The PC-1 Q121 Allele Is Exceptionally Prevalent in the Dominican Republic and Is Associated with Type 2 Diabetes

Abstract

The human glycoprotein PC-1 codon Q121 allele has been correlated with insulin resistance, but not with type 2 diabetes or obesity. We investigated the prevalence of PC-1 Q121 in the Dominican Republic population (755 subjects studied) and whether this variant is associated with insulin resistance, obesity, or type 2 diabetes. The prevalence of PC-1 Q121 was high compared with that in other populations. The proportions of genotypes detected were: KK, 21.6%; KQ, 48.3%; and QQ, 30.1%. This compares to approximately 74%, 24%, and 2% in other populations. Among nonobese, nondiabetic subjects, the insulin response of KQ (P = 0.027) and QQ (P = 0.031) subjects was greater during the oral glucose tolerance test than that of KK subjects, whereas plasma glucose profiles were comparable. The Q allele was more prevalent in obese type 2 diabetics than in controls (P = 0.026; odds ratio = 1.56). Multiple regression analysis, after adjusting for age, gender, and body mass index, showed the QQ genotype to be associated with type 2 diabetes (P = 0.043; odds ratio = 2.74), but not obesity (P = 0.068). These results indicate that the PC-1 Q121 allele is exceptionally prevalent in the Dominican Republic, contributing to both insulin resistance and type 2 diabetes.

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

“…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. Clearly, there must be other genetic and/or environmental factors beyond ENPP1 that account for the racial differences in susceptibility to increased adiposity.…”

“…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.…”