Genetic variants in COL13A1, ADIPOQ and SAMM50, in addition to the PNPLA3 gene, confer susceptibility to elevated transaminase levels in an admixed Mexican population

Non-alcoholic fatty liver disease (NAFLD) is the accumulation of extra fat in liver cells not caused by alcohol. Elevated transaminase levels are common indicators of liver disease, including NAFLD. Previously, we demonstrated that PNPLA3 (rs738409), LYPLAL1 (rs12137855), PPP1R3B (rs4240624), and GCKR (rs780094) are associated with elevated transaminase levels in overweight/obese Mexican adults. We investigated the association between 288 SNPs identified in genome-wide association studies and risk of elevated transaminase levels in an admixed Mexican-Mestizo sample of 178 cases of NAFLD and 454 healthy controls. The rs2896019, rs12483959, and rs3810622 SNPs in PNPLA3 and rs1227756 in COL13A1 were associated with elevated alanine aminotransferase (ALT, ≥40IU/L). A polygenic risk score (PRS) based on six SNPs in the ADIPOQ, COL13A1, PNPLA3, and SAMM50 genes was also associated with elevated ALT. Individuals carrying 9-12 risk alleles had 65.8% and 48.5% higher ALT and aspartate aminotransferase (AST) levels, respectively, than those with 1-4 risk alleles. The PRS showed the greatest risk of elevated ALT levels, with a higher level of significance than the individual variants. Our findings suggest a significant association between variants in COL13A1, ADIPOQ, SAMM50, and PNPLA3, and risk of NAFLD/elevated transaminase levels in Mexican adults with an admixed ancestry. This is the first study to examine high-density single nucleotide screening for genetic variations in a Mexican-Mestizo population. The extent of the effect of these variations on the development and progression of NAFLD in Latino populations requires further analysis

SFRP5 hepatic expression is associated with non-alcoholic liver disease in morbidly obese women

Background and aims. Secreted frizzled-related protein 5 (SFRP5) was recently described as a new adipokine protective for hepatic steatosis and other obesity-related complications in the mouse model. To date, SFRP5 expression in non-alcoholic fatty liver disease (NAFLD) has not been fully assessed in humans. We measured circulating SFRP5 levels and its expression in liver and adipose tissue, and evaluated its association with NAFLD in morbidly obese women.Material and methods. Fifty-four morbidly obese women undergoing bariatric surgery were included in the study. Liver biopsies were used for histology and hepatic triglyceride content quantification. Circulating SFRP5 levels were measured through enzyme-linked immunoabsorbent assay, and SFRP5 expression was performed in hepatic and adipose tissue (subcutaneous and visceral).Results. Although circulating SFRP5 levels showed a tendency to decrease with NAFLD progression, no significant differences were observed among non-alcoholic steatosis, steatohepatitis, and control subjects. Hepatic SFRP5 expression showed a negative correlation with hepatic triglyceride content (r = -0.349, P = 0.016 for mRNA and r = -0.291, P = 0.040 for SRFP5 protein) and ALT serum levels (r = -0.437, P = 0.001 for SRFP5 protein). In addition, hepatic SFRP5 protein levels were significantly lower in NASH than in control subjects (P = 0.006). Conclusion. This is the first study reporting an association of hepatic SFRP5 expression with NAFLD in humans

Association of the rs6232 and rs6235 with obesity in children and adult populations.

<p>Data are n (%). All odds ratios and <i>P</i>-values were calculated by logistic regression analyses using non-obese individuals as reference group, adjusting for age, sex and DT2. <i>P</i>_add, <i>P</i>-values for the additive model.</p

Glucose homeostasis parameters in nondiabetic children and adult populations according to <i>PCSK1</i> rs6235.

<p>Data are means ± s.d. or medians (interquantile range). <i>P_add</i>_-values were calculated by generalized linear regression using an additive model. BMI was adjusted for age and gender. Plasma glucose/insulin levels and HOMA indices were adjusted for age, gender and BMI. HOMA-B, homeostasis model assessment of beta-cell function; HOMA-S, homeostasis model assessment of insulin sensitivity.</p

Glucose homeostasis parameters in nondiabetic children and adult populations according to <i>PCSK1</i> rs6232.

<p>Data are means ± s.d. or medians (interquantile range). <i>P</i>-values were calculated by generalized linear regression. BMI was adjusted for age and gender. Plasma glucose/insulin levels and HOMA indices were adjusted for age, gender and BMI. HOMA-B, homeostasis model assessment of beta-cell function; HOMA-S, homeostasis model assessment of insulin sensitivity.</p

Characteristics of the cases and controls in the children and adult populations.

<p>Data are means ± s.d. or medians (interquantile range). HOMA-B, homeostasis model assessment of beta-cell function; HOMA-S, homeostasis model assessment of insulin sensitivity.</p