Protein Tyrosine Phosphatase-1B Gene PTPN1

Abstract

Protein tyrosine phosphatase-1B negatively regulates leptin and insulin signaling, potentially contributing to hormonal resistance. We selected six tagging single nucleotide polymorphisms (SNPs) representing 18 common variants in the protein tyrosine phosphatase-1B gene (PTPN1) and tested their effect on serum leptin, body fat, and measures of insulin sensitivity and the metabolic syndrome in a large sample of normal female Caucasian twins (n ‫؍‬ 2,777; mean age, 47.4 ؎ 12.5 years) from the St. Thomas' U.K. Adult Twin Registry. SNP rs718049 was significantly associated with waist circumference (P ‫؍‬ 0.008) and central fat (P ‫؍‬ 0.035) and also with Avignon's insulin sensitivity index (SiM) (P ‫؍‬ 0.007), fasting insulin (P ‫؍‬ 0.004), fasting glucose (P ‫؍‬ 0.022), triglyceride (P ‫؍‬ 0.023), and systolic blood pressure (P ‫؍‬ 0.046). SNPs rs2282146 and rs1885177 were associated with SiM (P ‫؍‬ 0.049 and P ‫؍‬ 0.013, respectively), and 1484insG was associated with triglyceride (P ‫؍‬ 0.029). A risk haplotype (7.3%) was associated with lower SiM (P ‫؍‬ 0.036) and a protective haplotype (5.2%) with higher SiM (P ‫؍‬ 0.057), with mean values in homozygotes differing by >1 SD (P ‫؍‬ 0.003). The protective haplotype also showed lower triglyceride (P ‫؍‬ 0.045) and lower systolic blood pressure (P ‫؍‬ 0.006). Fine mapping analyses predicted significant associations with SiM and fasting insulin for several ungenotyped SNPs. PTPN1 variants appear to contribute to central fat and metabolic syndrome traits, secondary to their effect on insulin sensitivity. Diabetes 54:3296 -3304, 2005 O besity poses one of the most pressing current public health problems and is a major risk factor for type 2 diabetes. Protein tyrosine phosphatase-1B (PTP-1B) negatively regulates the signaling pathways of insulin and leptin, two hormones involved in the central regulation of energy balance (1). Activated insulin receptor and receptor substrate-1 are dephosphorylated by PTP-1B (2), and phosphorylated JAK2 and STAT3 have been identified as its targets in the leptin pathway (3,4). PTP-1B-deficient mice are hypersensitive to insulin (5) and leptin (4,6) and are protected from diet-induced obesity (4 -6). Hence, increased activity of PTP-1B potentially contributes to leptin resistance associated with overweight (7) and resistance to insulin, which predisposes to type 2 diabetes. In humans, PTPN1, the gene coding for PTP-1B, maps to a region in which a major human quantitative trait locus for obesity and type 2 diabetes has been reported (8 -10). Several rare PTPN1 single nucleotide polymorphisms (SNPs) have been shown to be associated with insulin resistance and diabetes in different populations (11)(12)(13)(14). Recently, Palmer et al. (15) mounted an extensive study of 35 SNPs spanning a 161-kb region including the PTPN1 gene in Ͼ800 Hispanic Americans. Twenty SNPs showed significant association with fasting glucose and the insulin sensitivity index S i . Through its effect on insulin sensitivity, changes in PTP-1B activity may also be refl...

Protein Tyrosine Phosphatase N1 Gene Variants Associated with Type 2 Diabetes Mellitus and Its Related Phenotypes in the Korean Population

“…The association between the PTPN1 gene and blood pressure was greatly in concordance with previous two reports (Cheyssac et al, 2006;Spencer-Jones et al, 2005). Both reports suggested that PTPN1 gene variants increase blood pressure.…”

“…We also identified the increased tendency of TG in homozygotes of rs6020612; the minor allele homozygotes were observed in only two individuals. Although this association was reported in other reports (Cheyssac et al, 2006;Spencer-Jones et al, 2005), the associated SNP had a higher frequency of minor allele homozygotes. Therefore, the association between PTPN1 and TG should be confirmed using other SNPs that have been previously reported.…”

Protein tyrosine phosphatase 1B is not a major susceptibility gene for type 2 diabetes mellitus or obesity among Pima Indians

“…In a study of white subjects, Bento et al observed associations between several non-coding singlenucleotide polymorphisms (SNPs) positioned across PTPN1 and type 2 diabetes [2], whereas, in a study of Hispanic American subjects, Palmer et al observed associations between several of the same SNPs and insulin sensitivity and/or fasting glucose levels [3]. Subsequent replication studies of these initial reports have provided weaker or negative results for associations with type 2 diabetes or related phenotypes [4][5][6]. In the current study, we sought to determine whether SNPs in PTPN1 have a role in susceptibility to type 2 diabetes or obesity in the Pima Indian population of Arizona.…”

“…Therefore, it is possible that the nominal associations observed between SNPs in block 1 and insulin sensitivity in Pima Indians represent false associations due to multiple testing, rather than independent confirmation that this gene has a role in insulin action. Palmer et al also detected two SNPs (rs4811077 and Only non-diabetic subjects were used in this analysis p values were calculated under the additive model and were adjusted for: a age, sex and family membership b age, sex, per cent body fat and family membership c age, sex, per cent body fat, glucose disposal rate, 30-min glucose levels and family membership; analysis for 30-min insulin was done only in normal glucose tolerant subjects, n=186 d age, sex, per cent body fat, glucose disposal rate and family membership; analysis for acute insulin response was done only in normal glucose tolerant subjects, n (female/male): 1/1, 74 (17/57); 1/2, 91 (36/55); 2/2, 21 (8/13) EMBS, estimated metabolic body size [4] d SNPs associated with type 2 diabetes in white subjects [2] e SNPs associated with insulin sensitivity in Hispanic Americans [3] f SNPs associated with fasting glucose levels in Hispanic Americans [3] g SNPs associated with insulin sensitivity in female white twins [5] h SNPs associated with fasting insulin levels and glucose disappearance in white subjects from the HERITAGE Family study [11] i SNPs associated with type 2 diabetes in the Danish population [12] 1484insG) that were associated with the acute insulin response (AIR) [3], while Ukkola et al detected a single SNP (rs968701) that was associated with the AIR in white subjects [11]. None of the SNPs was associated with an AIR among 186 full-heritage Pima Indians with normal glucose tolerance (data shown for rs4811074 in Table 2).…”

TUB is a candidate gene for late-onset obesity in women

“…To control for population stratification bias, DZ twin pairs discordant for genotype were also used in a sibling transmission disequilibrium test (Sib-TDT) association analysis as described elsewhere [10,11].…”