title: Generalization of associations of kidney-related genetic loci to American Indians.
abstract: OBJECTIVE
  CKD disproportionally affects American Indians, who similar to other populations, show genetic susceptibility to kidney outcomes. Recent studies have identified several loci associated with kidney traits, but their relevance in American Indians is unknown.
  
  
  METHODS
  This study used data from a large, family-based genetic study of American Indians (the Strong Heart Family Study), which includes 94 multigenerational families enrolled from communities located in Oklahoma, the Dakotas, and Arizona. Individuals were recruited from the Strong Heart Study, a population-based study of cardiovascular disease in American Indians. This study selected 25 single nucleotide polymorphisms in 23 loci identified from recently published kidney-related genome-wide association studies in individuals of European ancestry to evaluate their associations with kidney function (estimated GFR; individuals 18 years or older, up to 3282 individuals) and albuminuria (urinary albumin to creatinine ratio; n=3552) in the Strong Heart Family Study. This study also examined the association of single nucleotide polymorphisms in the APOL1 region with estimated GFR in 1121 Strong Heart Family Study participants. GFR was estimated using the abbreviated Modification of Diet in Renal Disease Equation. Additive genetic models adjusted for age and sex were used.
  
  
  RESULTS
  This study identified significant associations of single nucleotide polymorphisms with estimated GFR in or nearby PRKAG2, SLC6A13, UBE2Q2, PIP5K1B, and WDR72 (P<2.1 × 10(-3) to account for multiple testing). Single nucleotide polymorphisms in these loci explained 2.2% of the estimated GFR total variance and 2.9% of its heritability. An intronic variant of BCAS3 was significantly associated with urinary albumin to creatinine ratio. APOL1 single nucleotide polymorphisms were not associated with estimated GFR in a single variant test or haplotype analyses, and the at-risk variants identified in individuals with African ancestry were not detected in DNA sequencing of American Indians.
  
  
  CONCLUSIONS
  This study extends the genetic associations of loci affecting kidney function to American Indians, a population at high risk of kidney disease, and provides additional support for a potential biologic relevance of these loci across ancestries.
authors: Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina;, †Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas;, ‡Center for American Indian Health Research, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;, §Missouri Breaks Industries Research, Inc., Timber Lake, South Dakota;, ‖Epidemiology and Biometry Program, National Heart, Lung, and Blood Institute, Bethesda, Maryland;, ¶MedStar Health Research Institute, Hyattsville, Maryland, *Georgetown and Howard Universities Center for Clinical and Translational Science, Washington, DC.
authors: Nora
authors: N
authors: Franceschini
authors: Karin
authors: K
authors: Haack
authors: Laura
authors: L
authors: Almasy
authors: Sandra
authors: S
authors: Laston
authors: Elisa T
authors: ET
authors: Lee
authors: Lyle G
authors: LG
authors: Best
authors: Richard R
authors: RR
authors: Fabsitz
authors: Jean W
authors: JW
authors: MacCluer
authors: Barbara V
authors: BV
authors: Howard
authors: Jason G
authors: JG
authors: Umans
authors: Shelley A
authors: SA
authors: Cole
mesh_terms: D000328:Adult; D000367:Age Factors; D000419:Albuminuria / Q000208:ethnology / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D005919:Glomerular Filtration Rate / Q000235:genetics; D006239:Haplotypes; D040941:Heredity; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D007668:Kidney / Q000503:physiopathology; D007674:Kidney Diseases / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012737:Sex Factors; D014481:United States / Q000453:epidemiology; D055815:Young Adult