BACKGROUND: Rare mutations in the leptin (LEP) gene cause severe obesity. Common polymorphisms of LEP have been associated with obesity, but their association with cardiovascular disease has been little studied. We have examined the impact of both common and rare polymorphisms of the LEP gene on blood pressure (BP), subclinical atherosclerosis as measured by carotid intima-medial thickness (CIMT), and body mass index (BMI) in a large family study. METHODS: Five polymorphisms spanning LEP were typed in 1428 individuals from 248 nuclear families. BP, CIMT, BMI, and plasma leptin were measured. RESULTS: The polymorphisms typed captured all common haplotypes present at LEP. There was strong association between a rare polymorphism in the 3' untranslated region of LEP (C538T) and both pulse pressure (p = 0.0001) and CIMT (p = 0.008). C/T heterozygotes had a 22% lower pulse pressure and a 17% lower CIMT than C/C homozygotes. The polymorphism accounted for 3-5% of the population variation in pulse pressure and CIMT. There was no association between any LEP polymorphism and either BMI or plasma leptin level. CONCLUSIONS: This large family study shows that the rare T allele at the C538T polymorphism of LEP substantially influences pulse pressure and CIMT, but does not appear to exert this effect through actions on plasma leptin level or BMI. This suggests that autocrine or paracrine effects in vascular tissue may be important physiological functions of leptin. This study also provides evidence that rare polymorphisms of particular genes may have substantial effects within the normal range of certain quantitative traits.
BACKGROUND: Rare mutations in the leptin (LEP) gene cause severe obesity. Common polymorphisms of LEP have been associated with obesity, but their association with cardiovascular disease has been little studied. We have examined the impact of both common and rare polymorphisms of the LEP gene on blood pressure (BP), subclinical atherosclerosis as measured by carotid intima-medial thickness (CIMT), and body mass index (BMI) in a large family study. METHODS: Five polymorphisms spanning LEP were typed in 1428 individuals from 248 nuclear families. BP, CIMT, BMI, and plasma leptin were measured. RESULTS: The polymorphisms typed captured all common haplotypes present at LEP. There was strong association between a rare polymorphism in the 3' untranslated region of LEP (C538T) and both pulse pressure (p = 0.0001) and CIMT (p = 0.008). C/T heterozygotes had a 22% lower pulse pressure and a 17% lower CIMT than C/C homozygotes. The polymorphism accounted for 3-5% of the population variation in pulse pressure and CIMT. There was no association between any LEP polymorphism and either BMI or plasma leptin level. CONCLUSIONS: This large family study shows that the rare T allele at the C538T polymorphism of LEP substantially influences pulse pressure and CIMT, but does not appear to exert this effect through actions on plasma leptin level or BMI. This suggests that autocrine or paracrine effects in vascular tissue may be important physiological functions of leptin. This study also provides evidence that rare polymorphisms of particular genes may have substantial effects within the normal range of certain quantitative traits.
Authors: C T Montague; I S Farooqi; J P Whitehead; M A Soos; H Rau; N J Wareham; C P Sewter; J E Digby; S N Mohammed; J A Hurst; C H Cheetham; A R Earley; A H Barnett; J B Prins; S O'Rahilly Journal: Nature Date: 1997-06-26 Impact factor: 49.962
Authors: B Keavney; C A McKenzie; J M Connell; C Julier; P J Ratcliffe; E Sobel; M Lathrop; M Farrall Journal: Hum Mol Genet Date: 1998-10 Impact factor: 6.150
Authors: B Carlsson; K Lindell; B Gabrielsson; C Karlsson; R Bjarnason; O Westphal; U Karlsson; L Sjöström; L M Carlsson Journal: Obes Res Date: 1997-01
Authors: M K Karvonen; U Pesonen; P Heinonen; M Laakso; A Rissanen; H Naukkarinen; R Valve; M I Uusitupa; M Koulu Journal: J Clin Endocrinol Metab Date: 1998-09 Impact factor: 5.958
Authors: G Erez; A Tirosh; A Rudich; V Meiner; D Schwarzfuchs; N Sharon; S Shpitzen; M Blüher; M Stumvoll; J Thiery; G M Fiedler; Y Friedlander; E Leiterstdorf; I Shai Journal: Int J Obes (Lond) Date: 2010-11-02 Impact factor: 5.095
Authors: Siim Sõber; Elin Org; Katrin Kepp; Peeter Juhanson; Susana Eyheramendy; Christian Gieger; Peter Lichtner; Norman Klopp; Gudrun Veldre; Margus Viigimaa; Angela Döring; Margus Putku; Piret Kelgo; Sue Shaw-Hawkins; Philip Howard; Abiodun Onipinla; Richard J Dobson; Stephen J Newhouse; Morris Brown; Anna Dominiczak; John Connell; Nilesh Samani; Martin Farrall; Mark J Caulfield; Patricia B Munroe; Thomas Illig; H-Erich Wichmann; Thomas Meitinger; Maris Laan Journal: PLoS One Date: 2009-06-29 Impact factor: 3.240
Authors: Ikechi G Okpechi; Brian L Rayner; Lize van der Merwe; Bongani M Mayosi; Adebowale Adeyemo; Nicki Tiffin; Rajkumar Ramesar Journal: PLoS One Date: 2010-02-05 Impact factor: 3.240
Authors: Duanduan Ma; Mary F Feitosa; Jemma B Wilk; Jason M Laramie; Kai Yu; Catherine Leiendecker-Foster; Richard H Myers; Michael A Province; Ingrid B Borecki Journal: Hypertension Date: 2009-02-09 Impact factor: 10.190
Authors: Judith A Goodship; Darroch Hall; Ana Topf; Chrysovalanto Mamasoula; Helen Griffin; Thahira J Rahman; Elise Glen; Huay Tan; Julian Palomino Doza; Caroline L Relton; Jamie Bentham; Shoumo Bhattacharya; Catherine Cosgrove; David Brook; Javier Granados-Riveron; Frances A Bu'Lock; John O'Sullivan; A Graham Stuart; Jonathan Parsons; Heather J Cordell; Bernard Keavney Journal: Circ Cardiovasc Genet Date: 2012-04-13