Evidence for two independent prostate cancer risk-associated loci in the HNF1B gene at 17q12

We carried out a fine-mapping study in the HNF1B gene at 17q12 in two study populations and identified a second locus associated with prostate cancer risk, approximately 26 kb centromeric to the first known locus (rs4430796); these loci are separated by a recombination hot spot. We confirmed the association with a SNP in the second locus (rs11649743) in five additional populations, with P = 1.7 x 10(-9) for an allelic test of the seven studies combined. The association at each SNP remained significant after adjustment for the other SNP.     

Millennial-scale trends in west Pacific warm pool hydrology since the Last Glacial Maximum

Models and palaeoclimate data suggest that the tropical Pacific climate system plays a key part in the mechanisms underlying orbital-scale and abrupt climate change. Atmospheric convection over the western tropical Pacific is a major source of heat and moisture to extratropical regions, and may therefore influence the global climate response to a variety of forcing factors. The response of tropical Pacific convection to changes in global climate boundary conditions, abrupt climate changes and radiative forcing remains uncertain, however. Here we present three absolutely dated oxygen isotope records from stalagmites in northern Borneo that reflect changes in west Pacific warm pool hydrology over the past 27,000 years. Our results suggest that convection over the western tropical Pacific weakened 18,000-20,000 years ago, as tropical Pacific and Antarctic temperatures began to rise during the early stages of deglaciation. Convective activity, as inferred from oxygen isotopes, reached a minimum during Heinrich event 1 (ref. 10), when the Atlantic meridional overturning circulation was weak, pointing to feedbacks between the strength of the overturning circulation and tropical Pacific hydrology. There is no evidence of the Younger Dryas event in the stalagmite records, however, suggesting that different mechanisms operated during these two abrupt deglacial climate events. During the Holocene epoch, convective activity appears to track changes in spring and autumn insolation, highlighting the sensitivity of tropical Pacific convection to external radiative forcing. Together, these findings demonstrate that the tropical Pacific hydrological cycle is sensitive to high-latitude climate processes in both hemispheres, as well as to external radiative forcing, and that it may have a central role in abrupt climate change events.     

Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk

Deletions on human chromosome 8p22-23 in prostate cancer cells and linkage studies in families affected with hereditary prostate cancer (HPC) have implicated this region in the development of prostate cancer. The macrophage scavenger receptor 1 gene (MSR1, also known as SR-A) is located at 8p22 and functions in several processes proposed to be relevant to prostate carcinogenesis. Here we report the results of genetic analyses that indicate that mutations in MSR1 may be associated with risk of prostate cancer. Among families affected with HPC, we identified six rare missense mutations and one nonsense mutation in MSR1. A family-based linkage and association test indicated that these mutations co-segregate with prostate cancer (P = 0.0007). In addition, among men of European descent, MSR1 mutations were detected in 4.4% of individuals affected with non-HPC as compared with 0.8% of unaffected men (P = 0.009). Among African American men, these values were 12.5% and 1.8%, respectively (P = 0.01). These results show that MSR1 may be important in susceptibility to prostate cancer in men of both African American and European descent.     

Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24

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 (approximately 42%) in African Americans. The newly identified variant shows a stronger association with affected individuals who have an earlier age at diagnosis.