title: Elevated C-reactive protein levels and ARMS2/HTRA1 gene variants in subjects without age-related macular degeneration.
abstract: OBJECTIVE
  To investigate the association between the serum high sensitivity C-reactive protein (hs-CRP) levels and variants in age-related maculopathy susceptibility 2 (ARMS2)/HtrA serine peptidase 1 (HTRA1) genes in normal subjects with no evidence of age-related macular degeneration (AMD).
  
  
  METHODS
  After clinical evaluation, information related to medical and social history was collected from 476 Japanese individuals (age range 17-89 years) along with blood samples. These subjects were medical checkup participants recruited at Nagoya University Hospital with no macular disease, as confirmed by fundus photographs. Serum hs-CRP levels were measured using a highly sensitive latex aggregation immunoassay. The genotypes of three polymorphisms in the ARMS2/HTRA1 locus, i.e., *372_815del443ins54 (del/ins), rs10490924, and rs11200638 were determined using direct sequencing and/or PCR-based assays. After the haplotype was constructed and analyzed, the associations between hs-CRP levels and representative del/ins genotypes were studied with and without adjustment for potential confounding factors.
  
  
  RESULTS
  All three polymorphisms in the ARMS2/HTRA1 region were in almost complete linkage disequilibrium. Haplotype analyses showed the existence of only two common haplotypes, together comprising 98.9%. Regression analyses showed that the level of hs-CRP was positively correlated with increasing age. This age-dependent increase of hs-CRP levels was greatest in those with homozygous del/ins alleles and lowest in those with homozygous wild-type alleles, which was significant assuming an additive model for gene-dosage association (univariate analyses: p=0.016, multivariate analyses including smoking status, past medical history, and BMI: p=0.043). Consequently, the level of hs-CRP was greatest in those with homozygous del/ins alleles and lowest in those with homozygous wild-type alleles when subjects older than 60 were analyzed. This was significant assuming an additive model for gene-dosage association (univariate analyses: p=0.032).
  
  
  CONCLUSIONS
  An age-dependent elevation of serum hs-CRP levels may be accelerated in normal subjects with one or two risk alleles in the ARMS2/HTRA1 locus compared to those with homozygous wild-type alleles. The results of the current study show that the as-yet undetermined function of variants in the ARMS2/HTRA1 locus might be linked to inflammation, possibly contributing to the development of neovascular AMD.
authors.affiliation: Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tetsuhiro R
authors.initials: TR
authors.lastname: Yasuma
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakamura
authors.forename: Koji M
authors.initials: KM
authors.lastname: Nishiguchi
authors.forename: Masato
authors.initials: M
authors.lastname: Kikuchi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kaneko
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Niwa
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Hamajima
authors.forename: Hiroko
authors.initials: H
authors.lastname: Terasaki
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000097:blood / Q000235:genetics; D002097:C-Reactive Protein / Q000378:metabolism*; D003710:Demography; D005260:Female; D006239:Haplotypes / Q000235:genetics; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D008268:Macular Degeneration / Q000097:blood* / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D012044:Regression Analysis; D012697:Serine Endopeptidases / Q000235:genetics*; D055815:Young Adult
chemical_list: C514392:ARMS2 protein, human; D011506:Proteins; D002097:C-Reactive Protein; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases