Pizzuti et al. (1999) described a polymorphism in exon 4 of the PC1 gene (K121Q; rs1044498) and demonstrated that it was strongly associated with insulin resistance (see 125853) in 121 healthy nonobese, nondiabetic Caucasians in Sicily. Compared with 80 KK allele subjects, Q allele carriers showed higher glucose and insulin levels during oral glucose tolerance tests and insulin resistance by euglycemic clamp. Q carriers had a higher risk of being hyperinsulinemic and insulin resistant. Insulin receptor autophosphorylation was reduced in cultured skin fibroblasts from KQ versus KK subjects. The results suggested that a Q-containing genotype may identify individuals who are at risk of developing insulin resistance, a condition that predisposes to type II diabetes (125853) and coronary artery disease (see 608320).
Frittitta et al. (2001) investigated whether the PC1 gene modulates insulin sensitivity independently of weight status. Although subjects were nondiabetic by selection criteria, plasma insulin concentrations during oral glucose tolerance test were higher (P less than 0.05) in Q allele-carrying subjects (K121Q or Q121Q genotypes), compared with K121K individuals, in both the nonobese and obese groups. The K121Q polymorphism was correlated with insulin sensitivity independently (P less than 0.05) of BMI, gender, age, and waist circumference. The authors concluded that the Q121 PC1 variant and obesity (601665) have independent and additive effects in causing insulin resistance.
Abate et al. (2003) determined the frequency of the PC1 K121Q and IRS1 G972R (147545.0002) polymorphisms in Asian Indians and Caucasians. (The authors referred to the IRS1 polymorphism as G972A.) The Asian Indian group included both subjects who had immigrated to the United States and those who were born in the United States. The frequency of carrying at least 1 copy of the PC1 121Q variant in Asian Indians was significantly higher than that in Caucasians (P = 0.01), but the frequency was similar for IRS1 972R (6% and 7%). A significantly higher insulin area under the curve during oral glucose tolerance testing (P less than 0.0001) and lower insulin sensitivity during glucose clamp studies (P = 0.04) were found in Asian Indians with the PC1 121Q variant compared with Asian Indians with wildtype PC1 and with Caucasians with or without the polymorphism. IRS1 972R was not associated with any change in insulin sensitivity. The authors concluded that the PC1 K121Q polymorphism associates with primary insulin resistance in migrant Asian Indians.
Hamaguchi et al. (2004) studied the prevalence of PC1 Q121 in a Dominican Republic population (755 subjects studied) and whether this variant is associated with insulin resistance, obesity, or type II diabetes. The prevalence of PC1 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 II diabetics than in controls (P = 0.026; odds ratio = 1.56). Multiple regression analysis, after adjusting for age, gender, and body mass index (BMI), showed the QQ genotype to be associated with type II diabetes (P = 0.043; odds ratio = 2.74) but not obesity (P = 0.068). The authors concluded that the PC1 Q121 allele is exceptionally prevalent in the Dominican Republic, contributing to both insulin resistance and type II diabetes.
Kubaszek et al. (2004) investigated whether the effect of the K121Q polymorphism on insulin sensitivity, and the occurrence of diabetes and hypertension, depends on size at birth. In a study of 489 subjects born in Helsinki between 1924 and 1933, they found that fasting insulin levels and insulin resistance were highest in subjects carrying the 121Q allele who were small at birth (P for interaction = 0.04 and 0.05). Additionally, in those whose birth length was up to 49 cm, the K121Q polymorphism was associated with a 2-fold higher incidence of type II diabetes. Kubaszek et al. (2004) concluded that the effect of the K121Q polymorphism on insulin levels and insulin sensitivity, measured as the homeostasis model assessment for insulin resistance, is dependent on birth length and that this interaction increases susceptibility to type II diabetes and hypertension in adulthood.
Meyre et al. (2005) analyzed the ENPP1 gene in 6,147 subjects and found an association between a 3-allele risk haplotype defined by the polymorphisms K121Q, IVS20delT-11 (173335.0001), and A-G+1044TGA (173335.0007) and childhood obesity (odds ratio = 1.69, P = 0.0006), morbid or moderate obesity in adults (odds ratio = 1.50, P = 0.006 or odds ratio = 1.37, P = 0.02, respectively), and type II diabetes (odds ratio = 1.56, P = 0.00002). The Genotype IBD Sharing Test suggested that this obesity-associated ENPP1 risk haplotype, which they referred to as QdelTG, contributes to the chromosome 6q linkage in childhood obesity reported by Meyre et al. (2004). The haplotype confers a higher risk of glucose intolerance with type II diabetes to obese children and their parents and associates with increased serum levels of soluble ENPP1 protein in children. Expression of a long ENPP1 mRNA isoform, which includes the obesity-associated A-G+1044TGA SNP, was specific for pancreatic islet beta cells, adipocytes, and liver. Meyre et al. (2004) concluded that several variants of ENPP1 have a primary role in mediating insulin resistance and in the development of both obesity and type II diabetes, suggesting that an underlying molecular mechanism is common to both conditions.
Bottcher et al. (2006) genotyped the K121Q, IVS20delT-11, and A/G+1044TGA ENPP1 genetic variants for association analyses in 712 school children and in independent cohorts of 205 obese children from Leipzig and 195 obese children from Datteln, Germany. They identified a significantly increased risk of obesity in Leipzig children carrying the 121Q variant (adjusted odds ratio, 1.82; 95% confidence interval, 1.30-2.56; P = 0.0005) or the Q-delT-G haplotype (1.75 (1.17-2.62), P = 0.006) as compared with a lean control group. Bottcher et al. (2006) concluded that their study suggested a potential role of the K121Q polymorphism or derived ENPP1 haplotypes in increased susceptibility to obesity and early impairment of glucose and insulin metabolism in children.
In a case-control study of 911 unrelated Japanese patients with type II diabetes and 876 Japanese controls, Keshavarz et al. (2006) found no significant differences in genotype distribution or allele frequency of the K121Q variant between the 2 groups. Keshavarz et al. (2006) concluded that K121Q has little if any impact on type II diabetes susceptibility in the Japanese population.
