👤 Kenneth J Ryan

To determine the relationship between two common apoA-IV variants (Thr347-->Ser; Gln360-->His), and body mass index (BMI) and percentage body fat. Cross-sectional study. Eight-hundred and forty-eight subjects screened for participation in ongoing clinical studies. ApoA-IV genotype, body mass index, waist-to-hip ratio and percentage body fat by bioelectric impedance. Participants had an average age of 41+/-12 y and an average BMI of 28.2+/-5.5 kg/m2. Individuals homozygous for the Ser347 allele had higher BMI (32.3+/-6.6 vs 28.6+/-5.3 kg/m2; P<0.01) and percentage body fat (36.9+/-7.8 vs 31.0+/-9.6%; P<0.05) compared with individuals homozygous for Thr347. In contrast, the presence of at least one copy of the His360 allele was associated with lower BMI (27.2+/-5.0 vs 28.4+/-5.6 kg/m2; P<0.05) and percentage body fat (28.6+/-8.2 vs 30.7+/-9.1%; P<0.05). The genotype effects persisted after normalization of the data for the potential confounding effects of gender, age and race. When grouped by BMI percentile, the frequency of the Ser347/Ser347 genotype increased while the frequency of the His360 allele decreased with increasing BMI. These data suggest a role for apoA-IV in fat storage or mobilization and that genetic variations in the apoA-IV gene may play a role in the development of obesity. Show less

Krüppel-associated box (KRAB) domains are present in approximately one-third of all human zinc finger proteins (ZFPs) and are potent transcriptional repression modules. We have previously cloned a corepressor for the KRAB domain, KAP-1, which is required for KRAB-mediated repression in vivo. To characterize the repression mechanism utilized by KAP-1, we have analyzed the ability of KAP-1 to interact with murine (M31 and M32) and human (HP1alpha and HP1gamma) homologues of the HP1 protein family, a class of nonhistone heterochromatin-associated proteins with a well-established epigenetic gene silencing function in Drosophila. In vitro studies confirmed that KAP-1 is capable of directly interacting with M31 and hHP1alpha, which are normally found in centromeric heterochromatin, as well as M32 and hHP1gamma, both of which are found in euchromatin. Mapping of the region in KAP-1 required for HP1 interaction showed that amino acid substitutions which abolish HP1 binding in vitro reduce KAP-1 mediated repression in vivo. We observed colocalization of KAP-1 with M31 and M32 in interphase nuclei, lending support to the biochemical evidence that M31 and M32 directly interact with KAP-1. The colocalization of KAP-1 with M31 is sometimes found in subnuclear territories of potential pericentromeric heterochromatin, whereas colocalization of KAP-1 and M32 occurs in punctate euchromatic domains throughout the nucleus. This work suggests a mechanism for the recruitment of HP1-like gene products by the KRAB-ZFP-KAP-1 complex to specific loci within the genome through formation of heterochromatin-like complexes that silence gene activity. We speculate that gene-specific repression may be a consequence of the formation of such complexes, ultimately leading to silenced genes in newly formed heterochromatic chromosomal environments. Show less