Obesity is a highly prevalent, multigenic trait that predicts increased morbidity and mortality. Here we report results from a genome scan based on 354 markers in 513 members of 92 nuclear families ascertained through extreme obesity and normal body weight. The average marker interval was approximately 10 cM. We examined four correlated obesity phenotypes, including the body-mass index (BMI) (both as a quantitative trait and as a discrete trait with a threshold of BMI > or /=30 kg/m2) and percentage of fat (both as a quantitative trait and as a discrete trait with a threshold of 40%) as assessed by bioelectrical impedance. In the initial stage of the genome scan, four markers in 20q gave positive evidence for linkage, which was consistent across most obesity phenotypes and analytic methods. After saturating 20q with additional markers (25 markers total) in an augmented sample of 713 members from 124 families, we found linkage to several markers in a region, 20q13, previously implicated in both human and animal studies. Three markers (D20S107, D20S211, and D20S149) in 20q13 had empirical P values (based on Monte Carlo simulations, which controlled for multiple testing) < or /=. 01 for single-point analysis. In addition, the parametric, affecteds-only analysis for D20S476 yielded a LOD score of 3.06 (P=. 00009), and the affected-sib-pair test yielded a LOD score of 3.17 (P=.000067). Multipoint analyses further strengthened and localized these findings. This region includes several plausible candidate genes for obesity. Our results suggest that one or more genes affecting obesity are located in 20q13.

Few mutations have been found in the human leptin gene and the relationship between leptin gene sequence variation and human overweight is uncertain. To determine whether sequence variation within the leptin gene and its regulatory elements contribute to extreme obesity, we screened " 3 kb of the 5h flanking region and the three exons in 125 unrelated extremely obese (BMI 40 kg\m#) and 86 average weight women (BMI 27 kg\m#). Within the protein coding regions only one heterozygous silent mutation was found (codon 102 ; AAC\AAT). Within the 5h flanking region, six frequent sequence variants were detected (q 0.10), and the allele frequencies of three of these variants differed between obese and average weight Caucasian women (j19, χ# l 4.46, p l 0.035 ; k1823, χ# l 4.36, p l 0.037 ; k2548, χ# l 5.73, p l 0.017). Nine infrequent sequence variants were detected (q 0.05) but they did not occur more often among obese women compared with those of average-weight. For extremely obese women, three polymorphisms (j19, k188, and k633) predicted the degree of obesity. Allelic variants may influence the regulation of the leptin gene and thereby influence body weight, particularly among extremely obese women. However, given the low variability in coding regions and the high variability in the 5h flanking region, discerning the functional significance of each variant is likely to be difficult. I Two families have been described with mutations in the protein coding regions of the leptin gene, and family members with these mutations recapitulate the phenotype of obese Lep ob mice (Montague et al. 1997 ; Strobel et al. 1998). Most obese subjects have no missense or nonsense mutations within the leptin gene (Considine et al.

Despite the success of tamoxifen in treating hormoneresponsive breast cancer, its use is limited by the development of resistance to the drug. Understanding the pathways involved in the growth of tamoxifen-resistant cells may lead to new ways to treat tamoxifen-resistant breast cancer. Here, we investigate the role of cyclin D1, a mediator of estrogendependent proliferation, in growth of tamoxifen-resistant cells using a cell culture model of acquired resistance to tamoxifen. We show that tamoxifen and 4-hydroxytamoxifen (OHT) promoted cell cycle progression of tamoxifen-resistant cells after growth-arrest mediated by the estrogen receptor downregulator ICI 182,780. Down-regulation of cyclin D1 with small interfering RNA blocked basal cell growth of tamoxifenresistant cells and induction of cell proliferation by OHT. In addition, pharmacologic inhibition of phosphatidylinositol 3-kinase/Akt or mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 pathways decreased basal cyclin D1 expression and impaired OHT-mediated cyclin D1 induction and cell cycle progression. These findings indicate that cyclin D1 expression is necessary for proliferation of tamoxifen-resistant cells and for tamoxifen-induced cell cycle progression. These results suggest that therapeutic strategies to block cyclin D1 expression or function may inhibit development and growth of tamoxifen-resistant tumors.

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Several groups have completed autosomal genome scans for human obesity, but only two have examined the X chromosome. A French group reported linkage of BMI to Xp and Xq markers, and a Finnish group reported linkage of BMI to Xq. We scanned the X chromosome in two cohorts, 190 European-American families (940 members) and 43 African-American families (208 members). We examined five correlated obesity phenotypes, BMI, body fat percentage, hip and waist circumferences, and plasma leptin concentration. We also examined leptin resistance (leptin/BMI) and fat patterning (waist-to-hip ratio [WHR]). Variables were adjusted for age within generation, race, and sex. We genotyped 20 markers with average spacing of 10 cM and no interval >22 cM and conducted nonparametric analyses. Suggestive linkage was found for WHR only. Linkage was supported in both family sets, and support was especially strong for females. Z scores for analyses of female phenotypes were 2.69, 1.73, and 2.37 (P ‫؍‬ 0.0036, 0.0418, and 0.0089) for African-Americans, EuropeanAmericans, and the combined sample, respectively. The peaks were 51-73 cM from the p terminus, 14 -34 cM distal of the French report in Xp22. Our results suggest that a quantitative trait locus influencing fat distribution in women may lie in chromosome region Xp21-22; however, the linked interval is large and differs substantially from that of the French and Finnish groups. Given the positive but divergent results, it would be worthwhile for others to examine the X chromosome. Diabetes 51: 1989 -1991, 2002 O besity is a common, multigenic trait that conveys an increased risk for several diseases, especially type 2 diabetes, cardiovascular disease, and hypertension. Several groups (1) including our own (2) have completed autosomal genome scans aimed at detecting linkage to obesity-related phenotypes. Only two groups have completed scans of the X chromosome, however. A French group (3) found linkage to a marker in chromosome region Xp22 and Xq, and a Finnish group (4) reported linkage to a marker in Xq24. Both studies used qualitative thresholds of BMI as the obesity phenotype.In the current study, we conducted a scan of the X chromosome in two sets of families having both extremely obese (BMI Ն40 kg/m 2 ) siblings and normal weight (BMI Ͻ27 kg/m 2 ) siblings and parents. One sample included 190 European-American families having 940 individuals; the other included 43 African-American families having 208 individuals. Family members were genotyped for 20 microsatellite markers with an average spacing of 10 cM. We examined four overlapping qualitative phenotypes-BMI Ն27, Ն30, Ն35, and Ն40 kg/m 2 -and five correlated obesity-related phenotypes-BMI, body fat percentage, waist circumference, hip circumference, and plasma leptin concentration. We also examined the waist-to-hip ratio (WHR) as a measure of fat patterning and the ratio of leptin to BMI as a measure of leptin resistance. All quantitative variables were adjusted for age within generation, sex, and race. We conducted nonparametri...