studies

1288A AASLD ABSTRACTS HEPATOLOGY, October, 2015
2216
The dual and opposite role of the TM6SF2-rs58542926
Variant in Protecting against Cardiovascular Disease
and Conferring Risk for Non-alcoholic fatty liver: A
meta-analysis
Carlos J. Pirola 2 , Silvia Sookoian 1 ; 1 Clinical and Molecular Hepatology,
IDIM-CONICET, Ciudad Autonoma de Buenos Aires,
Argentina; 2 Molecular Genetics and Biology of Complex Diseases,
IDIM CONICET, Buenos Aires, Argentina
Background: The nonsynonymous p.Glu167Lys (rs58542926
C/T, E167K) variant, located in TM6SF2 (transmembrane 6
superfamily member 2) gene, was associated not only with
blood lipid levels, including serum total cholesterol (TC),
low-density lipoprotein cholesterol (LDL-C) and triglycerides
(TG), but also myocardial infarction risk and NAFLD susceptibility.
This variant, which has a relatively low frequency not
only in Caucasian population (0.09) but globally (0.07), presents
a clinical paradox, as the C (Glu167) allele was shown
to be associated with increased CVD risk, while the T allele
(Lys167) was associated with NAFLD. Objective: to examine
the evidence provided in the available literature to estimate the
strength of the effect of rs58542926 on both circulating lipid
traits and NAFLD across different populations. In addition, we
assessed whether associations are consistent across studies
in magnitude and direction for all explored traits. Methods/
design: We performed a systematic review by a meta-analysis;
literature searches identified eleven studies. Results: The
rs58542926 exerts a significant role in modulating lipid traits,
including TC, LDL-C, TG, and NAFLD. However, this influence
on lipids and NAFLD is opposite between genotypes in the
dominant model of inheritance. Pooled estimates of random
effects in 193,931 individuals showed that, compared with
carriers of the minor K allele (EK+KK individuals), subjects
homozygous for the ancestral C allele (EE genotype) are at risk
of having higher levels of TC, LDL-C and TG; the differences
in mean±SE (mg/dL) are 7.4±2.3, 3.7±0.9 and 9.4±2.1,
respectively. The rs58542926 was not associated with HDL-C
in a large sample (n =91,937). Of note, the EE genotype is
associated with a relatively large effect on blood levels of TC
(about 2-3% increase on an upper limit of 200 mg/dL), LDL-C
(about 1-2% increase on an upper limit of 150 mg/dL), and
TG (about 6.4% increase on an upper limit of 150 mg/dL) for
a single variant influencing a polygenic trait. In contrast, homozygous
EE subjects appear to be protected against NAFLD
(OR 0.469, 95% CI 0.300-0.734, p = 0.0009, n = 3273),
while carriers of the K allele show about~ 2.2% higher lipid
fat content when compared with homozygous EE (n = 3,413),
and have 2.13-fold higher risk of developing NAFLD. Conclusion:
The rs58542926 appears to be an important modifier of
blood lipid traits in different populations. As a challenge for
the personalized medicine, the “major” C-allele, which has a
frequency as high as 93%, is associated with CVD risk, while
the “minor”-low frequency T allele confers risk for NAFLD; in
turn, CVD and NAFLD are strongly related outcomes.
Disclosures:
The following authors have nothing to disclose: Carlos J. Pirola, Silvia Sookoian
2217
Mitochondrial Mutator-Phenotype May Be Related
to Pathogenesis of Nonalcoholic Fatty Liver Disease:
Insights from Deep Sequencing of Liver Mitochondrial
Genomes
Carlos J. Pirola 1 , Romina Scian 1,2 , Cristian O. Rohr 3 , Hernán
Dopazo 3 , Gustavo O. Castaño 4 , Silvia Sookoian 2 ; 1 Molecular
Genetics and Biology of Complex Diseases, IDIM-CONICET,
Buenos Aires, Argentina; 2 Clinical and Molecular Hepatology,
IDIM-CONICET, Buenos Aires, Argentina; 3 Biomedical Genomics
and Evolution Laboratory, CONICET, Buenos Aires, Argentina;
4 Medicine and Surgery Department, Liver Unit, Hospital Abel Zubizarreta,
Buenos Aires, Argentina
Background: Mitochondrial (mt) dysfunction is involved in the
development of NAFLD; normal activity of mitochondria critically
determines fatty acid beta-oxidation, OXPHOS and insulin
signaling. In addition, liver mitochondrial biogenesis is reduced
in NAFLD. The mt-genome is highly polymorphic and variants
in mtDNA affect mt function. A small proportion of mtDNA
belongs to the control region involved in mtDNA duplication
(D-loop). To understand the clinical implications of mtDNA-variation
in the pathogenesis of NAFLD, we sequenced whole liver
mtDNA-genomes of 28 individuals, including patients with
NAFLD (n = 20) and age and sex-matched controls (n = 8). In
addition, we sequenced the entire nuclear POLG and POLG2
genes, which are involved in mtDNA-replication. Methods:
Liver mtDNA was first amplified by long-range PCR; deep next
generation sequencing was further performed. Results: We
achieved an average read depth >800 per individual; mtDNA
sequencing revealed 689 variants, 525 (76%) of them were
observed in NAFLD showing an enrichment of 1.28-fold mutation
fraction compared to controls (p = 0.0056). Ten of 16
base positions containing heteroplasmic variants were highly
polymorphic (>0.1) and were observed in NAFLD. The mutation
fraction of liver mtDNA-genomes in controls compared with
that in patients with simple steatosis (NAFL) shows no significant
differences. Remarkably, patients with NASH compared
with controls harbored a significantly higher number of mutations
in mitochondrially encoded ATP synthase 6 (p = 0.033),
cytochrome b (MT-CYB) (p = 0.011), and members of the
NADH-dehydrogenase complex (p = 4.5 E -5 ). The comparison
of liver mtDNA-diversity among patients with NAFL and NASH
showed that the disease severity was associated with increased
number of variants in the NADH-complex (p = 7.4 E -3 ). For variants
predicted to be deleterious, an allelic association analysis
was further conducted; we found a nonsynonymous variant in
MT-CYB (m.15326) and two mutations in D-loop (m.146 and
m.16298) that were significantly associated with the disease
severity. Overall, mutations located in the NADH-complex were
significantly associated with liver-related phenotypes and arterial
hypertension. The missense p.Gln1236His variant in POLG
was associated with liver mtDNA-copy number (p = 0.01) and
the POLG2- rs7223078 was associated with the degree of histological
steatosis (p = 0.036). Conclusion: The burden of mutations
in liver mt-genomes may contribute to the pathogenesis
of NAFLD and metabolic syndrome-associated comorbidities
explaining part of the “missing heritability”. NASH development
may be associated with an OXPHOS-negative phenotype.
Disclosures:
The following authors have nothing to disclose: Carlos J. Pirola, Romina Scian,
Cristian O. Rohr, Hernán Dopazo, Gustavo O. Castaño, Silvia Sookoian