Fine mapping and identification of serum urate loci in American Indians: The Strong Heart Family Study
Por:
Chittoor, Geetha, Haack, Karin, Balakrishnan, Poojitha, Bizon, Christopher, Laston, Sandra, Best, Lyle G., MacCluer, Jean W., North, Kari E., Umans, Jason G., Franceschini, Nora, Prasad, Gauri, Macias-Kauffer, Luis, Villarreal-Molina, Teresa, Bharadwaj, Dwaipayan, Canizales-Quinteros, Samuel, Navas-Acien, Ana, Cole, Shelley A., Voruganti, V. S.
Publicada:
29 nov 2019
Categoría:
Multidisciplinary
Resumen:
While studies have reported genetic loci affecting serum urate (SU)
concentrations, few studies have been conducted in minority populations.
Our objective for this study was to identify genetic loci regulating SU
in a multigenerational family-based cohort of American Indians, the
Strong Heart Family Study (SHFS). We genotyped 162,718 single nucleotide
polymorphisms (SNPs) in 2000 SHFS participants using an Illumina
MetaboChip array. A genome-wide association analysis of SU was conducted
using measured genotype analysis approach accounting for kinships in
SOLAR, and meta-analysis in METAL. Our results showed strong association
of SU with rs4481233, rs9998811, rs7696092 and rs13145758 (minor allele
frequency (MAF) = 25-44%; P < 3 x 10(-14)) of solute carrier family 2,
member 9 (SLC2A9) and rs41481455, rs2231142 and rs1481012 (MAF = 29%; p
< 3 x 10(-9)) of ATP-binding cassette protein, subfamily G, member 2
(ABCG2). Carriers of G alleles of rs9998811, rs4148155 and rs1481012 and
A alleles of rs4481233, rs7696092 and rs13145758 and rs2231142 had lower
SU concentrations as compared to non-carriers. Genetic analysis of SU
conditional on significant SLC2A9 and ABCG2 SNPs revealed new loci,
nucleobindin 1 (NUCB1) and neuronal PAS domain protein 4 (NPAS4) (p <6 x
10(-6)). To identify American Indian-specific SNPs, we conducted
targeted sequencing of key regions of SLC2A9. A total of 233 SNPs were
identified of which 89 were strongly associated with SU (p < 7.1 x
10(-10)) and 117 were American Indian specific. Analysis of key SNPs in
cohorts of Mexican-mestizos, European, Indian and East Asian ancestries
showed replication of common SNPs, including our lead SNPs. Our results
demonstrate the association of SU with uric acid transporters in a
minority population of American Indians and potential novel associations
of SU with neuronal-related genes which warrant further investigation.
Filiaciones:
Chittoor, Geetha:
Univ North Carolina Chapel Hill, Dept Nutr, Kannapolis, NC 28081 USA
Univ North Carolina Chapel Hill, UNC Nutr Res Inst, Kannapolis, NC 28081 USA
Geisinger, Biomed & Translat Informat, Danville, PA USA
Haack, Karin:
Texas Biomed Res Inst, Populat Hlth Program, San Antonio, TX USA
Balakrishnan, Poojitha:
Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, New York, NY USA
Bizon, Christopher:
Univ N Carolina, Renaissance Comp Inst, Chapel Hill, NC 27515 USA
Laston, Sandra:
Univ Texas Rio Grande Valley, South Texas Diabet & Obes Inst, Sch Med, Brownsville, TX USA
Best, Lyle G.:
Missouri Breaks Ind Res Inc, Eagle Butte, SD USA
MacCluer, Jean W.:
Texas Biomed Res Inst, Populat Hlth Program, San Antonio, TX USA
North, Kari E.:
Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27515 USA
Umans, Jason G.:
Medstar Hlth Res Inst, Hyattsville, MD USA
Franceschini, Nora:
Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27515 USA
Prasad, Gauri:
CSIR, Inst Genom & Integrat Biol, Genom & Mol Med Unit, New Delhi 110020, India
Acad Sci & Innovat Res, CSIR Inst Genom & Integrat Biol Campus, New Delhi 110020, India
Macias-Kauffer, Luis:
INMEGEN, Lab Enfermedades Cardiovasc, Mexico City 14610, DF, Mexico
Villarreal-Molina, Teresa:
INMEGEN, Lab Enfermedades Cardiovasc, Mexico City 14610, DF, Mexico
Bharadwaj, Dwaipayan:
Acad Sci & Innovat Res, CSIR Inst Genom & Integrat Biol Campus, New Delhi 110020, India
Jawaharlal Nehru Univ, Sch Biotechnol, Syst Genom Lab, New Delhi 110067, India
Canizales-Quinteros, Samuel:
Univ Nacl Autonoma Mexico, Inst Nacl Med Genom, Fac Quim, Unidad Genom Poblac Aplicada Salud, Mexico City, DF, Mexico
Navas-Acien, Ana:
Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, New York, NY USA
Cole, Shelley A.:
Texas Biomed Res Inst, Populat Hlth Program, San Antonio, TX USA
Voruganti, V. S.:
Univ North Carolina Chapel Hill, Dept Nutr, Kannapolis, NC 28081 USA
Univ North Carolina Chapel Hill, UNC Nutr Res Inst, Kannapolis, NC 28081 USA
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