Evidence for a Free Fatty Acid-related Diabetes Susceptibility Locus on Chromosome 22 in Finnish Subjects
Anne U. Jackson1, Richard M. Watanabe2, Laura J. Scott1, Karen L. Mohlke3, Kaisa Silander3, Timo T. Valle4, Kim Doheny5, Elizabeth Pugh5, Jaakko Tuomilehto4, Richard N. Bergman2, Francis S. Collins3, Michael Boehnke1
1University of Michigan, Ann Arbor, MI; 2University of Southern California, Los Angeles, CA; 3National Human Genome Research Institute, Bethesda, MD; 4National Public Health Institute, Helsinki, Finland, 5Center for Inherited Disease Research, Baltimore, MD.
Dyslipidemia is a hallmark of metabolic syndrome and a common characteristic of type 2 diabetes mellitus (T2DM). Free-fatty acids (FFA) are thought to be a key component in the regulation of hepatic glucose output. As such, understanding the genes underlying the regulation of FFAs and other lipids may provide unique insights into the genetic predisposition for T2DM and related complex diseases. In the Finland-United States Investigation of NIDDM Genetics (FUSION) study, we analyzed fasting and 2-hour FFA levels from the oral glucose tolerance test and fasting lipids in the 491 non-diabetic offspring (age: 34.9±7.3, BMI: 25.9±4.3 (mean±SD)) of a cohort of 201 families ascertained for T2DM affected sibling pairs. Mean fasting glucose and insulin were 5.0±0.5 mM and 65.7±32.8 pM, respectively. Mean fasting FFA levels were 0.45±.14 mM and 2-hr FFA levels were 0.17±.05 mM. We estimated trait heritabilities (h2) and performed quantitative trait locus (QTL) linkage analysis by variance components. h2 for fasting FFA and 2-hr FFA were 0.13 and 0.30, respectively. h2 estimates for total, HDL, and LDL cholesterol, and triglycerides were 0.64, 0.34, 0.57, and 0.39, respectively. h2 estimates were not significantly altered when traits were adjusted for age, sex, and BMI. QTL linkage analysis for 2-hr FFA, adjusted for age, sex, and BMI, in a genome scan based on 392 microsatellite markers, yielded a LOD score of 1.94 on chromosome 22 near marker D22S428. The 2-hr FFA linkage signal overlaps with a previously identified region of strong FUSION T2DM association at and around D22S423 (p=.00002) that is 0.6 cM from D22S428. We currently are measuring 2-hr FFA levels in additional family members in an effort to identify the variant(s) responsible for T2DM risk and FFA variability in this region.