Abstract for presentation at 11th International Congress of Human Genetics

A Genome-wide Screen Identifies a Quantitative Trait Locus for Human HDL-cholesterol

  • Mr Sampo Sammalisto, Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland
  • Mr Peter Almgren, 2Department of Clinical Sciences, Diabetes and Endocrinology, Wallenberg Laboratory, University Hospital MAS, Lund University, Sweden
  • Mr Hemang Parikh, 2Department of Clinical Sciences, Diabetes and Endocrinology, Wallenberg Laboratory, University Hospital MAS, Lund University, Sweden
  • Mr Tero Hiekkalinna, Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland
  • Prof Marja-Riitta Taskinen, 4Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
  • Dr Markus Perola, Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland
  • Prof Leena Peltonen, Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland
  • Prof Leif Groop, 2Department of Clinical Sciences, Diabetes and Endocrinology, Wallenberg Laboratory, University Hospital MAS, Lund University, Sweden

    • Dyslipidemia defined as high total cholesterol (TC), low HDL cholesterol (HDL-C) and/or elevated triglyceride (TG) levels represents one of the main risk factors for cardiovascular disease. Although many single-gene mutations have been described for rare disorders of lipid metabolism the genetics of dyslipidemia in the general population remains elusive. Despite substantial efforts to map genetic loci contributing to the normal population variance in lipid metabolism parameters success has not reached expectations. Systematic analyses of recent gene mapping efforts have implicated that the most critical factors associated with successful gene mapping are 1) increase in sample size and 2) increase in genetic homogeneity by sampling from a single ethnic group. To achieve both we combined the primary genotype data from four Finnish genome-wide screens ascertained for type 2 diabetes (T2D), familial combined hyperlipidemia (FCHL) and familial low HDL-C and performed variance-components linkage analysis for TC, HDL-C and TG on the pooled dataset of 1580 individuals from 291 families. After covariate adjustment for age, sex, BMI, affection status for T2D, FCHL and familial low HDL-C, recruitment centre as well as fasting glucose and insulin values the heritability estimates in our sample were 33% for TC, 49% for HDL-C and 43 % for TG. We observed suggestive multipoint linkage between TC and chromosome 11q (LOD = 2.04) as well as between HDL-C and 18p (LOD = 2.92). To asses the empirical significance of our linkage findings we simulated 100 genome-wide scans using a gene-dropping approach which were analyzed exactly like the actual data. According to these simulated data sets only the HDL-C locus on chromosome 18p remained significant (p = 0.01, 95% CI 0-0.05). The 1-LOD drop support region on 18p contains several functional candidate genes for HDL-C which we are currently investigating further.

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