Quantitative linkage analysis for pancreatic B-cell function and insulin resistance in a large twin cohort.
OBJECTIVE
Insulin resistance and disturbed glucose homeostasis are key characteristics of metabolic syndrome, diabetes, and cardiovascular disease. The recent nonlinear computer version of homeostasis model assessment (HOMA)2 provides an appropriate and convenient assessment of glucose metabolism, enabling gene-mapping studies in large population samples.


METHODS
Fasting insulin and glucose concentration were measured in 758 dizygous and 305 monozygous nondiabetic female pairs from the St. Thomas' U.K. adult twin registry (TwinsUK). Insulin resistance (IR) and pancreatic beta-cell function (BCF) were estimated from this data using the HOMA2 model.


RESULTS
Genome-wide variance component linkage analysis using 2,231 genetic markers identified a highly significant quantitative trait locus for BCF on chromosome 10p15 (logarithm of odds [LOD] 6.2, P = 0.0001), a region recently shown to contain a functional variant for type 1 diabetes. Both BCF and IR suggested a pleiotropic effect on 17q25 (univariate LOD 3.2, P = 0.0012, and 2.38, P = 0.0087; bivariate LOD 2.66), and one additional region showed linkage for IR on chromosome 22q11 (LOD 3.2, P = 0.0016), providing replication and refining previous findings for diabetes and associated traits.


CONCLUSIONS
To our best knowledge, this is the first genome-wide linkage screen for HOMA2 indexes in a large, healthy female sample. These results suggest that loci involved in control of normal glucose homeostasis among nondiabetic individuals might overlap with those involved in the development of diabetes. Linkage replications in independent studies and across populations provide information on important regions of common but potentially heterogeneous variability that can now be used for targeted positional candidate studies.
Falchi
Mario
M
Twin Research and Genetic Epidemiology Unit, St. Thomas' Campus, King's College London School of Medicine, London, UK.
Wilson
Scott G
SG
Paximadas
Dimitrios
D
Swaminathan
Ramasamyiyer
R
Spector
Tim D
TD
D000328:Adult; D000704:Analysis of Variance; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D002874:Chromosome Mapping; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000097:blood / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008875:Middle Aged; D018579:Patient Selection; D012042:Registries; D006113:United Kingdom
D001786:Blood Glucose; D007328:Insulin