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Metabolic syndrome (MetS) is a common multifactorial disorder that involves abdominal obesity, dyslipidemia, hypertension, and hyperglycemia. Genome-wide association studies have identified a major risk locus for coronary artery disease and myocardial infarction on chromosome 9p21. Here, we examined the frequency of single nucleotide polymorphisms (SNPs) on chromosome 9p21 in a sample of Turkish patients with MetS and further investigated the correlation between regional SNPs, haplotypes, and MetS. The real-time polymerase chain reaction (RT-PCR) was used to analyze 4 SNPs (rs10757274 A/G, rs2383207 A/G, rs10757278 A/G, rs1333049 C/G) in 291 MetS patients and 247 controls. Analysis of 4 SNPs revealed a significant difference in the genotype distribution for rs2383207, rs10757278, and rs1333049 between MetS patients and controls ( p = 0.041, p = 0.005, p = 0.023, respectively) but not for rs10757274 ( p = 0.211). MetS and control allelic frequencies for rs2383207, rs10757278, and rs1333049 were statistically different ( p < 0.05). The rs2383207 AG variant, was identified as a MetS risk factor ( p = 0.012, OR = 33.271; 95 % CI: 2.193-504.805) and the AA haplotype in block 1 and the GC, AG haplotypes in block 2 were associated with MetS ( χ = 3.875, p = 0.049; χ = 9.334, p = 0.0022; χ = 9.134, p = 0.0025, respectively). In this study, we found that chromosome 9p21 SNP rs10757278 and related haplotypes correlate with MetS risk. This is the first report showing an association between a 9p21 variant and MetS and suggests that rs10757278 polymorphism may confer increased risk for disease. [ABSTRACT FROM AUTHOR]

Recent genome-wide association studies have demonstrated that common genetic variants in a region of chromosome 9p21 confer risk of coronary artery disease (CAD) and other atherosclerotic conditions. Although the absolute increase in risk is small (some 20-30% increase in risk of CAD per copy of the deleterious alleles), the common occurrence of the variants means that their effect on the population risk of disease is estimated to be substantial. Studies investigating the relationship between risk variants and both 'classical' and 'emerging' atherosclerotic risk factors have found no evidence of association. This suggests that the effect of the 9p21 locus on atherosclerotic risk is mediated via a hitherto unknown pathway potentially amenable to therapeutic modulation. Investigation of potential disease mechanisms at this locus is therefore a focus of intense interest. In this review, we discuss the progress that has been made in the study of mechanisms and highlight the outstanding research questions. [ABSTRACT FROM AUTHOR]

Chromosome 9p21 has been implicated in the pathogenesis of cutaneous malignant melanoma (CMM). In addition to CDKN2A, the major known high-risk susceptibility gene for CMM, recent studies suggest that other 9p21 genes may be involved in melanoma/nevi development. To identify 9p21 variants that influence susceptibility to CMM and number of nevi in CMM-prone families with and without CDKN2A mutations, we analyzed 562 individuals (183 CMM) from 53 families (23 CDKN2A+, 30 CDKN2A−) for 233 tagging SNPs in 21 genes at 9p21. Single SNP- and gene-based regression analyses were used to assess the risk of CMM, nevi count, skin complexion, and tanning ability associated with these SNPs and genes. We found that SNP rs7023329 in the MTAP gene was associated with number of nevi ( P = 0.003) confirming a recent finding by a genome-wide association study. In addition, three SNPs in the ACO1 gene, rs7855483 ( P = 0.002), rs17288067 ( P = 0.0009), and rs10813813 ( P = 0.005), showed the strongest associations with CMM risk. None of the examined 9p21 SNPs was associated with skin complexion, whereas two SNPs, rs10964862 in IFNW1 ( P = 0.003), and rs13290968 in TUSC1 ( P = 0.0006), were associated with tanning ability. Gene-based analyses suggested that the ACO1 gene was significantly associated with CMM ( P = 0.0004); genes IFNW1 ( P = 0.002) and ACO1 ( P = 0.0002) were significantly associated with tanning ability. Our findings are consistent with recent proposals that additional 9p21 genes may contribute to CMM susceptibility in CMM-prone families. These genetic variants may, at least partially, exert their effects through nevi and tanning ability. [ABSTRACT FROM AUTHOR]

Meningioangiomatosis (MA) is a rare lesion appearing sporadically or as a part of neurofibromatosis 2. The occurrences of meningiomas arising from MA (MA-M) have raised doubts about the traditional concept of a hamartomatous origin for MA. Cytogenetic or molecular studies on MA, with or without meningiomas, are limited because of the rarity of MA. The current study was to evaluate the loss of heterozygosity (LOH) in seven cases of MA-M and two cases of pure MA. LOH on six chromosomes (1p32, 9p21, 13q14, 16q22, 17p, and 22q12) were investigated using 13 sets of microsatellite markers, including D1S193, D1S463, D22S193, D22S929, D22S282, TP53, D17S796, D16S421, D16S512, D13S118, D13S153, D9S162, and D9S104. PCR was performed using each marker and polymorphic analysis was accomplished by silver staining. Immunohistochemical stain for Ki-67 was carried out and labeling index was measured by using a semiquantitative manual counting method. The meningioma portions of MA-Ms showed LOH for loci on chromosomes 22q12, 9p21, and 1p32 in 57.1% (4/7), 28.6% (2/7), and 28.6% (2/7) of cases, respectively. The MA portions of MA-M had a LOH for loci on 22q12 in 28.6% (2/7) of cases, whereas each pure MA harbored one LOH on either chromosome 22q12 or 9p21. The proliferation indices of MA-Ms were significantly higher in the meningioma than in the MA components. Our data suggest that both the meningioma and the MA undergo the same overlapping clonal process, with the MA-M while undergoing additional genetic alterations that confer a greater proliferative potential. [ABSTRACT FROM AUTHOR]

Abdominal aortic aneurysm (AAA) is among a number of vascular disorders to be recently associated with a common allelic variant situated on chromosome 9p21. To further assess the significance of this region of the genome in AAA development, we genotyped the sequence variation tagged by rs10757278 in two geographically independent cohorts of patients and compared them to matched controls. We also assessed the impact of this variant on AAA growth rate in cohorts with a median surveillance period of 3.2 and 4.5 years. Using meta-analysis to combine the findings of both cohorts, we found a significant association between rs10757278-G and the presence of AAA (OR (95%CI) 1.38 (1.04–1.82) P=0.03), an effect size completely consistent with that originally reported. rs10757278 was not significantly associated with altered AAA growth rate in either cohort.European Journal of Human Genetics (2009) 17, 391–394; doi:10.1038/ejhg.2008.196; published online 15 October 2008 [ABSTRACT FROM AUTHOR]

Genome-wide single nucleotide polymorphism (SNP) association studies recently identified four SNPs (rs10757274, rs2383206, rs2383207, and rs10757278) on chromosome 9p21 that were associated with coronary artery disease (CAD) and myocardial infarction (MI) in Caucasian populations from northern Europe and North America. Our aim was to determine whether these SNPs were associated with MI in a southern Europe/Mediterranean population. We employed a case–control association design involving 416 MI patients and 308 non-MI controls from Italy. Significant allelic association was identified between all four SNPs and MI. The association remained significant after adjusting for covariates for MI ( P = 0.007–0.029). One risk haplotype (GGGG; P = 0.028) and one protective haplotype (AAAA; P = 0.047) were identified. Genotypic association analysis demonstrated that the SNPs conferred susceptibility to MI most likely in a dominant model ( P = 0.0007–0.013). When the case cohort was divided into a group of MI patients with a family history ( n = 248) and one group without it ( n = 168), the positive, significant association was identified only in the group with the family history. These results indicate that chromosome 9p21 confers risk for development of MI in an Italian population. [ABSTRACT FROM AUTHOR]

Homozygous deletions of the tumor suppressor gene p16INK4A and deficiency of methylthioadenosine phosphorylase (MTAP), both located on chromosome 9p21, have been independently reported in non-small cell lung cancer (NSCLC). To determine the frequency of co-deletion of these two genes, we investigated 50 samples of primary NSCLC using a quantitative PCR-ELISA. All specimens were fixed in formalin, paraffin embedded and stored until assayed. Histologic subtypes included 25 adenocarcinomas (50%), 21 squamous cell carcinomas (42%) and four large cell carcinomas (8%). Homozygous deletions of MTAP exon 8 could be detected in 19 of 50 NSCLC samples (38%). Adenocarcinoma (11 of 25, 44%) showed a higher deletion frequency than squamous cell carcinoma (six of 21, 29%). In contrast, homozygous p16INK4A deletions were detected in only nine of 50 (18%) samples using specific primers for p16INK4A exon 1α. No difference between the histological subtypes and p16INK4A deletion frequency was observed. We further investigated the ten samples with MTAP deletions but intact p16INK4A exon 1α with primers specific for p16INK4A exon 3, the exon nearest to MTAP exon 8. Interestingly, none of the ten samples had deletion of the p16INK4A exon 3 coding region. Fine mapping analysis performed in ten samples showed a frequent breakpoint between MTAP exon 4 and exon 5. In addition, p16 protein expression could not be detected in five out of six samples with intact p16 but deleted MTAP locus. These data show a high frequency of homozygous MTAP deletions in NSCLC which is associated with detectable co-deletion of p16INK4A in only half of the cases. This result suggests the existence either of another tumor suppressor gene telomeric of p16INK4A or of deletions involving 3′-untranslated (3′-UTR) regulatory regions of p16INK4A that can interfere with its expression or function. [ABSTRACT FROM AUTHOR]