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Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the third National Health and Nutrition Examination Survey.
Clin Gastroenterol Hepatol 2013; 11(9):1183-1190.e2CG

Abstract

BACKGROUND & AIMS

A genome-wide association study associated 5 genetic variants with hepatic steatosis (identified by computerized tomography) in individuals of European ancestry. We investigated whether these variants were associated with measures of hepatic steatosis (HS) in non-Hispanic white (NHW), non-Hispanic black, and Mexican American (MA) participants in the US population-based National Health and Nutrition Examination Survey III, phase 2.

METHODS

We analyzed data from 4804 adults (1825 NHW, 1442 non-Hispanic black, and 1537 MA; 51.7% women; mean age at examination, 42.5 y); the weighted prevalence of HS was 37.3%. We investigated whether ultrasound-measured HS, with and without increased levels of alanine aminotransferase (ALT), or level of ALT alone, was associated with rs738409 (patatin-like phospholipase domain-containing protein 3 [PNPLA3]), rs2228603 (neurocan [NCAN]), rs12137855 (lysophospholipase-like 1), rs780094 (glucokinase regulatory protein [GCKR]), and rs4240624 (protein phosphatase 1, regulatory subunit 3b [PPP1R3B]) using regression modeling in an additive genetic model, controlling for age, age-squared, sex, and alcohol consumption.

RESULTS

The G allele of rs738409 (PNPLA3) and the T allele of rs780094 (GCKR) were associated with HS with a high level of ALT (odds ratio [OR], 1.36; P = .01; and OR, 1.30; P = .03, respectively). The A allele of rs4240624 (PPP1R3B) and the T allele of rs2228603 (NCAN) were associated with HS (OR, 1.28; P = .03; and OR, 1.40; P = .04, respectively). Variants of PNPLA3 and NCAN were associated with ALT level among all 3 ancestries. Some single-nucleotide polymorphisms were associated with particular races or ethnicities: variants in PNPLA3, NCAN, GCKR, and PPP1R3B were associated with NHW and variants in PNPLA3 were associated with MA. No variants were associated with NHB.

CONCLUSIONS

We used data from the National Health and Nutrition Examination Survey III to validate the association between rs738409 (PNPLA3), rs780094 (GCKR), and rs4240624 (PPP1R3B) with HS, with or without increased levels of ALT, among 3 different ancestries. Some, but not all, associations between variants in NCAN, lysophospholipase-like 1, GCKR, and PPP1R3B with HS (with and without increased ALT level) were significant within subpopulations.

Authors+Show Affiliations

Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

23416328

Citation

Hernaez, Ruben, et al. "Association Between Variants in or Near PNPLA3, GCKR, and PPP1R3B With Ultrasound-defined Steatosis Based On Data From the Third National Health and Nutrition Examination Survey." Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association, vol. 11, no. 9, 2013, pp. 1183-1190.e2.
Hernaez R, McLean J, Lazo M, et al. Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the third National Health and Nutrition Examination Survey. Clin Gastroenterol Hepatol. 2013;11(9):1183-1190.e2.
Hernaez, R., McLean, J., Lazo, M., Brancati, F. L., Hirschhorn, J. N., Borecki, I. B., ... Speliotes, E. K. (2013). Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the third National Health and Nutrition Examination Survey. Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association, 11(9), pp. 1183-1190.e2. doi:10.1016/j.cgh.2013.02.011.
Hernaez R, et al. Association Between Variants in or Near PNPLA3, GCKR, and PPP1R3B With Ultrasound-defined Steatosis Based On Data From the Third National Health and Nutrition Examination Survey. Clin Gastroenterol Hepatol. 2013;11(9):1183-1190.e2. PubMed PMID: 23416328.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the third National Health and Nutrition Examination Survey. AU - Hernaez,Ruben, AU - McLean,Jody, AU - Lazo,Mariana, AU - Brancati,Frederick L, AU - Hirschhorn,Joel N, AU - Borecki,Ingrid B, AU - Harris,Tamara B, AU - ,, AU - Nguyen,Thutrang, AU - Kamel,Ihab R, AU - Bonekamp,Susanne, AU - Eberhardt,Mark S, AU - Clark,Jeanne M, AU - Kao,Wen Hong Linda, AU - Speliotes,Elizabeth K, Y1 - 2013/02/13/ PY - 2012/10/19/received PY - 2013/01/07/revised PY - 2013/02/01/accepted PY - 2013/2/19/entrez PY - 2013/2/19/pubmed PY - 2014/3/19/medline KW - ALT KW - AST KW - Candidate Gene Study KW - EAF KW - GCKR KW - Genome-wide Association Study KW - HDL-c KW - HS KW - LYPLAL1 KW - MA KW - Mexican American KW - NAFLD KW - NASH KW - NCAN KW - NHANES III KW - NHB KW - NHW KW - Nonalcoholic Fatty Liver Disease KW - OR KW - PNPLA3 KW - PPP1R3B KW - Replication KW - SNP KW - Third National Health and Nutrition Examination Survey KW - alanine aminotransferase KW - aspartate aminotransferase KW - effect allele frequency KW - glucokinase regulatory protein KW - hepatic steatosis KW - high-density lipoprotein cholesterol KW - lysophospholipase-like 1 KW - neurocan KW - non-Hispanic black KW - non-Hispanic white KW - nonalcoholic fatty liver disease KW - nonalcoholic steatohepatitis KW - odds ratios KW - patatin-like phospholipase domain-containing protein 3 KW - protein phosphatase 1, regulatory subunit 3b KW - single-nucleotide polymorphisms SP - 1183 EP - 1190.e2 JF - Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association JO - Clin. Gastroenterol. Hepatol. VL - 11 IS - 9 N2 - BACKGROUND & AIMS: A genome-wide association study associated 5 genetic variants with hepatic steatosis (identified by computerized tomography) in individuals of European ancestry. We investigated whether these variants were associated with measures of hepatic steatosis (HS) in non-Hispanic white (NHW), non-Hispanic black, and Mexican American (MA) participants in the US population-based National Health and Nutrition Examination Survey III, phase 2. METHODS: We analyzed data from 4804 adults (1825 NHW, 1442 non-Hispanic black, and 1537 MA; 51.7% women; mean age at examination, 42.5 y); the weighted prevalence of HS was 37.3%. We investigated whether ultrasound-measured HS, with and without increased levels of alanine aminotransferase (ALT), or level of ALT alone, was associated with rs738409 (patatin-like phospholipase domain-containing protein 3 [PNPLA3]), rs2228603 (neurocan [NCAN]), rs12137855 (lysophospholipase-like 1), rs780094 (glucokinase regulatory protein [GCKR]), and rs4240624 (protein phosphatase 1, regulatory subunit 3b [PPP1R3B]) using regression modeling in an additive genetic model, controlling for age, age-squared, sex, and alcohol consumption. RESULTS: The G allele of rs738409 (PNPLA3) and the T allele of rs780094 (GCKR) were associated with HS with a high level of ALT (odds ratio [OR], 1.36; P = .01; and OR, 1.30; P = .03, respectively). The A allele of rs4240624 (PPP1R3B) and the T allele of rs2228603 (NCAN) were associated with HS (OR, 1.28; P = .03; and OR, 1.40; P = .04, respectively). Variants of PNPLA3 and NCAN were associated with ALT level among all 3 ancestries. Some single-nucleotide polymorphisms were associated with particular races or ethnicities: variants in PNPLA3, NCAN, GCKR, and PPP1R3B were associated with NHW and variants in PNPLA3 were associated with MA. No variants were associated with NHB. CONCLUSIONS: We used data from the National Health and Nutrition Examination Survey III to validate the association between rs738409 (PNPLA3), rs780094 (GCKR), and rs4240624 (PPP1R3B) with HS, with or without increased levels of ALT, among 3 different ancestries. Some, but not all, associations between variants in NCAN, lysophospholipase-like 1, GCKR, and PPP1R3B with HS (with and without increased ALT level) were significant within subpopulations. SN - 1542-7714 UR - https://www.unboundmedicine.com/medline/citation/23416328/Association_between_variants_in_or_near_PNPLA3_GCKR_and_PPP1R3B_with_ultrasound_defined_steatosis_based_on_data_from_the_third_National_Health_and_Nutrition_Examination_Survey_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1542-3565(13)00188-2 DB - PRIME DP - Unbound Medicine ER -