Regional differences in genetic susceptibility to non-alcoholic liver disease in two distinct Indian ethnicities

Abstract

AIMTo validate the association of variants in PNPLA3 (rs2281135) and TM6SF2 (rs58542926) genes with ultrasound detected non-alcoholic fatty liver disease (NAFLD).METHODSA total of 503 individuals with and without fatty infiltration were recruited. Fatty infiltration was confirmed based on ultrasound findings. Anthropometric data and blood samples were collected from the study group. DNA was isolated from peripheral blood, quality and quantity was assessed by gel electrophoresis and spectrophotometer respectively. Genotyping of the variants in PNPLA3 and TM6SF2 genes was carried out by employing taqman probes (C_15875080_10 for PNPLA3 and C_8946351_10 for TM6SF2 SNP) on real time PCR (Stepone-Lifetechnologies). Genotype data was tested for deviations from Hardy-Weinberg equilibrium. χ2 test was used to analyze the statistical significance of the difference in genotype distribution of the studied variants in patients and controls and the strength of association was expressed as odds ratio (95%CI). A two-tailed P value of ≤ 0.05 was considered statistically significant.RESULTSThe study group comprised of 503 individuals of which 256 had fatty infiltration and 247 without fatty infiltration and thus formed the patient and control groups respectively. As the patient group could be divided in to two distinct ethnicities (ancestral South Indians-ASI and North-East Indians-NEI), further recruitment of control cohort and association analyses was carried out based on ethnicities. Of the 256 with fatty infiltration 93 were ASI and 163 were NEI and of the 247 controls 138 were ASI and 109 were NEI. As expected, there were significant differences in the anthropometric and other clinical data between the control and the patient groups. However significant differences within the ethnicities were also noted. While rs2281135 in PNPLA3 gene was significantly associated (P = 0.03) with higher risk (odds 1.9, 95%CI: 1.5-3.14, P = 0.03) of NAFLD in NEI ethnicity, rs58542926 in TM6SF2 gene was significantly associated with NAFLD with a 2.7 fold higher risk (odds 2.7, 95%CI: 1.37-5.3, P = 0.0004) of the disease. There were significantly higher proportions of individuals with variants in both the genes in the patient group in both ASI (patients - 14/93 and controls - 7/138; P = 0.009) and NEI ethnicities (patients - 17/163 and controls - 7/109; P = 0.01).CONCLUSIONAlthough the study identified distinct genetic susceptibility in the two ethnicities, transheterozygosity of the variants suggests higher risk of NAFLD in individuals with both the variants.

Patatin‐Like Phospholipase Domain‐Containing Protein 3 I148M and Liver Fat and Fibrosis Scores Predict Liver Disease Mortality in the U.S. Population

“…(17,18) rs2281135 is an intronic variant in linkage disequilibrium with I148M in blacks, whites, and Mexican Americans. (19) In an effort to combine genetic variants with established liver fat and fibrosis scores as markers of FLD injury progression, we questioned whether PNPLA3 variants would further predict long-term adverse hepatic outcomes among asymptomatic persons in the general population. (8) U.S. National Health and Nutrition Examination Survey (NHANES), 1988-1994 (NHANES III) mortality ascertainment is complete through 2015, providing up to 27 years of follow-up to study liver disease mortality relationships.…”

“…(39) In contrast to I148M, a missense variant resulting in loss of triglyceride hydrolysis function leading to HS, (40) PNPLA3 rs2281135-G>A is an intronic variant in linkage disequilibrium with I148M in blacks, whites, and Mexican Americans. (19) rs2281135 is less well studied, but associations with liver disease were reported. (16) In an exploratory phenome-wide association study linking genetic variants, including liverdisease-associated SNPs, to electronic health records from the Estonian Biobank, rs2281135 was associated with ICD-10, Clinical Modification code K76 (nonalcoholic liver diseases, including NAFLD).…”

“…rs2281135 was also associated with NAFLD diagnoses in Estonian Biobank electronic health records and with NAFLD and elevated alanine aminotransferase (ALT) in a Korean population . rs2281135 is an intronic variant in linkage disequilibrium with I148M in blacks, whites, and Mexican Americans …”

Difference in lifestyle and metabolic profile of non-alcoholic fatty liver disease with raised alanine amino-transferases between obese and non-overweight subjects

“…Single nucleotide polymorphism in the PNPLA3 gene has been associated with steatosis, fibrosis and elevated transaminases in individuals with NAFLD, with variations within different regions of India. This data has been published using the same blood samples collected for genetic analysis during the study 35 . In addition to genes, gut microbiota 36 was postulated to play an important role in the development of NAFLD and fibrosis in these patients, although it was beyond the scope of the study design.…”

A comprehensive look at the role of hyperlipidemia in promoting colorectal cancer liver metastasis

“…Obese subjects have an increased risk of non-alcoholic fatty liver disease (NAFLD) 73 . NAFLD includes steatosis and its progression to non-alcoholic steatohepatitis 74 . The NAFLD provides a microenvironment that is more susceptible to CRC metastasis by secreting increased levels of various signaling molecules, including MMPs 75 .…”