TY - JOUR
T1 - SMOC2 gene interacts with APOL1 in the development of end-stage kidney disease
T2 - A genome-wide association study
AU - Chaudhary, Ninad S.
AU - Armstrong, Nicole D.
AU - Hidalgo, Bertha A.
AU - Gutiérrez, Orlando M.
AU - Hellwege, Jacklyn N.
AU - Limdi, Nita A.
AU - Reynolds, Richard J.
AU - Judd, Suzanne E.
AU - Nadkarni, Girish N.
AU - Lange, Leslie
AU - Winkler, Cheryl A.
AU - Kopp, Jeffrey B.
AU - Arnett, Donna K.
AU - Tiwari, Hemant K.
AU - Irvin, Marguerite R.
N1 - Funding Information:
This study was supported by the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) grants R01HL123782 (MI) and R01HL136666 (MI and LL). The research project is supported by cooperative agreement U01 NS041588 co-funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Service. JK was supported by the Intramural Research Program of National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). CW was supported in part by the National Institutes of Health and the National Cancer Institute Intramural Research Program and under contract HHSN26120080001E. NC was supported by American Heart Association Predoctoral Fellowship (AHA Award #18PRE34000021). GN was supported by R01DK127139. JH was supported by K12 HD04348. The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center's BioVU which is supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH-funded Shared Instrumentation Grant S10RR025141; and CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, R01HD074711, and additional funding sources listed at https://victr.vumc.org/biovu-funding/ . Representatives from American Heart Association did not have any role in the design and conduct of the study, the collection, management, analysis, interpretation of the data, and the preparation or approval of the manuscript.
Publisher Copyright:
Copyright © 2022 Chaudhary, Armstrong, Hidalgo, Gutiérrez, Hellwege, Limdi, Reynolds, Judd, Nadkarni, Lange, Winkler, Kopp, Arnett, Tiwari and Irvin.
PY - 2022/9/28
Y1 - 2022/9/28
N2 - Background: Some but not all African-Americans (AA) who carry APOL1 nephropathy risk variants (APOL1) develop kidney failure (end-stage kidney disease, ESKD). To identify genetic modifiers, we assessed gene–gene interactions in a large prospective cohort of the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Methods: Genotypes from 8,074 AA participants were obtained from Illumina Infinium Multi-Ethnic AMR/AFR Extended BeadChip. We compared 388 incident ESKD cases with 7,686 non-ESKD controls, using a two-locus interaction approach. Logistic regression was used to examine the effect of APOL1 risk status (using recessive and additive models), single nucleotide polymorphism (SNP), and APOL1*SNP interaction on incident ESKD, adjusting for age, sex, and ancestry. APOL1*SNP interactions that met the threshold of 1.0 × 10−5 were replicated in the Genetics of Hypertension Associated Treatment (GenHAT) study (626 ESKD cases and 6,165 controls). In a sensitivity analysis, models were additionally adjusted for diabetes status. We conducted additional replication in the BioVU study. Results: Two APOL1 risk alleles prevalence (recessive model) was similar in the REGARDS and GenHAT studies. Only one APOL1–SNP interaction, for rs7067944 on chromosome 10, ~10 KB from the PCAT5 gene met the genome-wide statistical threshold (Pinteraction = 3.4 × 10−8), but this interaction was not replicated in the GenHAT study. Among other relevant top findings (with Pinteraction < 1.0 × 10−5), a variant (rs2181251) near SMOC2 on chromosome six interacted with APOL1 risk status (additive) on ESKD outcomes (REGARDS study, Pinteraction =5.3 × 10−6) but the association was not replicated (GenHAT study, Pinteraction = 0.07, BioVU study, Pinteraction = 0.53). The association with the locus near SMOC2 persisted further in stratified analyses. Among those who inherited ≥1 alternate allele of rs2181251, APOL1 was associated with an increased risk of incident ESKD (OR [95%CI] = 2.27[1.53, 3.37]) but APOL1 was not associated with ESKD in the absence of the alternate allele (OR [95%CI] = 1.34[0.96, 1.85]) in the REGARDS study. The associations were consistent after adjusting for diabetes. Conclusion: In a large genome-wide association study of AAs, a locus SMOC2 exhibited a significant interaction with the APOL1 locus. SMOC2 contributes to the progression of fibrosis after kidney injury and the interaction with APOL1 variants may contribute to an explanation for why only some APOLI high-risk individuals develop ESKD.
AB - Background: Some but not all African-Americans (AA) who carry APOL1 nephropathy risk variants (APOL1) develop kidney failure (end-stage kidney disease, ESKD). To identify genetic modifiers, we assessed gene–gene interactions in a large prospective cohort of the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Methods: Genotypes from 8,074 AA participants were obtained from Illumina Infinium Multi-Ethnic AMR/AFR Extended BeadChip. We compared 388 incident ESKD cases with 7,686 non-ESKD controls, using a two-locus interaction approach. Logistic regression was used to examine the effect of APOL1 risk status (using recessive and additive models), single nucleotide polymorphism (SNP), and APOL1*SNP interaction on incident ESKD, adjusting for age, sex, and ancestry. APOL1*SNP interactions that met the threshold of 1.0 × 10−5 were replicated in the Genetics of Hypertension Associated Treatment (GenHAT) study (626 ESKD cases and 6,165 controls). In a sensitivity analysis, models were additionally adjusted for diabetes status. We conducted additional replication in the BioVU study. Results: Two APOL1 risk alleles prevalence (recessive model) was similar in the REGARDS and GenHAT studies. Only one APOL1–SNP interaction, for rs7067944 on chromosome 10, ~10 KB from the PCAT5 gene met the genome-wide statistical threshold (Pinteraction = 3.4 × 10−8), but this interaction was not replicated in the GenHAT study. Among other relevant top findings (with Pinteraction < 1.0 × 10−5), a variant (rs2181251) near SMOC2 on chromosome six interacted with APOL1 risk status (additive) on ESKD outcomes (REGARDS study, Pinteraction =5.3 × 10−6) but the association was not replicated (GenHAT study, Pinteraction = 0.07, BioVU study, Pinteraction = 0.53). The association with the locus near SMOC2 persisted further in stratified analyses. Among those who inherited ≥1 alternate allele of rs2181251, APOL1 was associated with an increased risk of incident ESKD (OR [95%CI] = 2.27[1.53, 3.37]) but APOL1 was not associated with ESKD in the absence of the alternate allele (OR [95%CI] = 1.34[0.96, 1.85]) in the REGARDS study. The associations were consistent after adjusting for diabetes. Conclusion: In a large genome-wide association study of AAs, a locus SMOC2 exhibited a significant interaction with the APOL1 locus. SMOC2 contributes to the progression of fibrosis after kidney injury and the interaction with APOL1 variants may contribute to an explanation for why only some APOLI high-risk individuals develop ESKD.
KW - APOL1
KW - African-Americans
KW - SMOC2
KW - end-stage kidney disease
KW - gene–gene interaction
KW - genome-wide analysis
KW - kidney disease
UR - http://www.scopus.com/inward/record.url?scp=85139770435&partnerID=8YFLogxK
U2 - 10.3389/fmed.2022.971297
DO - 10.3389/fmed.2022.971297
M3 - Article
AN - SCOPUS:85139770435
VL - 9
JO - Frontiers in Medicine
JF - Frontiers in Medicine
SN - 2296-858X
M1 - 971297
ER -