Type 2 diabetes (T2D) is the result of interaction between environmental factors and a strong hereditary component. We review the heritability of T2D as well as the history of genetic and genomic research in this area. Very few T2D risk genes were identified using candidate gene and linkage-based studies, but the advent of genome-wide association studies has led to the identification of multiple genes, including several that were not previously known to play any role in T2D. Highly replicated genes, for example TCF7L2, KCNQ1 and KCNJ11, are discussed in greater detail. Taken together, the genetic loci discovered to date explain only a small proportion of the observed heritability. We discuss possible explanations for this "missing heritability", including the role of rare variants, gene-environment interactions and epigenetics. The clinical utility of current findings and avenues of future research are also discussed.

Fatty acid-binding proteins (FABPs) play regulatory roles at the nexus of lipid metabolism and signaling. Dyslipidemia in clinical manifestation frequently co-occurs with obesity, insulin resistance and hypertension in the Metabolic Syndrome (MetS). Animal studies have suggested FABPs play regulatory roles in expressing MetS phenotypes. In our family cohort of Northern European descent, transcript levels in peripheral white blood cells (PWBCs) of a key FABPs, FABP3, is correlated with the MetS leading components. However, evidence supporting the functions of FABPs in humans using genetic approaches has been scarce, suggesting FABPs may be under epigenetic regulation. The objective of this study was to test the hypothesis that CpG methylation status of a key regulator of lipid homeostasis, FABP3, is a quantitative trait associated with status of MetS phenotypes in humans. We used a mass-spec based quantitative method, EpiTYPER®, to profile a CpG island that extends from the promoter to the first exon of the FABP3 gene in our family-based cohort of Northern European descent (n=517). We then conducted statistical analysis of the quantitative relationship of CpG methylation and MetS measures following the variance-component association model. Heritability of each methylation and the effect of age and sex on CpG methylation were also assessed in our families. We find that methylation levels of individual CpG units and the regional average are heritable and significantly influenced by age and sex. Regional methylation was strongly associated with plasma total cholesterol (p=0.00028) and suggestively associated with LDL-cholesterol (p=0.00495). Methylation at individual units was significantly associated with insulin sensitivity, lipid particle sizing and diastolic blood pressure (p<0.0028, corrected for multiple testing for each trait). Peripheral white blood cell (PWBC) expression of FABP3 in a separate group of subjects (n=128) negatively correlated with adverse profiles of metabolism (βWHR=-0.72; βLDL-c=-0.53) while positively correlated with plasma adiponectin (β=0.24). Further, we show that differential methylation of FABP3 affects binding activity with nuclear proteins from heart tissue. This region that we found under methylation regulation overlaps with a region actively modified by histone codes in the newly available ENCODE data. Our findings suggest that DNA methylation of FABP3 strongly influences MetS, and this may have important implications for cardiovascular disease.

Context: Cerebral palsy is associated with osteopenia, increased fracture risk, short stature, and decreased muscle mass, whereas GH therapy is associated with increased bone mineral density (BMD) and linear growth and improvement in body composition. Objective: We conducted a pilot study to evaluate the effect of 18 months of GH therapy on spinal BMD, linear growth, biochemical markers, and functional measures in children with cerebral palsy. Design and Setting: The study was a randomized control trial, conducted from 2002–2005 at the University of California, Los Angeles, Orthopedic Hospital’s Center for Cerebral Palsy. Patients: Patients included 12 males with cerebral palsy, ages 4.5–15.4 yr. Intervention: We compared 18 months of GH (50 μg daily) vs. no treatment. Primary Outcome Measures: Spinal BMD (dual-energy x-ray absorptiometry scan), height, growth factors, and bone markers were assessed. Results: Ten subjects (five in each group) completed the study. Pre- and post-average height z-scores were −1.47 ± 0.23 and 0.8 ± 0.2 (GH-treated group) vs. −1.35 ± 1.26 and −1.36 ± 1.27 (control group) (Δ sd score, 0.67 vs. −0.01; P = 0.01). Average change in spinal BMD z-score (Δ sd score corrected for height) was 1.169 ± 0.614 vs. 0.24 ± 0.25 in the treated and control groups, respectively (P = 0.03). Osteocalcin, IGF-I, and IGF-binding protein 3 levels increased during GH therapy. There was no change in quality of life scores as measured by the Pediatric Orthopedic Disability Inventory. Conclusions: This small pilot study suggests that 18 months of GH therapy is associated with statistically significant improvement in spinal BMD and linear growth.

Metabolic syndrome (MetS) is an aberration associated with increased risk for cancer and inflammation. Adiponectin, an adipocyte-produced abundant protein hormone, has countering effect on the diabetogenic and atherogenic components of MetS. Plasma levels of adiponectin are negatively correlated with onset of cancer and cancer patient mortality. We previously performed microsatellite linkage analyses using adiponectin as a surrogate marker and revealed two QTLs on chr5 (5p14) and chr14 (14q13).