A Genome-Wide Linkage Scan for Steroids and SHBG Levels in Black and White Families: The HERITAGE Family Study
Olavi Ukkola,
Tuomo Rankinen,
Jacques Gagnon,
Arthur S. Leon,
James S. Skinner,
Jack H. Wilmore,
D. C. Rao and
Claude Bouchard
Pennington Biomedical Research Center (O.U., T.R., C.B.), Baton Rouge, Louisiana 70808; Department of Internal Medicine and Biocenter Oulu (O.U.), University of Oulu, FIN-90220, Oulu, Finland; Laboratory of Molecular Endocrinology (J.G.), Centre Hospitalier de l’Université Laval Research Center, Laval University, Québec GIK 7P4, Canada; School of Kinesiology and Leisure Studies (A.S.L.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Kinesiology (J.S.S.), Indiana University, Bloomington, Indiana 46405; Department of Health and Kinesiology (J.H.W.), Texas A&M University, College Station, Texas 77843-4243; and Division of Biostatistics (D.C.R.), Washington University School of Medicine, St. Louis, Missouri 63110
Address all correspondence and requests for reprints to: Claude Bouchard, Ph.D., Executive Director, Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, Louisiana 70808-4124. E-mail: . bouchac{at}pbrc.edu
Abstract
To identify loci-harboring genes affecting steroid hormone andSHBG plasma levels, a genomic-wide scan was performed in theHERITAGE Family Study at baseline. The following steroid hormoneswere assayed: androstane-3, 17ß-diol glucuronide,androsterone glucuronide, cortisol, dihydrotestosterone, estradiol,17-hydroxyprogesterone (OH-PROG), progesterone (PROG), pregnenoloneester, and testosterone. A total of 509 markers on the 22 autosomeswere genotyped, and a maximum of 357 pairs of siblings fromwhite families and 103 from black families were available forthe study. Significant linkages with LOD scores over 3.6 (P< 2.2 x 10-5) for SHBG were observed in blacks on 1q44 (D1S321),5p13.3 (D5S1986), 10q24.1 (D10S1239), and 12q12 (D12S1653) inboth singlepoint and multipoint analyses. Promising evidenceof linkage (1.75 < LOD < 3.6; 2.2 x 10-5 < P < 0.0023)for SHBG was observed on 1q44 in singlepoint analysis in whites.In addition, several other loci in blacks exhibited promisingevidence of linkage, suggesting that many genes can potentiallyregulate SHBG levels. In the case of C21 steroids, promisinglinkages were found on 1q43 (D1S517) for PROG, 2p25.1 (D2S1400)for pregnenolone ester, and 18q21.32 (D18S38) for OH-PROG inwhites and on 3q25.33 (D3S1763) for OH-PROG in blacks, bothsinglepoint and multipoint analyses (P < 0.0023). The strongestsignals for C19 steroids were found on 22q12.3 for testosteronein whites (P = 0.0024 in multipoint) and on 8q22.1 for dihydrotestosteronein blacks. In blacks, the strongest evidence of linkage forestradiol (C18 steroid) was provided by marker D1S1588 on 1p21.3and in whites by markers D2S2374 and D2S2347 on 2p21, and D6S465on 6p12.3. Several genes encoding enzymes of the steroid biosynthesispathways but also other potential candidate genes were locatedin the vicinity of the genomic regions showing evidence of linkagein this genomic scan.
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, 17ß-diol glucuronide, androsterone glucuronide, cortisol, dihydrotestosterone, estradiol, 17-hydroxyprogesterone (OH-PROG), progesterone (PROG), pregnenolone ester, and testosterone. A total of 509 markers on the 22 autosomes were genotyped, and a maximum of 357 pairs of siblings from white families and 103 from black families were available for the study. Significant linkages with LOD scores over 3.6 (P < 2.2 x 10-5) for SHBG were observed in blacks on 1q44 (D1S321), 5p13.3 (D5S1986), 10q24.1 (D10S1239), and 12q12 (D12S1653) in both singlepoint and multipoint analyses. Promising evidence of linkage (1.75 < LOD < 3.6; 2.2 x 10-5 < P < 0.0023) for SHBG was observed on 1q44 in singlepoint analysis in whites. In addition, several other loci in blacks exhibited promising evidence of linkage, suggesting that many genes can potentially regulate SHBG levels. In the case of C21 steroids, promising linkages were found on 1q43 (D1S517) for PROG, 2p25.1 (D2S1400) for pregnenolone ester, and 18q21.32 (D18S38) for OH-PROG in whites and on 3q25.33 (D3S1763) for OH-PROG in blacks, both singlepoint and multipoint analyses (P < 0.0023). The strongest signals for C19 steroids were found on 22q12.3 for testosterone in whites (P = 0.0024 in multipoint) and on 8q22.1 for dihydrotestosterone in blacks. In blacks, the strongest evidence of linkage for estradiol (C18 steroid) was provided by marker D1S1588 on 1p21.3 and in whites by markers D2S2374 and D2S2347 on 2p21, and D6S465 on 6p12.3. Several genes encoding enzymes of the steroid biosynthesis pathways but also other potential candidate genes were located in the vicinity of the genomic regions showing evidence of linkage in this genomic scan. 
