TY - JOUR
T1 - Association of Genetic Risk Score With NAFLD in An Ethnically Diverse Cohort
AU - Wang, Jun
AU - Conti, David V.
AU - Bogumil, David
AU - Sheng, Xin
AU - Noureddin, Mazen
AU - Wilkens, Lynne R.
AU - Le Marchand, Loic
AU - Rosen, Hugo R.
AU - Haiman, Christopher A.
AU - Setiawan, Veronica Wendy
N1 - Funding Information:
Supported by the National Cancer Institute (R01CA228589 to V.W.S. and U01CA164973 to L.L.M.).
Publisher Copyright:
© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
PY - 2021/10
Y1 - 2021/10
N2 - Most genetic studies of nonalcoholic fatty liver disease (NAFLD) have been conducted in Whites. In this large and ethnically diverse cohort, we assessed the transportability of previously identified genetic variants for NAFLD, built a genetic risk score (GRS), and examined its association with NAFLD risk in multiple ethnic groups. Thirty previously identified genome-wide association studies (GWAS) variants (P < 5 × 10−8) and 17 other variants associated with NAFLD were examined in a nested case-control study of NAFLD (1,448 cases/8,444 controls) in this multi-ethnic cohort study. We then built a GRS using 11 independent single-nucleotide polymorphisms from these prior studies and examined its association with NAFLD by cirrhosis status across multiple ethnic groups. Of the 30 GWAS SNPs, 20 (67%) were replicated (P < 0.05) in the pooled multi-ethnic population. The highest percentage of replication was seen in Latinos (43%), followed by Japanese Americans (37%), Whites (17%), and Native Hawaiians and African Americans (≤10%). Several genetic variants, including those in PNPLA3 (patatin-like phospholipase domain containing 3), HSD17B13 (hydroxysteroid 17-beta dehydrogenase 13), TM6SF2 (transmembrane 6 superfamily member 2), GATAD2A (GATA zinc finger domain containing 2A), GCKR (glucokinase regulator), SUGP1 (SURP and G-patch domain containing 1), MBOAT7 (membrane bound O-acyltransferase domain containing 7), TRIB1 (tribbles pseudokinase 1), SAMM50 (sorting and assembly machinery component), and ERLIN1 (ER lipid raft associated 1)–CHUK (component of inhibitor of nuclear factor kappa B kinase complex)–CWF19L1 (CWF19 like cell cycle control factor 1) gene cluster, were replicated in at least two ethnic groups. An 11-SNP weighted GRS was associated with NAFLD risk in the multi-ethnic population (odds ratio [OR] per SD increase = 1.41; 95% confidence interval [CI] = 1.32-1.50), as well as in each ethnic group (OR ranged from 1.30 in African Americans to 1.52 in Latinos). The GRS–NAFLD association was stronger for NAFLD with cirrhosis (OR = 1.67; 95% CI = 1.46-1.92) compared to NAFLD without cirrhosis (OR = 1.37; 95% CI = 1.28-1.46) (P heterogeneity = 0.003). Conclusion: In this ethnically diverse cohort, we replicated several key genetic variants for NAFLD and showed the utility of GRS based on the risk alleles for NAFLD risk stratification in multiple ethnic groups.
AB - Most genetic studies of nonalcoholic fatty liver disease (NAFLD) have been conducted in Whites. In this large and ethnically diverse cohort, we assessed the transportability of previously identified genetic variants for NAFLD, built a genetic risk score (GRS), and examined its association with NAFLD risk in multiple ethnic groups. Thirty previously identified genome-wide association studies (GWAS) variants (P < 5 × 10−8) and 17 other variants associated with NAFLD were examined in a nested case-control study of NAFLD (1,448 cases/8,444 controls) in this multi-ethnic cohort study. We then built a GRS using 11 independent single-nucleotide polymorphisms from these prior studies and examined its association with NAFLD by cirrhosis status across multiple ethnic groups. Of the 30 GWAS SNPs, 20 (67%) were replicated (P < 0.05) in the pooled multi-ethnic population. The highest percentage of replication was seen in Latinos (43%), followed by Japanese Americans (37%), Whites (17%), and Native Hawaiians and African Americans (≤10%). Several genetic variants, including those in PNPLA3 (patatin-like phospholipase domain containing 3), HSD17B13 (hydroxysteroid 17-beta dehydrogenase 13), TM6SF2 (transmembrane 6 superfamily member 2), GATAD2A (GATA zinc finger domain containing 2A), GCKR (glucokinase regulator), SUGP1 (SURP and G-patch domain containing 1), MBOAT7 (membrane bound O-acyltransferase domain containing 7), TRIB1 (tribbles pseudokinase 1), SAMM50 (sorting and assembly machinery component), and ERLIN1 (ER lipid raft associated 1)–CHUK (component of inhibitor of nuclear factor kappa B kinase complex)–CWF19L1 (CWF19 like cell cycle control factor 1) gene cluster, were replicated in at least two ethnic groups. An 11-SNP weighted GRS was associated with NAFLD risk in the multi-ethnic population (odds ratio [OR] per SD increase = 1.41; 95% confidence interval [CI] = 1.32-1.50), as well as in each ethnic group (OR ranged from 1.30 in African Americans to 1.52 in Latinos). The GRS–NAFLD association was stronger for NAFLD with cirrhosis (OR = 1.67; 95% CI = 1.46-1.92) compared to NAFLD without cirrhosis (OR = 1.37; 95% CI = 1.28-1.46) (P heterogeneity = 0.003). Conclusion: In this ethnically diverse cohort, we replicated several key genetic variants for NAFLD and showed the utility of GRS based on the risk alleles for NAFLD risk stratification in multiple ethnic groups.
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U2 - 10.1002/hep4.1751
DO - 10.1002/hep4.1751
M3 - Article
AN - SCOPUS:85108211247
SN - 2471-254X
VL - 5
SP - 1689
EP - 1703
JO - Hepatology Communications
JF - Hepatology Communications
IS - 10
ER -