Insulin clearance: confirmation as a highly heritable trait, and genome-wide linkage analysis

Abstract

Aims/hypothesis: We have previously documented a high heritability of insulin clearance in a Hispanic cohort. Here, our goal was to confirm the high heritability in a second cohort and search for genetic loci contributing to insulin clearance.

Methods: Hyperinsulinaemic-euglycaemic clamps were performed in 513 participants from 140 Hispanic families. Heritability was estimated for clamp-derived insulin clearance and a two-phase genome-wide linkage scan was conducted using a variance components approach. Linkage peaks were further investigated by candidate gene association analysis in two cohorts.

Results: The covariate-adjusted heritability of insulin clearance was 73%, indicating that the majority of the phenotypic variance is due to genetic factors. In the Phase 1 linkage scan, no signals with a logarithm of odds (LOD) score >2 were detected. In the Phase 2 scan, two linkage peaks with an LOD >2 for insulin clearance were identified on chromosomes 15 (LOD 3.62) and 20 (LOD 2.43). These loci harbour several promising candidate genes for insulin clearance, with 12 single nucleotide polymorphisms (SNPs) on chromosome 15 and six SNPs on chromosome 20 being associated with insulin clearance in both Hispanic cohorts.

Conclusions/interpretation: In a second Hispanic cohort, we confirmed that insulin clearance is a highly heritable trait and identified chromosomal loci that harbour genes regulating insulin clearance. The identification of such genes may improve our understanding of how the body clears insulin, thus leading to improved risk assessment, diagnosis, prevention and therapy of diabetes, as well as of other hyperinsulinaemic disorders, such as the metabolic syndrome and polycystic ovary syndrome.

Fig. 1

Plots of the maximum linkage signal for insulin clearance on chromosome 15 (a) and chromosome 20 (b). Microsatellite markers are listed at top. Solid line, linkage for the entire cohort; dashed line, linkage for Phase 1; dotted line, linkage for Phase 2

Fig. 2

Gene and linkage disequilibrium plot for the chromosome 15 SNPs associated with insulin clearance. Genes are indicated by arrows (arrow size not to scale). The locations of the genotyped SNPs relative to the genes are indicated. The linkage disequilibrium plot beneath the genes displays D′ values (%) for each pair of SNPs in the box at the intersection of the diagonals from each SNP. The bright red blocks indicate D′ = 1 (100%) for the corresponding pair of variants with an LOD score ≥2. The boxes with lighter shades of red indicate D′ <1, with an LOD score ≥2. The SNPs consist of a single SNP at MEGF11, plus two distinct blocks of SNPs. The region of the first block of SNPs is expanded to provide details. SNPs rs12899971 and rs2301249 are intronic; rs7085 resides in the 3′ untranslated region of CSK. SNPs that do not have rs numbers are indicated by genomic coordinates (NCBI Genome Build 36.3, www.ncbi.nlm.nih.gov/genome/guide/human/release_notes.html)

Fig. 3

Gene and linkage disequilibrium plot for the chromosome 20 SNPs associated with insulin clearance. Genes are indicated by arrows (arrow size not to scale). The locations of the genotyped SNPs relative to the genes are indicated. The linkage disequilibrium plot beneath the genes displays D′ values (%) for each pair of SNPs in the box at the intersection of the diagonals from each SNP. The bright red blocks indicate D′ = 1 (100%) for the corresponding pair of variants with an LOD score of ≥2. All intragenic SNPs are intronic. SNPs that do not have rs numbers are indicated by genomic coordinates (NCBI Genome Build 36.3, www.ncbi.nlm.nih.gov/genome/guide/human/release_notes.html)