Protein tyrosine phosphatase (PTP)-1B, encoded by the PTPN1 gene, catalyzes the dephosphorylation of proteins at tyrosyl residues. PTP-1B has been implicated in negatively regulating insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor. The genetic contribution of PTPN1 to measures of glucose homeostasis has been assessed in 811 Hispanic subjects from the Insulin Resistance Atherosclerosis Study Family Study (IRASFS). Thirty-five single nucleotide polymorphisms (SNPs) spanning 161 kb and containing the PTPN1 gene were genotyped and tested for association. All 20 SNPs with minor allele frequencies >0.1 in a single haplotype block covering the PTPN1 genomic sequence show significant association with the insulin sensitivity index (Si) (P = 0.044–0.003) and fasting glucose (P = 0.029 to <0.001). In contrast, there is no evidence for association of PTPN1 polymorphisms with acute insulin response (a measure of β-cell function). Haplotype analysis of eight SNP haplotypes that have independently been shown to be associated with type 2 diabetes risk and protection in Caucasian type 2 diabetic subjects are associated with lower (P = 0.007) and higher (P = 0.0002) Si and higher (P = 0.00007) and lower (P = 0.001) fasting glucose, respectively, in the IRASFS. This comprehensive genetic analysis of PTPN1 reveals significant association with metabolic traits consistent with the proposed in vivo role for the PTP-1B protein.

Protein phosphorylation at tyrosine is a key regulatory event that modulates intracellular signaling pathways involved in signal transduction. Protein tyrosine phosphatase (PTP)-1B is a ubiquitously expressed protein (1) that catalyzes the dephosphorylation of proteins at tyrosyl residues. PTP-1B has been implicated (2–4) in negatively regulating insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor kinase activation segment of the insulin receptor. In mouse models, disruption of the PTPN1 gene resulted in increased insulin sensitivity and resistance to diet-induced obesity (5,6). Further evidence for the role of PTP-1B in insulin sensitivity is seen in knockout mice, in which there was increased phosphorylation of the insulin receptor in liver and muscle tissue (5,6). These observations suggest that PTP-1B plays a role in modulating signal transduction, and defects in PTP-1B expression could lead to insulin resistance.

The 10 exons of PTPN1 span >74 kb of chromosome 20q13.13, with the first intron containing >50 kb of the sequence. Several investigators (7–9) have searched PTPN1 for DNA sequence variants, e.g., single nucleotide polymorphisms (SNPs). Variation within the coding region of PTPN1 is relatively uncommon. Echwald et al. (7) identified a P387L variant that was found in 2.6% of type 2 diabetic individuals and 1% of healthy control subjects, which showed evidence of impaired in vitro serine phosphorylation of the PTP-1B peptide. Mok et al. (8) identified a 981C→T polymorphism (5% minor allele frequency) that corresponded to a silent mutation in the PTP-1B protein and showed evidence of association with impaired glucose tolerance or type 2 diabetes in the Oji-Cree Indian tribe. Most recently, Di Paola et al. (9) reported evidence of an association between a 3′ untranslated region (UTR) SNP located at position 1484 of the cDNA and several features associated with insulin resistance, including the homeostasis model assessment of insulin resistance index, serum triglycerides, and total–to–HDL cholesterol ratio. These investigators (9) presented further evidence that this SNP, denoted 1484insG, is functional and leads to overexpression of PTP-1B mRNA in skeletal muscle due to increased stability in in vitro experiments.

Quantitative trait analysis offers a powerful approach to identify variants that contribute to specific components of biochemical pathways. We have systematically evaluated the association of the PTPN1 gene and quantitative measures of glucose homeostasis in Hispanic subjects extensively phenotyped for measures of glucose homeostasis in the Insulin Resistance Atherosclerosis Study Family Study (IRASFS). We hypothesized that variants within PTPN1 will be associated with quantitative traits that are dependent on or ultimately reflect the actions of the insulin receptor, consistent with the proposed role of PTP-1B in vivo.

We identified 35 SNPs that comprehensively covered the genomic region containing PTPN1 (Fig. 1). The majority of the SNPs had a minor allele frequency >0.20 and were found in noncoding regions. The average SNP density was 1 SNP/4.7 kb, with the largest gap between SNPs being 19.4 kb and the smallest 4 bp. Genotype frequencies were consistent with Hardy-Weinberg proportions.

Pairwise D′ was calculated for the PTPN1 SNPs. When using D′ >0.80 as criteria for evidence of significant linkage disequilibrium (LD), SNPs from rs4811077 to rs1060402, which spans 94 kb of sequence and encompasses the entire PTPN1 gene (data supplement [available at http://diabetes.diabetesjournals.org]), fall into a single LD haplotype block. A second, less well-defined block is comprised of SNPs 5′ to PTPN1 from rs1967439 to rs4811075, containing 22 kb of sequence.

Results of the association analysis are shown in Tables 1 (insulin sensitivity index [Si]), 2 (fasting glucose), and 3 (acute insulin response [AIR]). Each table lists the SNPs in order of 5′ to 3′ across PTPN1, the SNP alleles (e.g., G/C), the minor allele frequency, the mean trait values and SDs for each genotype, and the P value for association between trait and SNP from the GEE1 (generalized estimating equation) analysis. Results are reported for SNPs with minor allele frequencies >0.1 and the 1484insG SNP. As shown in Table 1, all 20 SNPs from rs3787334 (just distal to exon 1) through 1484insG (in the 3′ UTR) are significantly associated with Si (P = 0.044–0.003). A similar pattern of association is seen with fasting glucose (Table 2), in which all 22 SNPs between rs718630 (proximal to PTPN1 exon 1) and rs1060402 (distal to exon 10) show significant evidence of association (P = 0.029 to <0.0001). In contrast, there is little or no evidence of association with AIR, a measure of β-cell function (Table 3), with only 2 (1484insG and rs4811077) of 29 SNPs showing evidence of association.

Tables 4 and 5 show the results of eight SNP haplotype analyses (rs941798, rs3787345, rs754118, rs2282147, rs718049, rs718050, rs3787348, and 1484insG) with Si (Table 4) and fasting glucose (Table 5), respectively. The SNPs were chosen to tag all common haplotypes (≥10% frequency) and >85% of the variation in the LD block and, in addition, includes 1484insG. The Tables show the common (>1%) haplotypes, their frequency, P values for association under different models of inheritance, the mean trait values for the different haplotype combinations, and the effect of the specific haplotype on the trait. The haplotype ACTTCAG0 is significantly associated with lower Si (e.g., greater insulin resistance) and higher fasting glucose in the dominant model, and the haplotype GTCCTGT0 is significantly associated with higher Si (e.g., greater insulin sensitivity) and lower fasting glucose in the additive and recessive models. The remaining haplotype, ATCCTGG0, shows evidence of association with Si under the recessive model, but this result is driven by a relatively small number of homozygotes for this haplotype (∼1% subjects) and should be viewed cautiously. This haplotype has no evidence of association with fasting glucose, so we have tentatively designated ATCCTGG0 as neutral in its effect. It is noteworthy that the ACTTCAG0 and GTCCTGT0 haplotypes have independently been shown to be associated with type 2 diabetes risk and protection, respectively (10).

Protein tyrosine phosphatase-1B (PTP-1B) is a ubiquitously expressed phosphatase that dephosphorylates the phosphotyrosine residues of the active insulin receptor, disrupting the insulin signaling pathway. The PTPN1 gene has been the object of several searches for coding variants that would alter gene expression or function (7–9), but conventional coding variants of PTPN1 are few in number and have low heterozygosities (7,8).

We evaluated measures of glucose homeostasis for association with SNPs located within the genomic region containing PTPN1. Hispanic-American populations from the IRASFS formed the basis of this analysis. Each measure of glucose homeostasis explored represents a unique component of this balanced system.

The 35 SNPs (Fig. 1) genotyped in this study fall into two discrete LD blocks determined by D′ values (data supplement). A small block 5′ to the PTPN1 gene is formed from SNPs rs1967439 to rs4811075 and a larger block from rs4811077 to rs1060402 containing PTPN1. Within the larger LD block encompassing the PTPN1 coding sequence, there is consistent, significant evidence of association with Si and fasting glucose (Tables 1 and 2). These results are consistent with the proposed role of PTP-1B in the cell: regulation of insulin receptor activity by dephosphorylation of the insulin receptor kinase domain would lead to different levels of insulin sensitivity. Fasting glucose levels should reflect the body’s response to the efficiency of the insulin signaling pathway, with higher fasting glucose levels in subjects with PTPN1 alleles associated with lower Si. This is indeed what is observed (Tables 1 and 2). Evaluation of model-dependent (i.e., dominant, additive, and recessive) analyses did not suggest a specific mode of inheritance for the single PTPN1 SNPs and either phenotype (data not shown).

In contrast to Si and fasting glucose, there is little to no evidence of association of PTPN1 SNPs with AIR (Table 3). This result is again consistent with the cellular role of PTP-1B. AIR, a measure of β-cell function, would not be directly affected by alterations in the availability or function of the PTP-1B protein. This result would also suggest that β-cell function, as reflected in AIR, does not directly influence insulin resistance. We observed no significant evidence of association between PTPN1 SNPs and type 2 diabetes as a qualitative trait in this study (data not shown). The study design of large families with a relatively small number of type 2 diabetic subjects (16%, n = 129), however, has limited power to test for association with type 2 diabetes.

We also evaluated two previously described SNPs within the coding region of PTPN1 (7,8). The SNP identified by Mok et al. (8) (981 C→T) had a minor allele frequency of ∼4% in the Hispanic populations and no homozygotes for the T allele were found. There is no evidence of association with any of the six measures of glucose homeostasis examined in this study (data not shown). The coding mutation reported by Echwald et al. (7) was not observed, i.e., it was found to be monomorphic, in our Hispanic populations. It seems unlikely that these SNPs are responsible for the associations that we observe with glucose homeostasis phenotypes. In addition, we have evaluated whether the 1484insG SNP, located in the 3′ UTR, is the trait-defining variant. This SNP is associated with Si (P = 0.004) and fasting glucose (P = 0.013), as are other SNPs in the haplotype block. However, the phenotypic means for Si and fasting glucose do not present consistent evidence to confirm the association of the presence of the G allele with insulin resistance, i.e., individuals with the insertion have higher Si (are less insulin resistant), and there is no clear interpretation of the fasting glucose data. This result could be due to the low minor allele frequency (6%), resulting in only two homozygotes for the insertion. From this data, we cannot include or exclude this SNP as a contributor to the overall trait differences. It is noteworthy that in a study of Caucasian-American type 2 diabetic subjects and nondiabetic control subjects, the insertion G allele is not associated with diabetes risk (10).

Results of haplotype analysis are consistent with the single SNP results and the pattern of haplotypic association of PTPN1 SNPs with type 2 diabetes in Caucasians (10). For the eight-SNP haplotype, there is one common type 2 diabetes risk haplotype, ACTTCAGO, and one common type 2 diabetes protective haplotype, GTCCTGTO, in Caucasians. In the IRASFS Hispanics, a similar pattern is observed: the type 2 diabetes risk haplotype is common (39% of the chromosomes) and significantly associated with lower Si and higher fasting glucose. Likewise, the common type 2 diabetes protective haplotype (43% of the chromosomes) is significantly associated with higher Si and lower fasting glucose. The pattern and direction of associations is also consistent with single SNP results.

The purpose of this study was to evaluate the relationship between SNPs in the genomic region containing PTPN1 and quantitative measures of glucose homeostasis, including Si, glucose effectiveness (Sg), AIR, disposition index, fasting glucose, and fasting insulin. The results demonstrate a consistent pattern of association that was dictated by the LD structure within the region. Measures of glucose homeostasis, Si and fasting glucose, which are centered on the insulin signaling pathway (a major target of PTP-1B) were significantly associated with SNPs located within the LD block containing PTPN1. Although the high degree of LD could be masking the causal variant, all SNPs within the LD block show significant associations, and the magnitude of the association suggests that there is a causal variant or combination of variants that account for these associations. It is noteworthy that we have observed remarkably similar results in an evaluation of PTPN1 SNPs in studies of Caucasian-American type 2 diabetic case subjects and nondiabetic control subjects (10).

The study design, recruitment, and phenotyping for IRASFS have been described in detail elsewhere (11). Briefly, the IRASFS is designed to identify the genetic bases of insulin resistance and visceral adiposity, which are important risk factors for the development of type 2 diabetes and atherosclerosis. Subjects in the study have been recruited from clinical centers in San Luis Valley, Colorado (n = 494) (a rural Hispanic population), and San Antonio, Texas (n = 317) (an urban Hispanic population). Data from 55 pedigrees encompassing all 811 individuals were analyzed in this study. Diabetic subjects were not included in the analyses of glucose homeostasis measures. The clinical examination included an insulin-modified frequently sampled intravenous glucose tolerance test using the reduced sampling protocol (12) to compute glucose homeostasis measures, height, weight, and waist and hip circumferences and computed tomography to estimate visceral and subcutaneous fat, fasting blood draw, and medical history interview. Table 6 provides a descriptive summary of the primary phenotypes.

SNP selection and genotyping.

SNPs were selected from the dbSNP database, with the exception of the published SNP, 1484insG (9). Those SNPs with available frequency information were preferentially selected from the database. The majority of the SNPs in this study had a minor allele frequency >0.20. Genotyping was performed on the Sequenom MassArray Genotyping System using methods previously described (13). Discordance between blind duplicate samples included in the genotyping was <0.2%. All 35 SNPs were genotyped on all 811 subjects.

Initially, each of the PTPN1 SNPs evaluated was examined for Mendelian inconsistencies in their genotypes using PedCheck (14). Any genotypes inconsistent with Mendelian inheritance were converted to missing. This resulted in zeroing of 129 of the 40,320 genotypes generated across the 35 SNPs. Subsequently, maximum-likelihood estimates of allele frequencies were computed using the largest set of unrelated individuals and then tested for departures from Hardy-Weinberg proportions. To test for an association between individual SNPs and each trait, a series of GEE1 (15) was computed. Familial correlation was accounted for by using a sandwich estimator of the variance and exchangeable correlation. The two-degrees-of-freedom overall test of genotypic association was the principal analysis method. Tests reported here were computed adjusting for age, sex, recruitment center (San Antonio, Texas, and San Luis Valley, Colorado), and BMI. When necessary, quantitative traits were transformed to best approximate the distributional assumptions of the test (i.e., link function) and to minimize the heterogeneity of the variance. Approximately 16% of the subjects had a diagnosis of type 2 diabetes. Type 2 diabetic subjects were excluded from the analysis of the glucose homeostasis traits. A P value of <0.05 was considered significant.

To test for a haplotypic association between the glucose homeostasis traits and the PTPN1 polymorphisms, a weighted GEE1 analysis was computed as described above, with the weights being the probability for each possible haplo-genotype for an individual. Specifically, we computed the expectation-maximization algorithm estimates for haplotype frequencies from the family data using the software ZAPLO (16). To reduce the complexity of the problem, ZAPLO assumes zero recombination between markers. Using the expectation-maximization–based estimates, ZAPLO outputs all possible haplo-genotypes (i.e., haplotype combinations) for each individual. These data are input into PROFILER (17) to compute the joint probability distribution for the haplotypes of individuals within the pedigree. This joint probability distribution is then used to estimate the probability of each haplotype pair combination (haplo-genotype) possible for each individual, conditional on the family data. Each individual enters into the GEE1 analysis once for each haplo-genotype possibility, weighted by the haplo-genotype probability. Thus, the weight for each individual sums to 1. The weighted GEE1 analyses were completed as above using the same transformations and sandwich estimator of the variance to account for the within cluster correlation. Linear contrasts for the three a priori genetic models (i.e., dominant, additive, and recessive) in each of the primary haplotypes (5%) were computed.

The pairwise LD statistic D′ was calculated using the SNP-Analysis software package (http://www.fhcrc.org/labs/kruglyak/Downloads). A graphical summary of these LD values was generated using the GOLD software package.

FIG. 1.
FIG. 1. Genomic map of PTPN1 gene with locations of the genotyped SNPs. The shaded regions are exons, numbered 1–10. The ruler along the bottom represents the relative location and spacing of SNPs in kilobases within the 161-kb region containing PTPN1. Note that this does not have a uniform scale.
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Genomic map of PTPN1 gene with locations of the genotyped SNPs. The shaded regions are exons, numbered 1–10. The ruler along the bottom represents the relative location and spacing of SNPs in kilobases within the 161-kb region containing PTPN1. Note that this does not have a uniform scale.

FIG. 1.
FIG. 1. Genomic map of PTPN1 gene with locations of the genotyped SNPs. The shaded regions are exons, numbered 1–10. The ruler along the bottom represents the relative location and spacing of SNPs in kilobases within the 161-kb region containing PTPN1. Note that this does not have a uniform scale.
View largeDownload slide

Genomic map of PTPN1 gene with locations of the genotyped SNPs. The shaded regions are exons, numbered 1–10. The ruler along the bottom represents the relative location and spacing of SNPs in kilobases within the 161-kb region containing PTPN1. Note that this does not have a uniform scale.

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TABLE 1

Association analysis of PTPN1 SNPs with Si

SNPAllelesMAFPhenotypic mean ± SD
P
1/11/22/2
rs2904268 G/C 0.18 2.08 ± 1.89 2.21 ± 2.01 2.35 ± 1.74 0.936 
rs803742 C/T 0.32 2.18 ± 1.99 2.05 ± 1.91 2.33 ± 1.76 0.428 
rs1967439 G/A 0.41 2.28 ± 1.98 2.07 ± 1.79 2.07 ± 2.17 0.203 
rs4811074 C/T 0.31 2.27 ± 1.95 2.07 ± 1.87 2.09 ± 2.18 0.173 
rs4811075 G/A 0.40 2.28 ± 2.02 2.08 ± 1.93 2.03 ± 2.05 0.308 
rs4811077 T/C 0.12 2.16 ± 1.95 2.06 ± 2.00 2.13 ± 1.38 0.992 
rs718630 A/C 0.40 2.27 ± 1.91 2.07 ± 1.88 1.86 ± 1.89 0.088 
rs3787334 C/T 0.48 1.97 ± 1.86 2.04 ± 1.77 2.46 ± 2.19 0.022 
rs2206656 G/C 0.40 2.39 ± 2.08 1.94 ± 1.75 2.01 ± 1.97 0.003 
rs932420 C/T 0.48 1.96 ± 1.85 2.00 ± 1.76 2.41 ± 2.16 0.019 
rs2426158 A/G 0.35 2.34 ± 2.05 1.92 ± 1.70 1.91 ± 2.29 0.004 
rs2904269 A/C 0.48 1.98 ± 1.86 1.98 ± 1.74 2.39 ± 2.17 0.028 
rs941798 A/G 0.48 2.04 ± 2.06 1.97 ± 1.67 2.62 ± 2.27 0.010 
rs1570179 C/T 0.38 2.32 ± 2.02 1.99 ± 1.78 2.00 ± 2.07 0.020 
rs3787345 T/C 0.40 2.34 ± 2.07 1.96 ± 1.78 1.98 ± 2.00 0.008 
rs2038526 C/T 0.38 2.34 ± 2.04 2.00 ± 1.80 2.01 ± 2.05 0.025 
rs1885177 A/C 0.48 1.98 ± 1.85 2.00 ± 1.77 2.42 ± 2.17 0.028 
rs754118 C/T 0.38 2.34 ± 2.04 2.00 ± 1.79 2.01 ± 2.07 0.028 
rs3215684 T/O 0.39 2.30 ± 2.04 1.95 ± 1.80 2.01 ± 2.07 0.044 
rs968701 G/A 0.47 1.97 ± 1.85 2.02 ± 1.77 2.40 ± 2.14 0.043 
rs2282147 C/T 0.38 2.29 ± 1.99 1.99 ± 1.79 2.00 ± 2.06 0.027 
rs718049 T/C 0.39 2.30 ± 2.04 1.97 ± 1.78 1.93 ± 1.94 0.020 
rs718050 G/A 0.39 2.31 ± 2.06 1.97 ± 1.77 2.00 ± 2.03 0.026 
rs3787348 G/T 0.48 2.03 ± 2.04 1.94 ± 1.59 2.54 ± 2.22 0.006 
rs914460 T/C 0.38 2.31 ± 2.02 1.99 ± 1.78 2.00 ± 2.06 0.015 
rs2426164 A/G 0.41 2.33 ± 2.04 1.98 ± 1.82 2.08 ± 2.07 0.018 
1484insG O/G 0.06 2.10 ± 1.88 2.22 ± 1.74 2.18 ± 1.06 0.004 
rs1060402 G/A 0.49 1.95 ± 1.74 2.09 ± 1.91 2.34 ± 2.08 0.117 
rs914458 C/G 0.25 2.15 ± 2.05 2.12 ± 1.85 2.06 ± 1.56 0.655 
SNPAllelesMAFPhenotypic mean ± SD
P
1/11/22/2
rs2904268 G/C 0.18 2.08 ± 1.89 2.21 ± 2.01 2.35 ± 1.74 0.936 
rs803742 C/T 0.32 2.18 ± 1.99 2.05 ± 1.91 2.33 ± 1.76 0.428 
rs1967439 G/A 0.41 2.28 ± 1.98 2.07 ± 1.79 2.07 ± 2.17 0.203 
rs4811074 C/T 0.31 2.27 ± 1.95 2.07 ± 1.87 2.09 ± 2.18 0.173 
rs4811075 G/A 0.40 2.28 ± 2.02 2.08 ± 1.93 2.03 ± 2.05 0.308 
rs4811077 T/C 0.12 2.16 ± 1.95 2.06 ± 2.00 2.13 ± 1.38 0.992 
rs718630 A/C 0.40 2.27 ± 1.91 2.07 ± 1.88 1.86 ± 1.89 0.088 
rs3787334 C/T 0.48 1.97 ± 1.86 2.04 ± 1.77 2.46 ± 2.19 0.022 
rs2206656 G/C 0.40 2.39 ± 2.08 1.94 ± 1.75 2.01 ± 1.97 0.003 
rs932420 C/T 0.48 1.96 ± 1.85 2.00 ± 1.76 2.41 ± 2.16 0.019 
rs2426158 A/G 0.35 2.34 ± 2.05 1.92 ± 1.70 1.91 ± 2.29 0.004 
rs2904269 A/C 0.48 1.98 ± 1.86 1.98 ± 1.74 2.39 ± 2.17 0.028 
rs941798 A/G 0.48 2.04 ± 2.06 1.97 ± 1.67 2.62 ± 2.27 0.010 
rs1570179 C/T 0.38 2.32 ± 2.02 1.99 ± 1.78 2.00 ± 2.07 0.020 
rs3787345 T/C 0.40 2.34 ± 2.07 1.96 ± 1.78 1.98 ± 2.00 0.008 
rs2038526 C/T 0.38 2.34 ± 2.04 2.00 ± 1.80 2.01 ± 2.05 0.025 
rs1885177 A/C 0.48 1.98 ± 1.85 2.00 ± 1.77 2.42 ± 2.17 0.028 
rs754118 C/T 0.38 2.34 ± 2.04 2.00 ± 1.79 2.01 ± 2.07 0.028 
rs3215684 T/O 0.39 2.30 ± 2.04 1.95 ± 1.80 2.01 ± 2.07 0.044 
rs968701 G/A 0.47 1.97 ± 1.85 2.02 ± 1.77 2.40 ± 2.14 0.043 
rs2282147 C/T 0.38 2.29 ± 1.99 1.99 ± 1.79 2.00 ± 2.06 0.027 
rs718049 T/C 0.39 2.30 ± 2.04 1.97 ± 1.78 1.93 ± 1.94 0.020 
rs718050 G/A 0.39 2.31 ± 2.06 1.97 ± 1.77 2.00 ± 2.03 0.026 
rs3787348 G/T 0.48 2.03 ± 2.04 1.94 ± 1.59 2.54 ± 2.22 0.006 
rs914460 T/C 0.38 2.31 ± 2.02 1.99 ± 1.78 2.00 ± 2.06 0.015 
rs2426164 A/G 0.41 2.33 ± 2.04 1.98 ± 1.82 2.08 ± 2.07 0.018 
1484insG O/G 0.06 2.10 ± 1.88 2.22 ± 1.74 2.18 ± 1.06 0.004 
rs1060402 G/A 0.49 1.95 ± 1.74 2.09 ± 1.91 2.34 ± 2.08 0.117 
rs914458 C/G 0.25 2.15 ± 2.05 2.12 ± 1.85 2.06 ± 1.56 0.655 

Only nondiabetic subjects were included in this analysis. Boldface indicates statistical significance. MAF, minor allele frequency.

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TABLE 2

Association analysis of PTPN1 SNPs with fasting glucose (milligrams per deciliter)

SNPAllelesMAFPhenotypic mean ± SD
P
1/11/22/2
rs2904268 G/C 0.18 93.72 ± 9.85 92.96 ± 9.42 91.37 ± 9.17 0.719 
rs803742 C/T 0.32 93.32 ± 9.40 93.53 ± 9.95 94.46 ± 11.0 0.586 
rs1967439 G/A 0.41 93.27 ± 9.76 93.60 ± 9.32 93.05 ± 9.84 0.338 
rs4811074 C/T 0.31 93.40 ± 9.78 93.87 ± 9.69 93.01 ± 9.05 0.416 
rs4811075 G/A 0.40 93.52 ± 9.58 93.55 ± 9.79 93.07 ± 9.27 0.658 
rs4811077 T/C 0.12 93.36 ± 9.55 92.79 ± 9.73 96.61 ± 12.9 0.576 
rs718630 A/C 0.40 92.32 ± 9.30 94.35 ± 10.1 93.68 ± 8.91 0.024 
rs3787334 C/T 0.48 93.93 ± 9.64 93.80 ± 9.81 92.41 ± 9.86 0.001 
rs2206656 G/C 0.40 92.33 ± 9.59 94.21 ± 9.87 94.03 ± 9.20 0.006 
rs932420 C/T 0.48 94.07 ± 9.41 93.82 ± 9.70 92.64 ± 9.89 0.010 
rs2426158 A/G 0.35 92.21 ± 9.62 94.97 ± 9.68 93.79 ± 8.51 0.006 
rs2904269 A/C 0.48 93.84 ± 9.51 93.84 ± 9.71 92.63 ± 9.94 0.018 
rs941798 A/G 0.48 94.27 ± 9.81 94.15 ± 9.88 91.22 ± 9.13 0.001 
rs1570179 C/T 0.38 92.03 ± 9.43 94.60 ± 10.0 94.14 ± 9.34 <0.001 
rs3787345 T/C 0.40 92.18 ± 9.63 94.33 ± 9.75 94.26 ± 9.67 0.001 
rs2038526 C/T 0.38 92.10 ± 9.52 94.54 ± 9.92 93.47 ± 9.06 0.001 
rs1885177 A/C 0.48 93.85 ± 9.58 93.87 ± 9.66 92.42 ± 9.75 0.010 
rs754118 C/T 0.38 91.94 ± 9.31 94.59 ± 10.0 93.96 ± 9.37 <0.001 
rs3215684 T/O 0.39 92.14 ± 9.53 94.71 ± 9.88 93.96 ± 9.37 0.001 
rs968701 G/A 0.47 93.83 ± 9.61 93.85 ± 9.61 92.44 ± 9.74 0.008 
rs2282147 C/T 0.38 92.07 ± 9.37 94.54 ± 10.0 93.95 ± 9.30 <0.001 
rs718049 T/C 0.39 92.19 ± 9.53 94.61 ± 9.90 93.75 ± 9.28 <0.001 
rs718050 G/A 0.39 92.22 ± 9.55 94.70 ± 10.0 93.66 ± 9.24 <0.001 
rs3787348 G/T 0.48 94.19 ± 9.65 93.93 ± 9.83 91.72 ± 9.38 0.004 
rs914460 T/C 0.38 92.03 ± 9.44 94.55 ± 9.87 93.95 ± 9.30 <0.001 
rs2426164 A/G 0.41 92.05 ± 9.36 95.04 ± 10.1 93.51 ± 9.32 <0.001 
1484insG O/G 0.06 93.59 ± 9.78 91.41 ± 8.54 90.75 ± 4.56 0.013 
rs1060402 G/A 0.49 93.53 ± 9.08 93.86 ± 9.88 92.83 ± 9.94 0.029 
rs914458 C/G 0.25 93.72 ± 9.83 93.13 ± 9.59 96.27 ± 10.3 0.449 
SNPAllelesMAFPhenotypic mean ± SD
P
1/11/22/2
rs2904268 G/C 0.18 93.72 ± 9.85 92.96 ± 9.42 91.37 ± 9.17 0.719 
rs803742 C/T 0.32 93.32 ± 9.40 93.53 ± 9.95 94.46 ± 11.0 0.586 
rs1967439 G/A 0.41 93.27 ± 9.76 93.60 ± 9.32 93.05 ± 9.84 0.338 
rs4811074 C/T 0.31 93.40 ± 9.78 93.87 ± 9.69 93.01 ± 9.05 0.416 
rs4811075 G/A 0.40 93.52 ± 9.58 93.55 ± 9.79 93.07 ± 9.27 0.658 
rs4811077 T/C 0.12 93.36 ± 9.55 92.79 ± 9.73 96.61 ± 12.9 0.576 
rs718630 A/C 0.40 92.32 ± 9.30 94.35 ± 10.1 93.68 ± 8.91 0.024 
rs3787334 C/T 0.48 93.93 ± 9.64 93.80 ± 9.81 92.41 ± 9.86 0.001 
rs2206656 G/C 0.40 92.33 ± 9.59 94.21 ± 9.87 94.03 ± 9.20 0.006 
rs932420 C/T 0.48 94.07 ± 9.41 93.82 ± 9.70 92.64 ± 9.89 0.010 
rs2426158 A/G 0.35 92.21 ± 9.62 94.97 ± 9.68 93.79 ± 8.51 0.006 
rs2904269 A/C 0.48 93.84 ± 9.51 93.84 ± 9.71 92.63 ± 9.94 0.018 
rs941798 A/G 0.48 94.27 ± 9.81 94.15 ± 9.88 91.22 ± 9.13 0.001 
rs1570179 C/T 0.38 92.03 ± 9.43 94.60 ± 10.0 94.14 ± 9.34 <0.001 
rs3787345 T/C 0.40 92.18 ± 9.63 94.33 ± 9.75 94.26 ± 9.67 0.001 
rs2038526 C/T 0.38 92.10 ± 9.52 94.54 ± 9.92 93.47 ± 9.06 0.001 
rs1885177 A/C 0.48 93.85 ± 9.58 93.87 ± 9.66 92.42 ± 9.75 0.010 
rs754118 C/T 0.38 91.94 ± 9.31 94.59 ± 10.0 93.96 ± 9.37 <0.001 
rs3215684 T/O 0.39 92.14 ± 9.53 94.71 ± 9.88 93.96 ± 9.37 0.001 
rs968701 G/A 0.47 93.83 ± 9.61 93.85 ± 9.61 92.44 ± 9.74 0.008 
rs2282147 C/T 0.38 92.07 ± 9.37 94.54 ± 10.0 93.95 ± 9.30 <0.001 
rs718049 T/C 0.39 92.19 ± 9.53 94.61 ± 9.90 93.75 ± 9.28 <0.001 
rs718050 G/A 0.39 92.22 ± 9.55 94.70 ± 10.0 93.66 ± 9.24 <0.001 
rs3787348 G/T 0.48 94.19 ± 9.65 93.93 ± 9.83 91.72 ± 9.38 0.004 
rs914460 T/C 0.38 92.03 ± 9.44 94.55 ± 9.87 93.95 ± 9.30 <0.001 
rs2426164 A/G 0.41 92.05 ± 9.36 95.04 ± 10.1 93.51 ± 9.32 <0.001 
1484insG O/G 0.06 93.59 ± 9.78 91.41 ± 8.54 90.75 ± 4.56 0.013 
rs1060402 G/A 0.49 93.53 ± 9.08 93.86 ± 9.88 92.83 ± 9.94 0.029 
rs914458 C/G 0.25 93.72 ± 9.83 93.13 ± 9.59 96.27 ± 10.3 0.449 

Only nondiabetic subjects were included in this analysis. Boldface indicates statistical significance. MAF, minor allele frequency.

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TABLE 3

Association analysis of PTPN1 SNPs with AIR

SNPAllelesMAFPhenotypic mean ± SD
P
1/11/22/2
rs2904268 G/C 0.18 740 ± 594 817 ± 703 618 ± 553 0.311 
rs803742 C/T 0.32 756 ± 605 745 ± 618 738 ± 674 0.971 
rs1967439 G/A 0.41 740 ± 648 724 ± 531 849 ± 785 0.918 
rs4811074 C/T 0.31 743 ± 651 722 ± 513 929 ± 828 0.439 
rs4811075 G/A 0.40 762 ± 664 734 ± 560 857 ± 770 0.435 
rs4811077 T/C 0.12 745 ± 606 804 ± 701 421 ± 298 0.012 
rs718630 A/C 0.40 776 ± 668 744 ± 564 740 ± 702 0.374 
rs3787334 C/T 0.48 755 ± 663 787 ± 634 686 ± 560 0.327 
rs2206656 G/C 0.40 734 ± 597 795 ± 652 718 ± 645 0.361 
rs932420 C/T 0.48 755 ± 663 796 ± 636 705 ± 594 0.356 
rs2426158 A/G 0.35 737 ± 586 692 ± 553 719 ± 576 0.427 
rs2904269 A/C 0.48 754 ± 661 781 ± 626 714 ± 603 0.533 
rs941798 A/G 0.48 734 ± 689 766 ± 576 756 ± 644 0.593 
rs1570179 C/T 0.38 772 ± 634 764 ± 629 670 ± 595 0.214 
rs3787345 T/C 0.40 766 ± 643 771 ± 613 740 ± 676 0.541 
rs2038526 C/T 0.38 766 ± 631 775 ± 640 662 ± 588 0.200 
rs1885177 A/C 0.48 750 ± 663 787 ± 631 724 ± 602 0.548 
rs754118 C/T 0.38 778 ± 636 753 ± 610 668 ± 596 0.171 
rs3215684 T/O 0.39 775 ± 645 774 ± 632 668 ± 596 0.238 
rs968701 G/A 0.47 751 ± 664 783 ± 633 717 ± 606 0.464 
rs2282147 C/T 0.38 774 ± 638 760 ± 629 666 ± 591 0.194 
rs718049 T/C 0.39 775 ± 644 777 ± 631 667 ± 582 0.125 
rs718050 G/A 0.39 773 ± 648 766 ± 627 661 ± 580 0.140 
rs3787348 G/T 0.48 725 ± 682 780 ± 589 744 ± 642 0.407 
rs914460 T/C 0.38 774 ± 635 765 ± 624 666 ± 591 0.183 
rs2426164 A/G 0.41 764 ± 646 726 ± 619 721 ± 667 0.498 
1484insG O/G 0.06 735 ± 605 937 ± 692 637 ± 71 <0.001 
rs1060402 G/A 0.49 785 ± 694 767 ± 618 707 ± 590 0.788 
rs914458 C/G 0.25 771 ± 619 732 ± 594 614 ± 500 0.547 
SNPAllelesMAFPhenotypic mean ± SD
P
1/11/22/2
rs2904268 G/C 0.18 740 ± 594 817 ± 703 618 ± 553 0.311 
rs803742 C/T 0.32 756 ± 605 745 ± 618 738 ± 674 0.971 
rs1967439 G/A 0.41 740 ± 648 724 ± 531 849 ± 785 0.918 
rs4811074 C/T 0.31 743 ± 651 722 ± 513 929 ± 828 0.439 
rs4811075 G/A 0.40 762 ± 664 734 ± 560 857 ± 770 0.435 
rs4811077 T/C 0.12 745 ± 606 804 ± 701 421 ± 298 0.012 
rs718630 A/C 0.40 776 ± 668 744 ± 564 740 ± 702 0.374 
rs3787334 C/T 0.48 755 ± 663 787 ± 634 686 ± 560 0.327 
rs2206656 G/C 0.40 734 ± 597 795 ± 652 718 ± 645 0.361 
rs932420 C/T 0.48 755 ± 663 796 ± 636 705 ± 594 0.356 
rs2426158 A/G 0.35 737 ± 586 692 ± 553 719 ± 576 0.427 
rs2904269 A/C 0.48 754 ± 661 781 ± 626 714 ± 603 0.533 
rs941798 A/G 0.48 734 ± 689 766 ± 576 756 ± 644 0.593 
rs1570179 C/T 0.38 772 ± 634 764 ± 629 670 ± 595 0.214 
rs3787345 T/C 0.40 766 ± 643 771 ± 613 740 ± 676 0.541 
rs2038526 C/T 0.38 766 ± 631 775 ± 640 662 ± 588 0.200 
rs1885177 A/C 0.48 750 ± 663 787 ± 631 724 ± 602 0.548 
rs754118 C/T 0.38 778 ± 636 753 ± 610 668 ± 596 0.171 
rs3215684 T/O 0.39 775 ± 645 774 ± 632 668 ± 596 0.238 
rs968701 G/A 0.47 751 ± 664 783 ± 633 717 ± 606 0.464 
rs2282147 C/T 0.38 774 ± 638 760 ± 629 666 ± 591 0.194 
rs718049 T/C 0.39 775 ± 644 777 ± 631 667 ± 582 0.125 
rs718050 G/A 0.39 773 ± 648 766 ± 627 661 ± 580 0.140 
rs3787348 G/T 0.48 725 ± 682 780 ± 589 744 ± 642 0.407 
rs914460 T/C 0.38 774 ± 635 765 ± 624 666 ± 591 0.183 
rs2426164 A/G 0.41 764 ± 646 726 ± 619 721 ± 667 0.498 
1484insG O/G 0.06 735 ± 605 937 ± 692 637 ± 71 <0.001 
rs1060402 G/A 0.49 785 ± 694 767 ± 618 707 ± 590 0.788 
rs914458 C/G 0.25 771 ± 619 732 ± 594 614 ± 500 0.547 

Only nondiabetic subjects were included in this analysis. Boldface indicates statistical significance. MAF, minor allele frequency.

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TABLE 4

PTPN1 haplotype association with Si in Hispanic subjects in the IRASFS

HaplotypeFrequencyDispositionP for each model
Haplo-genotype mean Si
DominantAdditiveRecessive+/+*+/−†−/−‡
GTCCTGTO 0.43 Protective: higher Si 0.28 0.00098 0.00024 2.45 ± 2.46 1.81 ± 1.41 1.82 ± 1.97 
ACTTCAGO 0.39 Risk: lower Si 0.0064 0.11 0.47 1.74 ± 2.00 1.84 ± 1.58 2.20 ± 2.06 
ATCCTGGO 0.10 Neutral 0.81 0.96 0.00004 1.06 ± 0.94 1.91 ± 1.93 2.00 ± 1.81 
HaplotypeFrequencyDispositionP for each model
Haplo-genotype mean Si
DominantAdditiveRecessive+/+*+/−†−/−‡
GTCCTGTO 0.43 Protective: higher Si 0.28 0.00098 0.00024 2.45 ± 2.46 1.81 ± 1.41 1.82 ± 1.97 
ACTTCAGO 0.39 Risk: lower Si 0.0064 0.11 0.47 1.74 ± 2.00 1.84 ± 1.58 2.20 ± 2.06 
ATCCTGGO 0.10 Neutral 0.81 0.96 0.00004 1.06 ± 0.94 1.91 ± 1.93 2.00 ± 1.81 

Data are means ± SD. Boldface indicates statistical significance.

*

Two copies of the haplotype of interest;

†

one copy of the haplotype of interest and any other haplotype;

‡

any other haplotype combination.

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TABLE 5

PTPN1 haplotype association with fasting glucose in Hispanic subjects in the IRASFS

HaplotypeFrequencyDispositionP for each model
Haplo-genotype mean fasting glucose
DominantAdditiveRecessive+/+*+/−†−/−‡
GTCCTGTO 0.43 Protective: lower fasting glucose 0.28 0.018 0.0015 100.24 ± 30.76 103.76 ± 27.55 108.52 ± 37.08 
ACTTCAGO 0.39 Risk: higher fasting glucose 0.00007 0.35 0.58 112.15 ± 43.20 105.19 ± 29.75 100.50 ± 27.96 
ATCCTGGO 0.10 Neutral 0.21 0.87 0.17 105.83 ± 37.59 105.62 ± 30.28 103.74 ± 30.82 
HaplotypeFrequencyDispositionP for each model
Haplo-genotype mean fasting glucose
DominantAdditiveRecessive+/+*+/−†−/−‡
GTCCTGTO 0.43 Protective: lower fasting glucose 0.28 0.018 0.0015 100.24 ± 30.76 103.76 ± 27.55 108.52 ± 37.08 
ACTTCAGO 0.39 Risk: higher fasting glucose 0.00007 0.35 0.58 112.15 ± 43.20 105.19 ± 29.75 100.50 ± 27.96 
ATCCTGGO 0.10 Neutral 0.21 0.87 0.17 105.83 ± 37.59 105.62 ± 30.28 103.74 ± 30.82 

Data are means ± SD. Boldface indicates statistical significance.

*

Two copies of the haplotype of interest;

†

one copy of the haplotype of interest and any other haplotype;

‡

any other haplotype combination.

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TABLE 6

Characteristics of Hispanic IRASFS participants

nMean ± SDMedian
N 811   
Demographic    
    Age (years) 719 42.2 ± 14.5 40.8 
    BMI (kg/m2) 714 29.15 ± 6.16 28.39 
    Female sex 57% — — 
    Diabetic 129 — — 
Glucose homeostasis    
    Si (MINMOD) 583 2.13 ± 1.92 1.61 
    Sg (MINMOD) 583 0.021 ± 0.009 0.020 
    Disposition index (AIR × Si) 583 1,318 ± 1,271 995 
    Fasting glucose (mg/dl) 616 93.4 ± 9.70 92.0 
    Fasting insulin (μU/ml) 618 15.5 ± 11.1 13.0 
    AIR (μU/ml) 583 758 ± 625 598 
nMean ± SDMedian
N 811   
Demographic    
    Age (years) 719 42.2 ± 14.5 40.8 
    BMI (kg/m2) 714 29.15 ± 6.16 28.39 
    Female sex 57% — — 
    Diabetic 129 — — 
Glucose homeostasis    
    Si (MINMOD) 583 2.13 ± 1.92 1.61 
    Sg (MINMOD) 583 0.021 ± 0.009 0.020 
    Disposition index (AIR × Si) 583 1,318 ± 1,271 995 
    Fasting glucose (mg/dl) 616 93.4 ± 9.70 92.0 
    Fasting insulin (μU/ml) 618 15.5 ± 11.1 13.0 
    AIR (μU/ml) 583 758 ± 625 598 
View Large

Additional information for this article can be found in a data supplement at http://diabetes.diabetesjournals.org.

This work was supported by National Institutes of Health Grants R01 HL60894 and DK56289 (to D.W.B.), HL60944, HL61210, HL61019, HL60894, and HL60931.

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Supplementary data

Marker to marker D’(A) and r2(B) for the PTPN1 SNPs.- doc file