Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes.
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.
Woon
Peng Y
PY
Wellcome Trust Centre for Human Genetics and Department of Cardiovascular Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom.
Kaisaki
Pamela J
PJ
Bragança
José
J
Bihoreau
Marie-Thérèse
MT
Levy
Jonathan C
JC
Farrall
Martin
M
Gauguier
Dominique
D
D056930:ARNTL Transcription Factors; D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001794:Blood Pressure; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000150:complications* / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011788:Quality of Life; D051381:Rats; D011918:Rats, Inbred SHR; D012307:Risk Factors; D014158:Transcription, Genetic / Q000235:genetics
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D050991:GATA4 Transcription Factor; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse