Skip to main content
Login | Suomeksi | På svenska | In English

Browsing by Author "Rämö, Joel"

Sort by: Order: Results:

  • Obesity Is Associated With Low NAD+/SIRT Pathway Expression in Adipose Tissue of BMI-Discordant Monozygotic Twins 
    Jukarainen, Sakari; Heinonen, Sini; Rämö, Joel; Rinnankoski-Tuikka, Rita; Rappou, Elisabeth; Tummers, Mark; Muniandy, Maheswary; Hakkarainen, Antti; Lundbom, Jesper; Lundbom, Nina; Kaprio, Jaakko; Rissanen, Aila; Pirinen, Eija; Pietiläinen, Kirsi (2016)
    Context: Sirtuins (SIRTs) regulate cellular metabolism and mitochondrial function according to the energy state of the cell reflected by NAD+‚ levels. Objective: Our aim was to determine whether expressions of SIRTs and NAD+‚ biosynthesis genes are affected by acquired obesity and how possible alterations are connected with metabolic dys-function while controlling for genetic and familial factors. Design and Participants: We studied a cross-sectional sample of 40 healthy pairs of monozygotic twins, including 26 pairs who were discordant for body mass index (within-pair difference +ƒ 3 kg/m2), from the FinnTwin12 and FinnTwin16 cohorts. Main Outcome Measures: Subcutaneous adipose tissue (SAT) transcriptomics was analyzed by using Affymetrix U133 Plus 2.0 chips, total SAT (poly-ADP) ribose polymerase (PARP) activity by an ELISA kit, body composition by dual-energy x-ray absorptiometry and magnetic resonance imaging/spectroscopy, and insulin sensitivity by an oral glucose tolerance test. Results: SIRT1, SIRT3, SIRT5, NAMPT, NMNAT2, NMNAT3, and NRK1 expressions were significantly down-regulated and the activity of main cellular NAD+‚ consumers, PARPs, trended to be higher in the SAT of heavier cotwins of body mass index–discordant pairs. Controlling for twin-shared factors, SIRT1, SIRT3, NAMPT, NMNAT3, and NRK1 were significantly negatively correlated with adiposity, SIRT1, SIRT5, NMNAT2, NMNAT3, and NRK1 were negatively correlated with inflammation, and SIRT1 and SIRT5 were positively correlated with insulin sensitivity. Expressions of genes involved in mitochondrial unfolded protein response were also significantly down-regulated in the heavier cotwins. Conclusions: Our data highlight a strong relationship of reduced NAD+‚/SIRT pathway expression with acquired obesity, inflammation, insulin resistance, and impaired mitochondrial protein homeostasis in SAT.
  • The Contribution of GWAS Loci in Familial Dyslipidemias 
    Rämö, Joel (2016)
    Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 affected FCH individuals across the families, seven (3%) carried Mendelian variants and 83 (35%) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined.

Yhteystiedot

HELSINGIN YLIOPISTO