Haplotypic analyses of the IGF2-INS-TH gene cluster in relation to cardiovascular risk traits

Abstract

The IGF2-INS-TH genomic region has been implicated in various common disorders including the metabolic syndrome, type 2 diabetes and coronary heart disease (CHD). Here we present detailed haplotype analysis of 2743 males 51-62 years old in relation to body weight and composition, blood pressure (BP) and plasma triglycerides (TG). Use of the total data set was complicated by the number of loci typed, missing data, multi-allelic markers and continuous trait phenotypes. Different algorithms and subsets of the data were analysed using the programmes haplotype trend regression, haplo.score, evolutionary-based haplotype analysis package and Phase, in conjunction with SPSS. Ten haplotypes designated in frequency order *1(20.0%) to *10(3.4%) represented 89% of all haplotypes. Haplotype *5 protected against obesity. Haplotype *4 carriers exhibited elevated BP and fat mass, haplotype *6 was associated with raised plasma TG levels. Haplotype *8 also showed similar magnitude effects as *4. These cohort trait analyses and detailed haplotypic analyses enable integration with published case data. Haplotypes *4, *6 and *8 are the only INS VNTR class III-bearing haplotypes, although differing in flanking haplotype, whereas *5 displays unique features in all three genes (with significant commonality with type 1 diabetes-predisposition haplotypes). We propose that long repeat insertion in the insulin gene promoter ('class III'), reported to result in low insulin production, predisposes to the metabolic syndrome features of elevated BP, fat mass or TG level, therefore appearing more frequently in type 2 diabetic, polycystic ovary syndrome and CHD cases. The functional element(s) of *5 for weight-lowering could reside in any of the three genes.

Replication of IGF2-INS-TH*5 haplotype effect on obesity in older men and study of related phenotypes

“…9 More detailed analyses of the most common microsatellite loci tagging haplotypes of the IGF2-INS-TH cluster as defined by a set of SNPs identified in IGF2, 10 TH01 alleles 11 and INS VNTR class I subclasses 12 has identified an extended haplotype designated IGF2-INS-TH*5 (hereafter *5), consisting of allele A of IGF2 ApaI, allele 9 of TH01 and a subset of class I alleles of INS VNTR, which is associated with lower BMI and fat mass in the NPHSII cohort. 13 In vitro functional studies (references in Rodríguez et al 13 ) are also consistent with any gene of the IGF2-INS-TH cluster influencing weight. However, replication of genetic association in independent samples is important.…”

“…13 In brief, we used the PHASE program version 2.0 16 in order to determine, with a predefined level of confidence set at Z90%, the two haplotypes resulting from the combination of the TH01 microsatellite and the SNPs IGF2 ApaI and INS HphI for each one of the individuals analysed. We have previously shown that the resulting haplotypes tag the most common haplotypes of 14 polymorphisms spanning this gene cluster, giving haplotypic analyses with an increased power (due to fewer missing data) and a reduced risk of false positive findings related to low-frequency haplotypes.…”

IGF2 DNA methylation is a modulator of newborn’s fetal growth and development

“…28 However, significant associations with obesity, hypertension and dyslipidemia in healthy mid-age men were also reported. 29 This suggests that the IGF2/H19 epigenotypes we have uncovered could also be associated with obesity and its cardiometabolic risk factors. Whether those associations are linked through the effect on birth weight remain to be tested.…”

IGF2 Gene Variants and Risk of Hypertension in Obese Children and Adolescents

“…Specific haplotypes of IGF2-INS-TH gene cluster are associated with significantly fat mass and high blood pressure in humans, thus representing cardiovascular risk traits (19). Experiments in Prague hereditary hypertriglyceridemic (HTG) and hypertensive rats confirmed the importance of IGF2 gene for determining metabolic and cardiovascular phenotypes.…”

“…This imprinted gene lies in close proximity to the insulin and tyrosine hydroxylase genes on chromosome 11p15, in a genomic region related to regulation of both body weight and cardiovascular risk (15,(17)(18)(19). Moreover, a recent study conducted on Prague hypertriglyceridemic rats demonstrated a possible important role of IGF2 gene in lipid metabolism and blood pressure regulation (20).…”