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Submitted on July 19, 2004
Accepted on December 28, 2004
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, 02139; Departments of Medicine, Molecular Biology and Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts, 02114; Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii 96813
* To whom correspondence should be addressed. E-mail: haiman{at}usc.edu.
Steroid hormone binding globulin (SHBG) transports sex steroid hormones in the blood and levels in humans are thought to partially be genetically determined. Recently, studies have found a pentanucleotide (TAAAA)n repeat polymorphism in the promoter of the SHBG gene, and a missense polymorphism in exon 6 (Asp327Asn) to predict circulating SHBG levels. Based on the potential role of common genetic variation in SHBG to serve as a marker of SHBG levels in the general population, we evaluated the association between the (TAAAA)n repeat polymorphism, Asp327Asn polymorphism and SHBG levels in a population of African-American, Native Hawaiian, Japanese, Latina and white healthy postmenopausal women from the Multiethnic Cohort study (n = 372). Mean SHBG levels were not significantly different between carriers and non-carriers of the Asn327 allele (minor allele frequency range across ethnic groups: 0.02-0.14; Asp/Asn + Asn/Asn genotypes, 33.6 mol/liter, 95% CI (28.2-40.0), n = 49; Asp/Asp genotype, 30.8 mol/liter, 95% CI (28.7-33.1), n = 296, P = 0.37). For the repeat polymorphism, we observed 6 different SHBG repeat alleles segregating in the population (TAAAA6-11) and the distribution of these alleles varied widely across populations. We found suggestive evidence of linkage disequilibrium between the Asn327 allele and the 8 repeat allele in all populations except African Americans (P 
0.08). In the analysis of the repeat polymorphism, SHBG levels among carriers of two short alleles (
7 repeats, 31.2 nmol/liter, 95% CI (27.3-35.6), n = 82) were not statistically different from those of carriers of two long alleles (>7 repeats, 32.7 nmol/liter, 95% CI (29.4-36.3), n = 124; P = 0.59). We did however, observe individual genotypic classes (n = 16) to contribute modestly to the overall prediction of SHBG levels (ANCOVA P = 0.03). Carriers of the 6 repeat allele (27.9 nmol/liter, 95% CI (25.2-30.8), n = 147) were found to have nominally significantly lower SHBG levels than non-carriers (32.4 nmol/liter, 95% CI (29.7-35.2), n = 202; P = 0.03). We also observed this effect to be stronger among the subset of women who also carried the Asn327 allele (interaction P = 0.006). In summary, these results suggest that genetic variation at the SHBG locus may contribute to modest differences in SHBG levels among healthy postmenopausal women, and that much larger studies will be needed to better comprehend the effects of common variation at this locus in predicting circulating SHBG levels.
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