title: Genetic variants in loci 1p13 and 9p21 and fatal coronary heart disease in a Norwegian case-cohort study.
abstract: Single nucleotide polymorphisms (SNPs) in loci 1p13 and 9p21 have previously been found to be associated with incident coronary heart disease (CHD). This study aimed to investigate whether these SNPs show associations with fatal CHD in a population-based cohort study after adjustment for socioeconomic- and lifestyle-related CHD risk factors not commonly included in genetic association studies. Using the population-based Cohort of Norway (CONOR), a nested case-cohort study was set up and DNA from 2,953 subjects (829 cases and 2,124 non-cases) were genotyped. The association with fatal CHD was estimated for four SNPs, three from locus 1p13 and one from locus 9p21. Multivariable Cox regression was used to estimate unstratified and gender-stratified hazard ratios while adjusting for major CHD risk factors. The associations between three SNPs from locus 1p13 and non-HDL cholesterol levels were also estimated. Men homozygous for the risk alleles on rs1333049 (9p21) and rs14000 (1p13) were found to have significantly increased hazard ratios in crude and adjusted models, and the hazard ratios remained statistically significant when both genders were analyzed together. Adjustment for additional socioeconomic- and lifestyle-related CHD risk factors influenced the association estimates only slightly. No significant associations were observed between the other two SNPs in loci 1p13 (rs599839 and rs646776) and CHD mortality in either gender. Both rs599839 and rs646776 showed significant, gradual increases in non-HDL cholesterol levels with increasing number of risk alleles. This study confirms the association between 9p21 (rs1333049) and fatal CHD in a Norwegian population-based cohort. The effect was not influenced by several socioeconomic- and lifestyle-related risk factors. Our results show that 1p13 (rs14000) may also be associated with fatal CHD. SNPs at 1p13 (rs599839 and rs646776) were associated with non-HDL cholesterol levels.
authors.affiliation: Division of Epidemiology, Norwegian Institute of Public Health, Postboks 4404 Nydalen, 0403, Oslo, Norway, monadjansen@hotmail.com.
authors.forename: Mona Dverdal
authors.initials: MD
authors.lastname: Jansen
authors.forename: Gun Peggy
authors.initials: GP
authors.lastname: Knudsen
authors.forename: Ronny
authors.initials: R
authors.lastname: Myhre
authors.forename: Gudrun
authors.initials: G
authors.lastname: Høiseth
authors.forename: Jørg
authors.initials: J
authors.lastname: Mørland
authors.forename: Øyvind
authors.initials: Ø
authors.lastname: Næss
authors.forename: Kristian
authors.initials: K
authors.lastname: Tambs
authors.forename: Per
authors.initials: P
authors.lastname: Magnus
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D002878:Chromosomes, Human, Pair 1; D002899:Chromosomes, Human, Pair 9; D003327:Coronary Disease / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009664:Norway; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics*
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