title: New susceptibility locus for obesity and dyslipidaemia on chromosome 3q22.3.
abstract: BACKGROUND
  The muscle Ras (MRAS) gene resides on chromosome 3q22.3 and encodes a member of the membrane-associated Ras small GTPase proteins, which function as signal transducers in multiple processes including cell growth and differentiation. Its role in cardiovascular disease is not fully understood yet. In a preliminary study in heterozygous familial hypercholesterolaemia, we identified a locus linking the early onset of coronary artery disease (CAD) to chromosome 3q.22 and elected to sequence the MRAS gene using the MegaBACE DNA analysis system. In the present study, we investigated the association of seven single-nucleotide polymorphisms (SNPs) at this locus with CAD and its dyslipidaemia-related risk traits in 4,650 Saudi angiographed individuals using TaqMan assays by the Applied Biosystems real-time Prism 7900HT Sequence Detection System.
  
  
  RESULTS
  Among the studied SNPs, rs6782181 (p = 0.017) and rs9818870T (p = 0.009) were associated with CAD following adjustment for sex, age and other confounding risk factors. The rs6782181_GG also conferred risk for obesity (1,764 cases vs. 2,586 controls) [1.16(1.03-1.30); p = 0.017], hypercholesterolaemia (1,686 vs. 2,744) [1.23(1.02-1.47); p = 0.019], hypertriglyceridaemia (1,155 vs. 3,496) [1.29(1.01-1.45); p = 0.043] and low high-density lipoprotein-cholesterol (lHDL-chol) levels (1,935 vs. 2,401) [1.15(1.02-1.30); p = 0.023] after adjustment. Additionally, rs253662_(CT+TT) [1.16(1.01-1.32); p = 0.030] was associated with lHDL-chol levels. Interestingly, rs253662 (p = 0.014) and rs6782181 (p = 0.019) were protective against acquiring high low-density lipoprotein-cholesterol (hLDL-chol) levels (p = 0.014), while rs1720819 showed similar effects against CAD (p < 0.0001). More importantly, a 7-mer haplotype, ACCTGAC (χ2 = 7.66; p = 0.0056), constructed from the studied SNPs, its 6-mer derivative CCTGAC (χ2 = 6.90; p = 0.0086) and several other shorter derivatives conferred risk for obesity. hLDL-chol was weakly linked to CTAA (χ2 = 3.79; p = 0.052) and CCT (χ2 = 4.32; p = 0.038), while several other haplotypes were protective against both obesity and hLDL-chol level.
  
  
  CONCLUSIONS
  Our results demonstrate that the genomic locus for the MRAS gene confers risk for CAD, obesity and dyslipidaemia and point to the possible involvement of other genes or regulatory elements at this locus, rather than changes in the M-Ras protein function, in these events.
authors.affiliation: King Faisal Heart Institute, MBC-16, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
authors.forename: Maie
authors.initials: M
authors.lastname: Alshahid
authors.forename: Salma M
authors.initials: SM
authors.lastname: Wakil
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Najai
authors.forename: Nzioka P
authors.initials: NP
authors.lastname: Muiya
authors.forename: Samar
authors.initials: S
authors.lastname: Elhawari
authors.forename: Daisy
authors.initials: D
authors.lastname: Gueco
authors.forename: Editha
authors.initials: E
authors.lastname: Andres
authors.forename: Samia
authors.initials: S
authors.lastname: Hagos
authors.forename: Nejat
authors.initials: N
authors.lastname: Mazhar
authors.forename: Brian F
authors.initials: BF
authors.lastname: Meyer
authors.forename: Nduna
authors.initials: N
authors.lastname: Dzimiri
mesh_terms: D008076:Cholesterol, HDL / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics; D050171:Dyslipidemias / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D008076:Cholesterol, HDL; C109523:MRAS protein, human; D018631:ras Proteins