Protein Tyrosine Phosphatase-1B Gene PTPN1: Selection of Tagging Single Nucleotide Polymorphisms and Association With Body Fat, Insulin Sensitivity, and the Metabolic Syndrome in a Normal Female Population

Nicola J. Spencer-Jones; Xiaoling Wang; Harold Snieder; Tim D. Spector; Nicholas D. Carter; Sandra D. O’Dell

doi:10.2337/diabetes.54.11.3296

Genetics

Protein Tyrosine Phosphatase-1B Gene PTPN1

Selection of Tagging Single Nucleotide Polymorphisms and Association With Body Fat, Insulin Sensitivity, and the Metabolic Syndrome in a Normal Female Population

Nicola J. Spencer-Jones1,
Xiaoling Wang2,
Harold Snieder2,3,
Tim D. Spector3,
Nicholas D. Carter1 and
Sandra D. O’Dell1

¹Department of Clinical Developmental Sciences, St. George’s, University of London, London, U.K
²Georgia Prevention Institute, Department of Pediatrics, Medical College of Georgia, Augusta, Georgia
³Twin Research and Genetic Epidemiology Unit, St. Thomas’ Hospital, London, U.K

Address correspondence and reprint requests to Dr. Sandra D. O’Dell, Nutrition Food and Health Centre, King’s College London, Franklin-Wilkins Building, 150 Stamford St., London SE19H, U.K. E-mail: sandra.o'dell{at}kcl.ac.uk

Diabetes 2005 Nov; 54(11): 3296-3304. https://doi.org/10.2337/diabetes.54.11.3296

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FIG. 1.
Genomic map of PTPN1 gene with locations and MAFs of the validated SNPs genotyped in 94 subjects. ▪, exons; □, untranslated regions. MAFs are indicated next to corresponding rs numbers.
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FIG. 2.
Associations of PTP1N SNPs (both unmeasured SNPs and tSNPs) with SiM, fasting insulin, and fasting glucose under the additive genetic model. Associations of tSNPs and predicted values for unmeasured SNPs are indicated by −¹⁰Log (P). Points above the dotted line representing −¹⁰Log 0.05 represent SNP associations found or predicted to be significant at the P = 0.05 level.

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TABLE 1

General characteristics of subjects

Variable	n	Means ± SD
Age (years)	2,777*	47.4 ± 12.5
Postmenopausal (%)	2,454	47.7
Obesity-related variables
Leptin (ng/ml)	2,777	16.5 ± 11.9
BMI (kg/m²)	2,758	24.7 ± 4.4
Weight (kg)	2,759	65.3 ± 11.8
Waist circumference (cm)	2,707	78.3 ± 10.2
Total fat (kg)	2,718	23.4 ± 8.8
Total fat (%)	2,677	35.6 ± 8.0
Central fat (kg)	2,695	1.33 ± 0.73
Central fat (%)	2,695	31.2 ± 11.5
Insulin sensitivity†
Fasting glucose (mmol/l)	2,319	4.49 ± 0.56
Fasting insulin (pmol/l)	1,992	6.90 ± 5.40
2-h glucose (mmol/l)	759	5.18 ± 1.10
2-h insulin (μU/ml)	759	33.3 ± 23.1
SiM (10¹¹ · l · pmol⁻¹ · mmol⁻¹)	759	89.5 ± 68.5
Other components of the metabolic syndrome
Triglyceride‡ (mmol/l)	2,485	1.27 ± 0.80
HDLc‡ (mmol/l)	2,606	1.55 ± 0.39
SBP§ (mmHg)	2,586	120.9 ± 17.6
DBP§ (mmHg)	2,586	76.1 ± 11.1

* Number of subjects (842 monozygotic and 1,935 dizygotic) with leptin data and genotype data on at least one tSNP.
† Nonfasting subjects, patients with either type 1 or type 2 diabetes, and patients on any antidiabetic drugs were all excluded.
‡ Subjects using lipid-lowering agents were excluded.
§ Subjects using antihypertensive medications were excluded. HDLc, HDL cholesterol.

TABLE 2

tSNP selection based on haplotype prediction (R_H²) and single SNP prediction (R_L²)

Haplotype	rs3787334	rs6020572	rs932420	rs10485614	rs2426157	rs6067484	rs2426159	rs3787345	rs2038526	rs6060608
1	1	1	1	1	1	1	1	1	1	1
2	2	2	2	1	2	2	2	2	2	2
3	2	2	2	2	1	1	2	1	1	1
4	2	2	2	1	1	1	2	2	2	1
5	2	2	2	1	1	1	2	2	1	1
6	2	2	2	1	1	1	2	2	1	1
7	1	1	1	1	1	1	1	1	1	1
8	2	2	2	1	2	2	2	2	2	2
9	2	2	2	1	2	2	2	2	2	2
10	1	1	1	1	1	1	1	1	1	1
11	2	2	2	2	1	1	2	1	1	2
12	2	2	2	1	1	2	2	2	2	2
13	2	1	2	1	2	2	2	2	2	2
14	2	2	2	1	2	2	2	2	2	2
15	2	2	2	1	1	1	2	2	2	1
16	2	2	2	1	1	1	2	2	2	1
R_L²	0.965	0.928	0.965	0.882	0.970	—	0.965	0.955	0.961	0.927
1	1	1	1	1	1	2	1	0.471	0.471	0.999
2	2	2	2	1	2	1	1	0.256	0.727	0.899
2	1	2	1	1	1	1	2	0.087	0.814	0.884
2	2	2	2	2	2	1	1	0.042	0.856	0.967
2	1	2	1	1	1	1	1	0.019	0.875	0.990
2	1	2	1	1	2	1	1	0.019	0.894	0.953
1	1	1	1	1	1	1	1	0.019	0.913	0.956
1	2	2	2	1	2	1	1	0.012	0.925	—
2	2	2	2	1	2	1	2	0.012	0.936	—
2	1	1	1	1	1	2	1	0.010	0.946	—
2	1	2	1	1	1	1	2	0.010	0.956	—
2	2	2	2	1	2	1	1	0.010	0.966	—
2	2	2	2	1	2	1	1	0.009	0.975	—
2	2	2	2	2	2	1	1	0.009	0.984	—
1	2	2	2	2	2	1	1	0.008	0.992	—
2	2	2	2	2	2	1	2	0.008	1.0000	—
—	0.961	0.965	0.961	—	—	—	—	—	—	—

tSNPs printed in boldface. R_H², measure of association between the true and predicted haplotype dosage based on knowledge of tSNPs (20). R_L², the proportion of variance of each nontagging SNP explained by regression on the tSNPs (19). Cum freq, cumulative frequency; Freq, frequency.

TABLE 3

Genotype, allele, and haplotype distributions

tSNP*	Genotype			Total	Hardy-Weinberg test†		MAF (95% CI) (%)
tSNP*	11	12	22	Total	χ²	P	MAF (95% CI) (%)
rs6067484	1,093	743	126	1,962	0.18	NS	25.4 (24.0–26.8)
rs1885177	619	1,109	485	2,213	0.03	NS	47.0 (45.5–48.5)
rs2282146	1,713	286	12	2,011	0.22	NS	7.7 (6.9–8.6)
rs718049	813	951	282	2,046	0.01	NS	37.0 (35.5–38.5)
rs3787348	516	998	410	1,924	1.37	NS	47.2 (45.7–48.8)
1484insG	1,697	185	7	1,889	3.82	NS	5.3 (4.6–6.0)
Haplotype‡	rs6067484	rs1885177	rs2282146	rs718049	rs3787348	1484insG	Frequency (SE)
1	1	1	1	1	2	1	0.432 (0.0019)
2	2	2	1	2	1	1	0.242 (0.0016)
3	1	1	1	1	1	1	0.075 (0.0019)
4	1	2	2	2	1	1	0.073 (0.0015)
5	1	2	1	1	1	1	0.052 (0.0024)
6	1	2	1	1	1	2	0.052 (0.0017)
7	1	2	1	2	1	1	0.028 (0.0021)
8	1	1	1	2	2	1	0.016 (0.0010)
9	2	2	1	1	1	1	0.008 (0.0010)

* Includes one monozygotic and both dizygotic twins for each pair.
† Tested in one of each monozygotic pair (one of each dizygotic pair and all singleton dizygotic twins).
‡ Includes both dizygotic pairs and one of monozygotic pairs with genotype data on at least three tSNPs (n = 2,320).

TABLE 4

Association analyses of PTPN1 tSNPs with SiM, fasting insulin, and components of metabolic syndrome

SNP		No.	Means ± SD			P
SNP		11/12/22	11	12	22	GEE*	STDT
rs6067484	SiM	342/230/47	89.3 ± 65.4	91.1 ± 67.4	88.7 ± 96.6	NS	NS
	Insulin	921/618/115	6.70 ± 5.38	6.85 ± 5.33	7.25 ± 5.28	NS	NS
	Glucose	1076/745/124	4.48 ± 0.53	4.50 ± 0.58	4.41 ± 0.52	NS	NS
	SBP	1195/808/141	121.1 ± 17.9	120.3 ± 17.1	122.1 ± 17.7	NS	NS
	TG	1171/769/137	1.26 ± 0.81	1.28 ± 0.79	1.26 ± 0.60	NS	NS
	HDLc	1222/800/146	1.58 ± 0.40	1.52 ± 0.36	1.53 ± 0.38	NS	NS
	Waist circ	1255/850/150	78.1 ± 10.2	78.5 ± 10.1	78.6 ± 12.4	NS	NS
rs1885177	SiM	162/302/136	88.6 ± 67.0	94.9 ± 75.8	81.6 ± 70.2	0.013†	0.039†
	Insulin	535/923/415	6.66 ± 5.19	6.72 ± 4.89	7.37 ± 6.43	NS	NS
	Glucose	598/1106/475	4.47 ± 0.55	4.51 ± 0.54	4.47 ± 0.57	NS	NS
	SBP	691/1198/538	121.6 ± 17.4	120.2 ± 17.0	121.1 ± 17.4	NS	NS
	TG	655/1152/518	1.30 ± 0.81	1.23 ± 0.75	1.28 ± 0.89	NS	NS
	HDLc	695/1207/542	1.56 ± 0.39	1.54 ± 0.38	1.56 ± 0.39	NS	NS
	Waist circ	708/1270/562	78.1 ± 10.1	78.4 ± 9.8	78.6 ± 10.9	NS	NS
rs2282146	SiM	553/100/1	90.7 ± 69.7	81.5 ± 64.3	19.6 ± 0.0	0.049‡	0.062‡
	Insulin	1462/238/11	6.93 ± 5.35	6.81 ± 5.70	9.86 ± 6.72	NS	NS
	Glucose	1684/295/11	4.46 ± 0.55	4.53 ± 0.57	4.31 ± 0.46	NS	NS
	SBP	1870/333/14	120.5 ± 17.6	121.1 ± 16.9	125.3 ± 20.9	NS	NS
	TG	1807/315/13	1.26 ± 0.77	1.26 ± 0.92	1.29 ± 0.87	NS	NS
	HDLc	1894/332/13	1.55 ± 0.39	1.53 ± 0.41	1.65 ± 0.28	NS	NS
	Waist circ	1966/341/12	78.2 ± 10.1	79.2 ± 10.9	78.3 ± 11.0	NS	NS
rs718049	SiM	252/300/87	91.6 ± 68.7	92.1 ± 71.8	78.4 ± 78.2	<0.001†	0.002†
	Insulin	681/806/248	6.57 ± 4.74	6.92 ± 5.16	7.97 ± 7.37	0.004†	0.028†
	Glucose	790/937/283	4.47 ± 0.55	4.51 ± 0.55	4.54 ± 0.62	0.045†	NS
	SBP	892/1043/315	121.0 ± 17.6	120.8 ± 17.4	122.5 ± 17.4	0.017†	0.025†
	TG	865/986/300	1.25 ± 0.81	1.29 ± 0.82	1.28 ± 0.77	0.023‡	NS
	HDLc	899/1026/318	1.57 ± 0.41	1.54 ± 0.38	1.54 ± 0.38	NS	NS
	Waist circ	933/1094/329	78.0 ± 9.9	78.6 ± 9.9	79.1 ± 11.6	0.022‡	0.008^‡
rs3787348	SiM	173/316/121	92.4 ± 83.2	92.1 ± 68.9	87.4 ± 68.1	NS	NS
	Insulin	426/824/354	7.73 ± 6.97	6.82 ± 5.20	6.88 ± 5.46	NS	NS
	Glucose	500/961/398	4.52 ± 0.57	4.49 ± 0.55	4.49 ± 0.56	NS	NS
	SBP	582/1078/464	121.2 ± 18.3	121.0 ± 17.9	122.3 ± 17.9	NS	NS
	TG	554/1045/442	1.30 ± 0.75	1.26 ± 0.79	1.31 ± 0.83	NS	NS
	HDLc	578/1101/462	1.53 ± 0.34	1.55 ± 0.39	1.54 ± 0.38	NS	NS
	Waist circ	605/1140/478	78.8 ± 11.2	78.1 ± 9.9	77.7 ± 10.0	NS	NS
1484insG	SiM	554/58/3	88.4 ± 67.5	84.3 ± 71.6	99.4 ± 55.2	NS	NS
	Insulin	1462/148/7	6.94 ± 5.57	6.67 ± 4.85	5.39 ± 2.63	NS	NS
	Glucose	1693/184/7	4.78 ± 0.56	4.57 ± 0.57	4.44 ± 0.36	NS	NS
	SBP	1893/201/6	120.7 ± 17.2	120.0 ± 16.9	140.4 ± 42.0	NS	NS
	TG	1800/204/7	1.28 ± 0.78	1.15 ± 0.58	0.96 ± 0.30	0.029‡	NS
	HDLc	1882/208/7	1.54 ± 0.38	1.59 ± 0.40	1.78 ± 0.47	NS	NS
	Waist circ	1971/212/9	78.3 ± 10.3	78.2 ± 10.0	79.7 ± 8.0	NS	NS

* Age-adjusted P value;
† P value under the recessive genetic model;
‡ P value under the dominant genetic model. HDLc, HDL cholesterol; TG, triglyceride; Waist circ, waist circumference.

TABLE 5

Estimated frequencies (>2%) of the six tSNPs haplotypes and association tests with SiM, SBP, and TG

Haplo-type	SNP no.						Frequency	SiM (10¹¹ · l · pmol⁻¹ · mmol⁻¹		SBP (mmHg)		TG (mmol/l)
Haplo-type	rs6067484	rs1885177	rs2282146	rs718049	rs3787348	1484 insG	Frequency	β	P	β	P	β	P
1*	1	1	1	1	2	1	0.4316	—	—	—	—	—	—
2	2	2	1	2	1	1	0.2417	−6.35	NS	1.16	NS	0.01	NS
3	1	1	1	1	1	1	0.0751	9.68	NS	−0.51	NS	−0.12	NS
4	1	2	2	2	1	1	0.0732	−18.6	0.036	1.11	NS	−0.11	NS
5	1	2	1	1	1	1	0.0521	52.52	0.057	−7.20	0.006	−0.17	0.045
6	1	2	1	1	1	2	0.0517	−9.63	NS	0.57	NS	−0.14	NS
7	1	2	1	2	1	1	0.0280	−12.90	NS	1.48	NS	0.38	0.022
Overall	—	—	—	—	—	—	0.9533	—	0.085	—	0.117	—	0.026