Common Genetic Variation in the Sex Steroid Hormone-Binding Globulin (SHBG) Gene and Circulating SHBG Levels among Postmenopausal Women: The Multiethnic Cohort
Christopher A. Haiman,
Stephanie E. Riley,
Matthew L. Freedman,
Veronica W. Setiawan,
David V. Conti and
Loïc Le Marchand
Department of Preventive Medicine, Keck School of Medicine, University of Southern California (C.A.H., S.E.R., V.W.S., D.V.C.), Los Angeles, California 90089; Broad Institute of Massachusetts Institute of Technology and Harvard (M.L.F.), Cambridge, Massachusetts 02139; Departments of Medicine, Molecular Biology, and Hematology/Oncology, Massachusetts General Hospital (M.L.F.), Boston, Massachusetts 02114; and Etiology Program, Cancer Research Center of Hawaii, University of Hawaii (L.L.M.), Honolulu, Hawaii 96813
Address all correspondence and requests for reprints to: Dr. Christopher Haiman, University of Southern California/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, California 90089. E-mail: haiman{at}usc.edu.
SHBG transports sex steroid hormones in the blood, and levelsin humans are thought to partially be genetically determined.Recently, studies have found a pentanucleotide (TAAAA)n repeatpolymorphism in the promoter of the SHBG gene and a missensepolymorphism in exon 6 (Asp327Asn) to predict circulating SHBGlevels. Based on the potential role of common genetic variationin 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 postmenopausalwomen from the Multiethnic Cohort Study (n = 372). Mean SHBGlevels were not significantly different between carriers andnoncarriers of the Asn327 allele [minor allele frequency rangeacross ethnic groups, 0.02–0.14; Asp/Asn and Asn/Asn genotypes,33.6 mol/liter; 95% confidence interval (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 observedsix different SHBG repeat alleles segregating in the population(TAAAA6–11), and the distribution of these alleles variedwidely across populations. We found suggestive evidence of linkagedisequilibrium between the Asn327 allele and the eight-repeatallele in all populations except African-Americans (P 0.08).In analysis of the repeat polymorphism, SHBG levels among carriersof two short alleles (seven or fewer repeats; 31.2 nmol/liter;95% CI, 27.3–35.6; n = 82) were not statistically differentfrom those of carriers of two long alleles (more than sevenrepeats; 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 ofSHBG levels (by analysis of covariance, P = 0.03). Carriersof the six-repeat allele (27.9 nmol/liter; 95% CI, 25.2–30.8;n = 147) were found to have nominally significantly lower SHBGlevels than noncarriers (32.4 nmol/liter; 95% CI, 29.7–35.2;n = 202; P = 0.03). This effect was stronger among the subsetof women who also carried the Asn327 allele (interaction, P= 0.006). In summary, these results suggest that genetic variationat the SHBG locus may contribute to modest differences in SHBGlevels among healthy postmenopausal women, and that much largerstudies will be needed to better comprehend the effects of commonvariations at this locus in predicting circulating SHBG levels.
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0.08). In analysis of the repeat polymorphism, SHBG levels among carriers of two short alleles (seven or fewer 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 (more than seven 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 (by analysis of covariance, P = 0.03). Carriers of the six-repeat allele (27.9 nmol/liter; 95% CI, 25.2–30.8; n = 147) were found to have nominally significantly lower SHBG levels than noncarriers (32.4 nmol/liter; 95% CI, 29.7–35.2; n = 202; P = 0.03). This effect was 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 variations at this locus in predicting circulating SHBG levels. 
