TY - JOUR
T1 - A common variant in PNPLA3 is associated with age at diagnosis of NAFLD in patients from a multi-ethnic biobank
AU - Walker, Ryan W.
AU - Belbin, Gillian M.
AU - Sorokin, Elena P.
AU - Van Vleck, Tielman
AU - Wojcik, Genevieve L.
AU - Moscati, Arden
AU - Gignoux, Christopher R.
AU - Cho, Judy
AU - Abul-Husn, Noura S.
AU - Nadkarni, Girish
AU - Kenny, Eimear E.
AU - Loos, Ruth J.F.
N1 - Funding Information:
R.W.W. was supported by the National Institutes of Health , National Institute of Child Health and Human Development (NICHD) ( P30ES023515 ) at the time of this study. E.E.K., N.S.A-H. and G.M.B. are supported by the National Institutes of Health ; National Human Genome Research Institute (NHGRI) and National Institute on Minority Health and Health Disparities (NIMHD) ( U01 HG009610 ). E.E.K, and C.R.G. are supported by NHGRI ( R01 HG010297 , U01 HG009080 ) and the National Heart, Lung, and Blood Institute (NHLBI) ( R01 HL104608 ). E.E.K. is also supported by the NIMHD ( UM1 HG0089001 , U01 HG007417 ), the ( NHLBI ) ( X01 HL1345 ), and the National Institute of Diabetes and Kidney and Digestive Disease ( R01 DK110113 ). C.R.G. is also supported by the NIH ( R56HG010297 ). R.J.F.L. is supported by the NIH ( U01 HG007417 ; R01 DK110113 ; R56HG010297 ; X01 HL134588 ; R01 DK107786 ; R01 HL142302 ; R01 DK075787 ). We would like to thank participants of the BioMe Biobank for their permission to use their health and genomic information. We acknowledge a collaboration with Regeneron Genetics Center, who performed genotyping in BioMe. (Regeneron Genetics Center had no input as to the design and conduct of the study; the interpretation of the data; preparation or review of the manuscript; and decision to submit the manuscript for publication.)
Publisher Copyright:
© 2020 European Association for the Study of the Liver
PY - 2020/6
Y1 - 2020/6
N2 - Background & Aims: The Ile138Met variant (rs738409) in the PNPLA3 gene has the largest effect on non-alcoholic fatty liver disease (NAFLD), increasing the risk of progression to severe forms of liver disease. It remains unknown if the variant plays a role in age of NAFLD onset. We aimed to determine if rs738409 impacts on the age of NAFLD diagnosis. Methods: We applied a novel natural language processing (NLP) algorithm to a longitudinal electronic health records (EHR) dataset of >27,000 individuals with genetic data from a multi-ethnic biobank, defining NAFLD cases (n = 1,703) and confirming controls (n = 8,119). We conducted i) a survival analysis to determine if age at diagnosis differed by rs738409 genotype, ii) a receiver operating characteristics analysis to assess the utility of the rs738409 genotype in discriminating NAFLD cases from controls, and iii) a phenome-wide association study (PheWAS) between rs738409 and 10,095 EHR-derived disease diagnoses. Results: The PNPLA3 G risk allele was associated with: i) earlier age of NAFLD diagnosis, with the strongest effect in Hispanics (hazard ratio 1.33; 95% CI 1.15–1.53; p <0.0001) among whom a NAFLD diagnosis was 15% more likely in risk allele carriers vs. non-carriers; ii) increased NAFLD risk (odds ratio 1.61; 95% CI 1.349–1.73; p <0.0001), with the strongest effect among Hispanics (odds ratio 1.43; 95% CI 1.28–1.59; p <0.0001); iii) additional liver diseases in a PheWAS (p <4.95 × 10−6) where the risk variant also associated with earlier age of diagnosis. Conclusion: Given the role of the rs738409 in NAFLD diagnosis age, our results suggest that stratifying risk within populations known to have an enhanced risk of liver disease, such as Hispanic carriers of the rs738409 variant, would be effective in earlier identification of those who would benefit most from early NAFLD prevention and treatment strategies. Lay summary: Despite clear associations between the PNPLA3 rs738409 variant and elevated risk of progression from non-alcoholic fatty liver disease (NAFLD) to more severe forms of liver disease, it remains unknown if PNPLA3 rs738409 plays a role in the age of NAFLD onset. Herein, we found that this risk variant is associated with an earlier age of NAFLD and other liver disease diagnoses; an observation most pronounced in Hispanic Americans. We conclude that PNPLA3 rs738409 could be used to better understand liver disease risk within vulnerable populations and identify patients that may benefit from early prevention strategies.
AB - Background & Aims: The Ile138Met variant (rs738409) in the PNPLA3 gene has the largest effect on non-alcoholic fatty liver disease (NAFLD), increasing the risk of progression to severe forms of liver disease. It remains unknown if the variant plays a role in age of NAFLD onset. We aimed to determine if rs738409 impacts on the age of NAFLD diagnosis. Methods: We applied a novel natural language processing (NLP) algorithm to a longitudinal electronic health records (EHR) dataset of >27,000 individuals with genetic data from a multi-ethnic biobank, defining NAFLD cases (n = 1,703) and confirming controls (n = 8,119). We conducted i) a survival analysis to determine if age at diagnosis differed by rs738409 genotype, ii) a receiver operating characteristics analysis to assess the utility of the rs738409 genotype in discriminating NAFLD cases from controls, and iii) a phenome-wide association study (PheWAS) between rs738409 and 10,095 EHR-derived disease diagnoses. Results: The PNPLA3 G risk allele was associated with: i) earlier age of NAFLD diagnosis, with the strongest effect in Hispanics (hazard ratio 1.33; 95% CI 1.15–1.53; p <0.0001) among whom a NAFLD diagnosis was 15% more likely in risk allele carriers vs. non-carriers; ii) increased NAFLD risk (odds ratio 1.61; 95% CI 1.349–1.73; p <0.0001), with the strongest effect among Hispanics (odds ratio 1.43; 95% CI 1.28–1.59; p <0.0001); iii) additional liver diseases in a PheWAS (p <4.95 × 10−6) where the risk variant also associated with earlier age of diagnosis. Conclusion: Given the role of the rs738409 in NAFLD diagnosis age, our results suggest that stratifying risk within populations known to have an enhanced risk of liver disease, such as Hispanic carriers of the rs738409 variant, would be effective in earlier identification of those who would benefit most from early NAFLD prevention and treatment strategies. Lay summary: Despite clear associations between the PNPLA3 rs738409 variant and elevated risk of progression from non-alcoholic fatty liver disease (NAFLD) to more severe forms of liver disease, it remains unknown if PNPLA3 rs738409 plays a role in the age of NAFLD onset. Herein, we found that this risk variant is associated with an earlier age of NAFLD and other liver disease diagnoses; an observation most pronounced in Hispanic Americans. We conclude that PNPLA3 rs738409 could be used to better understand liver disease risk within vulnerable populations and identify patients that may benefit from early prevention strategies.
KW - Biobank
KW - Electronic health record
KW - Genetic
KW - Hispanic
KW - NAFLD
KW - Natural language processing
KW - Non-alcoholic fatty liver disease
KW - PNPLA3
KW - PheWAS
KW - Phenome-wide association study
KW - Survival
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U2 - 10.1016/j.jhep.2020.01.029
DO - 10.1016/j.jhep.2020.01.029
M3 - Article
C2 - 32145261
AN - SCOPUS:85081983854
SN - 0168-8278
VL - 72
SP - 1070
EP - 1081
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 6
ER -