The global endemic of cardiovascular diseases calls for improved risk assessment and treatment. Here, we describe an association between myocardial infarction (MI) and a common sequence variant on ...chromosome 9p21. This study included a total of 4587 cases and 12,767 controls. The identified variant, adjacent to the tumor suppressor genes CDKN2A and CDKN2B, was associated with the disease with high significance. Approximately 21% of individuals in the population are homozygous for this variant, and their estimated risk of suffering myocardial infarction is 1.64 times as great as that of noncarriers. The corresponding risk is 2.02 times as great for early-onset cases. The population attributable risk is 21% for MI in general and 31% for early-onset cases.
Familial clustering studies indicate that breast cancer risk has a substantial genetic component. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 ...Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then tested selected SNPs in five replication sample sets. Overall, we studied 4,554 affected individuals and 17,577 controls. Two SNPs consistently associated with breast cancer: ∼25% of individuals of European descent are homozygous for allele A of rs13387042 on chromosome 2q35 and have an estimated 1.44-fold greater risk than noncarriers, and for allele T of rs3803662 on 16q12, about 7% are homozygous and have a 1.64-fold greater risk. Risk from both alleles was confined to estrogen receptor-positive tumors. At present, no genes have been identified in the linkage disequilibrium block containing rs13387042. rs3803662 is near the 5′ end of
TNRC9
, a high mobility group chromatin-associated protein whose expression is implicated in breast cancer metastasis to bone.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of ...80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left-right asymmetry of the heart.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Prostate cancer is the most prevalent noncutaneous cancer in males in developed regions, with African American men having among the highest worldwide incidence and mortality rates. Here we report a ...second genetic variant in the 8q24 region that, in conjunction with another variant we recently discovered, accounts for about 11%-13% of prostate cancer cases in individuals of European descent and 31% of cases in African Americans. We made the current discovery through a genome-wide association scan of 1,453 affected Icelandic individuals and 3,064 controls using the Illumina HumanHap300 BeadChip followed by four replication studies. A key step in the discovery was the construction of a 14-SNP haplotype that efficiently tags a relatively uncommon (2%-4%) susceptibility variant in individuals of European descent that happens to be very common (∼42%) in African Americans. The newly identified variant shows a stronger association with affected individuals who have an earlier age at diagnosis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The investigators, recognizing that coronary artery disease (CAD), including acute myocardial infarction (MI), is the leading cause of death worldwide, carried out a genome-wide associational study ...on Icelandic patients with MI. Initially more than 300,000 single nucleotide polymorphisms (SNPs) were examined for any association with MI. Ultimately, the study enrolled 4587 cases and 12,769 controls. The strongest association with MI was noted with 3 correlated SNPs, all located within a 190-kb linkage disequilibrium block on chromosome 9p21. The association with MI was replicated in case-control sample sets of persons of European descent from 3 US cities. The identified variant was adjacent to the tumor suppressor genes CDKN2A and CDKN2B. It was associated with MI at a high level of significance (P = 1.2 × 10). The proteins encoded by these genes have a key role in regulating cell proliferation, cell senescence, and apoptosis—all important features of atherogenesis.Approximately 21% of individuals in the study population are homozygous for the variant, and it is estimated that their risk of having MI is 1.64-fold greater than for noncarriers. The risk is 2.02-fold greater for early-onset cases. The population-attributable risk was estimated as 21% for MI in general and 31% for early-onset cases. This is the first common variant found to consistently confer a substantial risk of MI, defined as an odds ratio exceeding 1.20, in multiple case-control groups of European descent. The variant poses a substantial risk from a public health viewpoint, but it explains only a small part of familial clustering of the disease and would not yield high linkage scores. The implication is that other susceptibility variants are as yet unidentified. In addition to MI, there is reason to believe that the present variant might increase the risk of CAD in general. Just how genetic variants influence the pathogenesis of MI remains to be clarified.
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