCACCTCA
			Genotyping primer	AAGGGGGTGGGGTGGGAGCTGTGGG
	rs739837	Reverse	Forward primer	CACCCAGCCCATTCTCTCT	55
			Reverse primer	GGGAAGAAAACCCACCTCA
			Genotyping primer	CTCAACATCAGTCAGCAGCCACTTA
	rs9729	Forward	Forward primer	agcaggtaccactgatttgga	60
			Reverse primer	gtctcgaactcccgacctc
			Genotyping primer	TGCTAAACGAGTcaatcccMtcatt
FGFR1	rs13317	Forward	Forward primer	aattatccaggcatggtg	55
			Reverse primer	CCCAACAAATACAGTCTGGT
			Genotyping primer	TCTATGTGGGCATGGTTTTGCC
KL	rs1207568	Reverse	Forward primer	CTCACCTAAGGGGGAATC	55
			Reverse primer	ACGCTCAGGTTCATTCTCT
			Genotyping primer	cggggagaaaaggcgcSgaccaacttt
RGS14	rs4074995	Forward	Forward primer	GGAATGGAGAGAAGTGGAC	55
			Reverse primer	GAGGGTGGAAGAGCTGTAG
			Genotyping primer	CATTTCATGCCAGCAGCTACGTTTCTC
SLC34A1*	rs3812035	Forward	Forward primer	CATCCCCTTTCTGGGACAG	55
			Reverse primer	ccaggTTGCAAGTCCTCAA
			Genotyping primer	TCCCTTCCAACCTGTTCCCATTGAC
ALPL	rs1697421	Forward	Forward primer	TTGGAGTGCAGTGGTGTGA	55
			Reverse primer	GCAGCTCCCAAAGAAGAGG
			Genotyping primer	CCCTTATGAGCACTTCTTAAAGGCA
	rs3200254	Forward	Forward primer	ACCAGGCTGGGAAAGTGTC	55
			Reverse primer	TCTGGTATCCCCTCCAAGG
			Genotyping primer	CACCTGGAAGAGCTTCAAACCGAGA
	rs2242420	Reverse	Forward primer	ACTACGTCCCCCACGTGAT	60
			Reverse primer	CCTGGTGGTCTTGGAGTGA
			Genotyping primer	AGAGGTAAGGAGATGGGAGTGGGA
	rs2242421	Forward	Forward primer	ACTACGTCCCCCACGTGAT	60
			Reverse primer	CCTGGTGGTCTTGGAGTGA
			Genotyping primer	CCTCTGGAACCCCCCAGGCCCTACA
	rs1697405	Reverse	Forward primer	ACTACGTCCCCCACGTGAT	60
			Reverse primer	CCTGGTGGTCTTGGAGTGA
			Genotyping primer	GGCCCCCACCTCCCTGCCCCTTGAK
	rs1697406	Forward	Forward primer	ACTACGTCCCCCACGTGAT	60
			Reverse primer	CCTGGTGGTCTTGGAGTGA
			Genotyping primer	CTGCAACTGCAAGAAAGGGGACCCA
NR4A2	rs12803	Reverse	Forward primer	GGCAGAGATAGCCGTGTGA	55
			Reverse primer	TGGGCTAGGCAGTACAATCTG
			Genotyping primer	atccacataagagctctgaggggaa
PTHLH	rs2796	Forward	Forward primer	TGCTCTCAGCTGGGTTTTG	55
			Reverse primer	CATGATGCTGTTCTGCAGTGT
			Genotyping primer	TCAGAATATTGTCTGCCTTAAAGCA
	rs6253	Forward	Forward primer	TGCTCTCAGCTGGGTTTTG	55
			Reverse primer	CATGATGCTGTTCTGCAGTGT
			Genotyping primer	TCTTCATAATTTGCTGGAGAAGTGT
	rs6245	Forward	Forward primer	TGCTCTCAGCTGGGTTTTG	55
			Reverse primer	CATGATGCTGTTCTGCAGTGT
			Genotyping primer	TCCAGCACCATAGAGAGGCGYTAGA

Note:

* SLC34A4 was not included in the final analysis because it didn’t meet the Hardy Weinberg Equilibrium (HWE).

Table S2 Association between biochemical parameters and the genotypes* of four SNPs of CASR

Parameter	Total Δ% (mean ± SD)	Δ% by genotypes, median (range)
		rs1042636		rs2221266		rs10190		rs1802757
		AA (n=14)	GA + GG (n=56)	CC (n=24)	CT + TT (n=46)	CC (n=24)	CT + TT (n=41)	CC (n=25)	CT + TT (n=40)
Ca mg/dL	−6.64	−6.22	−6.64	−6.27	−6.38	−6.27	−6.50	−5.75	−6.68
	(−19.09–15.81)	(−19.17–15.81)	(−25.67–5.07)	(−25.67–5.07)	(−19.17–15.81)	(−25.67–5.07)	(−19.17–15.81)	(−25.67–5.07)	(−19.17–15.81)
P-value		0.622		0.889		0.863		0.590
P mg/dL	−8.13	−3.87	−9.35	−6.81	−9.23	−8.64	−9.84	−8.87	−9.23
	(−43.69–69.43)	(−69.23–72.44)	(−57.73–69.43)	(−42.08–40.00)	(−69.23–72.44)	(−42.08–63.83)	(−69.23–72.44)	(−42.08–63.83)	(−69.23–72.44)
P-value		0.463		0.934		0.714		0.989
Ca × P mg^2/dL^2	−12.22	−6.66	−14.80	−9.82	−14.80	−12.73	−14.90	−13.68	−14.80
	(−44.87–68.70)	(−71.13–43.70)	(−64.98–68.70)	(−48.81–30.50)	(−71.13–68.70)	(−48.81–41.24)	(−71.13–68.70)	(−48.81–41.24)	(−71.13–68.70)
P-value		0.686		0.874		0.647		0.862
ALP IU/l	2.36	8.85	2.35	2.04	2.36	0.69	6.67	0.91	5.14
	(−28.48–146.58)	(−29.26–84.42)	(−28.48–146.58)	(−28.48–93.89)	(−29.26–146.58)	(−28.48–93.89)	(−29.26–146.58)	(−28.48–93.89)	(−29.26–146.58)
P-value		0.310		0.614		0.197		0.373

Note:

* Analyzed by a dominant genetic model.

Abbreviations: ALP, alkaline phosphatase; SD, standard deviation; SNP, single nucleotide polymorphism.