Novel 6p21.3 Risk Haplotype Predisposes to Acute Coronary Syndrome.

BACKGROUND: The HLA-DRB1*01 allele of the human leukocyte antigen has been associated with acute coronary syndrome. Genome-wide association studies have revealed associations with human leukocyte antigen and non-human leukocyte antigen genes of 3 major histocompatibility complex gene classes but not at allelic level. METHODS AND RESULTS: We conducted a large-scale genetic analysis on a case-control cohort comprising 5376 acute coronary syndrome cases and 4852 unrelated controls from 4 populations of 2 European countries. We analyzed the risk candidate allele of HLA-DRB1*01 by genomic real-time polymerase chain reaction together with high-density single nucleotide polymorphisms of the major histocompatibility complex to precisely identify risk loci for acute coronary syndrome with effective clinical implications. We found a risk haplotype for the disease containing single nucleotide polymorphisms from BTNL2 and HLA-DRA genes and the HLA-DRB1*01 allele. The association of the haplotype appeared in 3 of the 4 populations, and the direction of the effect was consistent in the fourth. Coronary samples from subjects homozygous for the disease-associated haplotype showed higher BTNL2 mRNA levels (r=0.760; P<0.00001).We localized, with immunofluorescence staining, BTNL2 in CD68-positive macrophages of the coronary artery plaques. In homozygous cases, BTNL2 blocking, in T-cell stimulation assays, enhanced CD4(+)FOXP3(+) regulatory T cell proliferation significantly (blocking versus nonblocking; P<0.05). CONCLUSIONS: In cases with the risk haplotype for acute coronary syndrome, these results suggest involvement of enhanced immune reactions. BTNL2 may have an inhibitory effect on FOXP3(+) T cell proliferation, especially in patients homozygous for the risk alleles. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov; Unique Identifier: NCT00417534.

Genetic variation on the BAT1-NFKBIL1-LTA region of major histocompatibility complex class III associates with periodontitis.

Periodontitis is a chronic inflammatory disease with a multifactorial etiology. We investigated whether human major histocompatibility complex (MHC) polymorphisms (6p21.3) are associated with periodontal parameters. Parogene 1 population samples (n = 169) were analyzed with 13,245 single nucleotide polymorphisms (SNPs) of the MHC region. Eighteen selected SNPs (P ≤ 0.001) were replicated in Parogene 2 population samples (n = 339) and the Health 2000 Survey (n = 1,420). All subjects had a detailed clinical and radiographic oral health examination. Serum lymphotoxin-α (LTA) concentrations were measured in the Parogene populations, and the protein was detected in inflamed periodontal tissue. In the Parogene 1 population, 10 SNPs were associated with periodontal parameters. The strongest associations emerged from the parameters bleeding on probing (BOP) and a probing pocket depth (PPD) of ≥6 mm with the genes BAT1, NFKBIL1, and LTA. Six SNPs, rs11796, rs3130059, rs2239527, rs2071591, rs909253, and rs1041981 (r(2), ≥0.92), constituted a risk haplotype. In the Parogene 1 population, the haplotype had the strongest association with the parameter BOP, a PPD of ≥6 mm, and severe periodontitis with odds ratios (95% confidence intervals) of 2.63 (2.21 to 3.20), 2.90 (2.37 to 3.52), and 3.10 (1.63 to 5.98), respectively. These results were replicated in the other two populations. High serum LTA concentrations in the Parogene population were associated with the periodontitis risk alleles of the LTA SNPs (rs909253 and rs1041981) of the haplotype. In addition, the protein was expressed in inflamed gingival connective tissue. We identified a novel BAT1-NFKBIL1-LTA haplotype as a significant contributor to the risk of periodontitis. The genetic polymorphisms in the MHC class III region may be functionally important in periodontitis susceptibility.

New paraoxonase 1 polymorphism I102V and the risk of prostate cancer in Finnish men.

BACKGROUND: Human serum paraoxonase eliminates carcinogenic lipid-soluble radicals. Because expression of the main human paraoxonase gene PON1 varies widely in humans, certain PON1 polymorphisms might be associated with increased risks of cancer. We sought new functional mutations in PON1 and determined whether known or new PON1 mutations were associated with the risk for prostate cancer in a prospective, random, population-based sample of Finnish men and in a case-control study. METHODS: Serum paraoxonase activity was measured in 835 healthy men in the Kuopio Ischaemic Heart Disease Risk Factor Study. PON1 mutations were identified by hierarchical phenotype-targeted sequencing in DNAs from the 100 men with the lowest paraoxonase activity in this cohort, and 1595 men in the cohort were genotyped for PON1 mutations by restriction fragment length polymorphism. Multivariable analysis was used to investigate the association of known and new PON1 mutations with incident prostate cancer in 1569 cancer-free men in the cohort followed for 9-14 years. In a case-control study of Finnish men, the association of prostate cancer with the PON1 mutation identified in the cohort study was investigated in 69 case patients with familial prostate cancer and 69 unmatched healthy control subjects. RESULTS: We identified a new single-nucleotide PON1 polymorphism associated with decreased serum paraoxonase activity that caused an isoleucine-->valine change at codon 102 in exon 4 (I102V). Of the 1569 men cancer-free at baseline, 56 (3.6%) were carriers of the I102V mutation. After adjusting for age and cholesterol-lowering medications, the relative risk for developing prostate cancer during follow-up was 6.3 (95% confidence interval [CI] = 2.1 to 19.2) among 102V allele carriers compared with noncarriers. Other PON1 alleles were not statistically significantly associated with prostate cancer. In the case-control study, patients with familial prostate cancer were more likely to be carriers of the PON1 I102V mutation than control subjects (odds ratio = 4.3, 95% CI = 0.9 to 21.5). CONCLUSION: The PON1 102V allele appears to be associated with an increased risk for prostate cancer.