Many aspects of physiology and behavior follow a circadian rhythm. Brain and muscle Arnt-like protein-1 (BMAL1) is a key component of the mammalian molecular clock, which controls circadian oscillations. In the rat, the gene encoding Bmal1 is located within hypertension susceptibility loci. We analyzed the SNP distribution pattern in a congenic interval associated with hypertension in the spontaneously hypertensive rat (SHR), and we show that Bmal1 maps close to a region genetically divergent between SHR and its normotensive (Wistar-Kyoto) counterpart. Bmal1 sequencing in rat strains identified 19 polymorphisms, including an SHR promoter variant that significantly affects Gata-4 activation of transcription in transient transfection experiments. A genetic association study designed to test the relevance of these findings in 1,304 individuals from 424 families primarily selected for type 2 diabetes showed that two BMAL1 haplotypes are associated with type 2 diabetes and hypertension. This comparative genetics finding translated from mouse and rat models to human provides evidence of a causative role of Bmal1 variants in pathological components of the metabolic syndrome.comparative genomics ͉ genetic polymorphism ͉ molecular clock ͉ SNP ͉ sequence variation

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Genetic studies based on cohorts with rare and extreme bone phenotypes have shown that the LRP5 gene is an important genetic modulator of BMD. Using family-based and case-control approaches, this study examines the role of the LRP5 gene in determining normal population variation of BMD and describes significant association and suggestive linkage between LRP5 gene polymorphisms and BMD in >900 individuals with a broad range of BMD.Introduction: Osteoporosis is a common, highly heritable condition determined by complex interactions of genetic and environmental etiologies. Genetic factors alone can account for 50 -80% of the interindividual variation in BMD. Mutations in the LRP5 gene on chromosome 11q12-13 have been associated with rare syndromes characterized by extremely low or high BMD, but little is known about the contribution of this gene to the development of osteoporosis and determination of BMD in a normal population. Materials and Methods:To examine the entire spectrum of low to high BMD, 152 osteoporotic probands, their families (597 individuals), and 160 women with elevated BMD (T score Ͼ 2.5) were recruited. BMD at the lumbar spine, femoral neck, and hip were measured in each subject using DXA. Results: PAGE sequencing of the LRP5 gene revealed 10 single nucleotide polymorphisms (SNPs), 8 of which had allele frequencies of Ͼ5%, in exons 8, 9, 10, 15, and 18 and in introns 6, 7, and 21. Within families, a strong association was observed between an SNP at nucleotide C171346A in intron 21 and total hip BMD (p Ͻ 1 ϫ 10

Type II SH2 domain-containing inositol 5-phosphatase (INPPL1, or SHIP2) plays an important role in the control of insulin sensitivity. INPPL1 mutations affecting gene function have been found in rat models of type 2 diabetes and hypertension and in type 2 diabetic patients. We investigated the influence of nucleotide variation in INPPL1 on components of the metabolic syndrome. Following comprehensive resequencing of the gene, we genotyped 12 informative polymorphisms in 1,304 individuals from 424 British type 2 diabetes families that were characterized for several metabolic phenotypes. We have found highly significant associations of single nucleotide polymorphisms (SNPs) and haplotypes of INPPL1 with hypertension as well as with other components of the metabolic syndrome. In a cohort of 905 French type 2 diabetic patients, we found evidence of association of INPPL1 SNPs with the presence of hypertension. We conclude that INPPL1 variants may impact susceptibility to disease and/or to subphenotypes involved in the metabolic syndrome in some diabetic patients. Diabetes 53: 1900 -1904, 2004 T he metabolic syndrome, a cluster of metabolic abnormalities that can include type 2 diabetes, hypertension, central obesity, and dyslipidemia, occurs at a high rate in the U.S., Europe, and Scandinavia (1-4). Insulin resistance is the focal component of the metabolic syndrome, and both genetic and environmental factors contribute to its development (4). Much progress has been made toward understanding the regulation of insulin action and the molecular defects that give rise to insulin resistance (5).INPPL1 is a negative regulator of insulin signaling, and Inppl1 inactivation in mice results in increased insulin sensitivity (6). INPPL1 is in human chromosome 11q13-14, which has suggested linkage to type 2 diabetes, hypertension, and insulin resistance (7-9). In the rat, Inppl1 is in an interval on chromosome 1 linked to glucose intolerance and adiposity in the spontaneously diabetic (type 2) GotoKakizaki rat (10,11) and to hypertension in the spontaneously hypertensive rat (12). We identified a missense variant in Inppl1 specific to both rat strains that increases inhibition of insulin signaling compared with wild-type Inppl1 (10). Furthermore, in type 2 diabetic patients, we found a 16-bp deletion of an adenylate/uridylate-rich element in the 3Ј untranslated region of INPPL1, which in vitro causes changes consistent with a role in insulin resistance (10). Seven of nine patients with this mutation were hypertensive, and five were obese.To investigate the role of genetic variation in INPPL1 in the metabolic syndrome, we first resequenced the gene (15.2 kb), including all exons and introns in a panel of 64 individuals. We describe a total of 49 variants ( Fig. 1; a table of single nucleotide polymorphisms [SNPs] is available in the online appendix at http:// diabetes.diabetesjournal.org and at http://www.well. ox.ac.uk/rat_mapping_resources/SHIP2). At first we genotyped all polymorphic markers, but in later stages we discarde...