A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance.

Abstract

The genes responsible for insulin resistance are poorly defined. Plasma cell differentiation antigen (PC-1) glycoprotein inhibits insulin receptor signaling and is associated with insulin resistance. We describe here a novel polymorphism in exon 4 of the PC-1 gene (K121Q) and demonstrate that it is strongly associated with insulin resistance in 121 healthy nonobese (BMI <30 kg/m2) nondiabetic (by oral glucose tolerance test [OGTT]) Caucasians from Sicily. Compared with 80 KK subjects, Q allele carriers (n = 41, 39 KQ and 2 QQ) showed higher glucose and insulin levels during OGTT (P < 0.001 by two-way analysis of variance) and insulin resistance by euglycemic clamp (M value = 5.25 +/- 1.38 [n = 24] vs. 6.30 +/- 1.39 mg x kg(-1) x min(-1) [n = 49], P = 0.005). Q carriers had higher risk of being hyperinsulinemic and insulin resistant (odds ratio [CI]: 2.99 [1.28-7.0], P < 0.001). Insulin receptor autophosphorylation was reduced (P < 0.01) in cultured skin fibroblasts from KQ versus KK subjects. Skeletal muscle PC-1 content was not different in 11 KQ versus 32 KK subjects (33 +/- 16.1 vs. 17.5 +/- 15 ng/mg protein, P = 0.3). These results suggest a cause-effect relationship between the Q carrying genotype and the insulin resistance phenotype, and raise the possibility that PC-1 genotyping could identify individuals who are at risk of developing insulin resistance, a condition that predisposes to type 2 diabetes and coronary artery disease.

Association of K121Q polymorphism in ENPP1 (PC-1) with BMI in Caucasian and African-American adults

“…The frequency of the K121 allele in Caucasians in our study is similar to that found in previous studies, [5][6][7][8]10,11 and has been reported to be much higher in Caucasians (79.9%) than African-Americans (25.9%) or Dominicans (45.8%). 9 Although the K121 allele frequency is higher in Caucasians than African-Americans in our study sample, the average BMI at each percentile was higher in African-Americans than in Caucasians.…”

“…Previous studies have demonstrated associations of the Q121 allele with increased adiposity in Caucasian children and Mexican-Americans and increased fasting plasma glucose and insulin resistance in adult Caucasians, Mexican Americans, Spaniards, and Dominicans. [5][6][7][8][9]12,13 In contrast, we found a higher K121 allele frequency in our adult obese Caucasian and African-American subjects, and do not have sufficient endophenotypic data to address the possible role of K121Q alleles on insulin homeostasis in our sample. Our association of the K121 rather than the Q121 allele with increased BMI could reflect differences in the effects of the two alleles on weight gain at different ages (Caucasians), or in different racial groups (AfricanAmericans).…”

“…Alternatively, the K121 allele may be in linkage disequilibrium with other ENPP1 polymorphisms (or other genes) in our study sample that is genetically different (African-Americans) and perhaps more heterogeneous (Caucasians) than the samples studied previously. Several studies have demonstrated an association of the Q121 allele with insulin resistance in adults, [5][6][7][8][9] but these studies have failed to demonstrate an association of this allele with obesity. [5][6][7][8][9][10][11] However, the range of BMIs in these studies was between 24 and 28 kg/m 2 , with sample sizes that were much smaller than our study, and were not powered to detect small BMI effects of the magnitude we report.…”

“…Several studies have demonstrated an association of the Q121 allele with insulin resistance in adults, [5][6][7][8][9] but these studies have failed to demonstrate an association of this allele with obesity. [5][6][7][8][9][10][11] However, the range of BMIs in these studies was between 24 and 28 kg/m 2 , with sample sizes that were much smaller than our study, and were not powered to detect small BMI effects of the magnitude we report. Due to the high frequency of the K/K genotype in Caucasians, the effect of the 1.3 kg/m 2 increase in BMI we detected could significantly increase the obesity-related risk of many co-morbid conditions such as coronary artery disease, diabetes, and cancer.…”

“…Constanzo et al 4 showed that the human Q121 allele has more potent inhibitory effects on IR autophosphorylation than the K121 allele in vitro. Q121 carriers have been reported to have higher plasma glucose and insulin during oral glucose tolerance testing (OGTT), and relative insulin resistance as measured by euglycemic clamp in some studies [5][6][7][8][9] but not others. 10,11 Meyre et al 12 reported that obese French children have a higher frequency of the Q121 allele than nonobese controls.…”