title: Linkage study of fibrinogen levels: the Strong Heart Family Study.
abstract: BACKGROUND
  The pathogenesis of atherosclerosis involves both hemostatic and inflammatory mechanisms. Fibrinogen is associated with both risk of thrombosis and inflammation. A recent meta-analysis showed that risk of coronary heart disease may increase 1.8 fold for 1 g/L of increased fibrinogen, independent of traditional risk factors. It is known that fibrinogen levels may be influenced by demographic, environmental and genetic factors. Epidemiologic and candidate gene studies are available; but few genome-wide linkage studies have been conducted, particularly in minority populations. The Strong Heart Study has demonstrated an increased incidence of cardiovascular disease in the American Indian population, and therefore represents an important source for genetic-epidemiological investigations.
  
  
  METHODS
  The Strong Heart Family Study enrolled over 3,600 American Indian participants in large, multi-generational families, ascertained from an ongoing population-based study in the same communities. Fibrinogen was determined using standard technique in a central laboratory and extensive additional phenotypic measures were obtained. Participants were genotyped for 382 short tandem repeat markers distributed throughout the genome; and results were analyzed using a variance decomposition method, as implemented in the SOLAR 2.0 program.
  
  
  RESULTS
  Data from 3535 participants were included and after step-wise, linear regression analysis, two models were selected for investigation. Basic demographic adjustments constituted model 1, while model 2 considered waist circumference, diabetes mellitus and postmenopausal status as additional covariates. Five LOD scores between 1.82 and 3.02 were identified, with the maximally adjusted model showing the highest score on chromosome 7 at 28 cM. Genes for two key components of the inflammatory response, i.e. interleukin-6 and "signal transducer and activator of transcription 3" (STAT3), were identified within 2 and 8 Mb of this 1 LOD drop interval respectively. A LOD score of 1.82 on chromosome 17 between 68 and 93 cM is supported by reports from two other populations with LOD scores of 1.4 and 1.95.
  
  
  CONCLUSIONS
  In a minority population with a high prevalence of cardiovascular disease, strong evidence for a novel genetic determinant of fibrinogen levels is found on chromosome 7 at 28 cM. Four other loci, some of which have been suggested by previous studies, were also identified.
authors.affiliation: Missouri Breaks Industries Research Inc, Timber Lake, SD, USA. sbest@utma.com
authors.forename: Lyle G
authors.initials: LG
authors.lastname: Best
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.forename: Vittorio
authors.initials: V
authors.lastname: Palmieri
authors.forename: Jason G
authors.initials: JG
authors.lastname: Umans
authors.forename: Jean
authors.initials: J
authors.lastname: MacCluer
authors.forename: Sandy
authors.initials: S
authors.lastname: Laston
authors.forename: Karin
authors.initials: K
authors.lastname: Haack
authors.forename: Harald
authors.initials: H
authors.lastname: Goring
authors.forename: Vincent P
authors.initials: VP
authors.lastname: Diego
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
authors.forename: Elisa T
authors.initials: ET
authors.lastname: Lee
authors.forename: Russell P
authors.initials: RP
authors.lastname: Tracy
authors.forename: Shelley
authors.initials: S
authors.lastname: Cole
mesh_terms: D000328:Adult; D001130:Arizona / Q000453:epidemiology; D050197:Atherosclerosis / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D002874:Chromosome Mapping; D015331:Cohort Studies; D005260:Female; D005340:Fibrinogen / Q000235:genetics*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D007198:Indians, North American / Q000706:statistics & numerical data*; D016014:Linear Models; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D009658:North Dakota / Q000453:epidemiology; D009825:Oklahoma / Q000453:epidemiology; D012307:Risk Factors; D013023:South Dakota / Q000453:epidemiology
chemical_list: D005340:Fibrinogen