SummaryThe search for longevity-determining genes in human has largely neglected the operation of genetic interactions. We have identified a novel combination of common variants of three genes that has a marked association with human lifespan and healthy aging. Subjects were recruited and stratified according to their genetically inferred ethnic affiliation to account for population structure. Haplotype analysis was performed in three candidate genes, and the haplotype combinations were tested for association with exceptional longevity. An HRAS1 haplotype enhanced the effect of an APOE haplotype on exceptional survival, and a LASS1 haplotype further augmented its magnitude. These results were replicated in a second population. A profile of healthy aging was developed using a deficit accumulation index, which showed that this combination of gene variants is associated with healthy aging. The variation in LASS1 is functional, causing enhanced expression of the gene, and it contributes to healthy aging and greater survival in the tenth decade of life. Thus, rare gene variants need not be invoked to explain complex traits such as aging; instead rare congruence of common gene variants readily fulfills this role. The interaction between the three genes described here suggests new models for cellular and molecular mechanisms underlying exceptional survival and healthy aging that involve lipotoxicity.

Licensed human papillomavirus (HPV) vaccines are expected to prevent high‐risk (hr) HPV‐infections (most notably types 16 and 18). Whether HPV vaccination will change the distribution of hrHPVs at the population level is open, since competition between HPV types is not well understood. Two stratified random subcohorts (1983–1997 and 1995–2003) of 7,815 and 3,252 women with a minimum of 2 pregnancies (<32 years) were selected from the Finnish Maternity Cohort. Using ELISA based on virus‐like particles (VLP), we determined antibodies to HPV11, 16, 18 and 31 in paired sera of the women and used Poisson regression models to estimate the risk of further infection with other HPV types in those positive for HPV16 or HPV18 at baseline. Baseline HPV16 seropositivity was associated with increased risk of later infections with HPV18 (3.1, 95% CI: 1.7, 5.6). HPV18 seropositivity was associated with increased risk of HPV16 (3.9, 95% CI: 2.5, 6.1). Our observations favor a coinfection rather than superinfection model for the different HPV types and are not suggestive for type‐replacement following HPV vaccination. © 2009 UICC

BACKGROUND The authors examined subsite‐specific and histology‐specific esophageal and gastric carcinoma incidence patterns among the Asians/Pacific Islander (API) population in the United States and compared them with those among whites and blacks. METHODS Data on newly diagnosed esophageal and gastric carcinomas during 1996–2000 were obtained from 24 population‐based central cancer registries, representing approximately 80% of the API population in the United States. Age‐adjusted rates, using the 2000 United States standard population, and age‐specific rates were computed by anatomic subsite, histology, race, and gender. The difference in the age‐adjusted rates between APIs and other races were examined using the two‐tailed z statistic. RESULTS Greater than 75% of esophageal carcinomas among APIs, both males and females, were squamous cell carcinoma. Adenocarcinoma accounted for < 20% of all esophageal carcinomas. This pattern was similar to that among blacks but was completely opposite to that among whites. The rate of esophageal squamous cell carcinoma was 81% higher among API males compared with white males, but it was 64% less compared with black males. The rates of esophageal adenocarcinoma were significantly lower among APIs than among both whites and blacks both males and females. The majority of gastric carcinomas among APIs were noncardia adenocarcinoma, whereas cardia adenocarcinoma accounted for only 11% of gastric carcinomas among API males and 6% of gastric carcinomas among API females. The age‐adjusted incidence rate of cardia adenocarcinoma was 23% lower among API males compared with white males, but it was 26% higher compared with black males. In contrast, the rates of noncardia adenocarcinoma among APIs were approximately 3.7 times the rate among whites for both males and females and 33% higher than the rate among blacks. CONCLUSIONS Subsite‐specific and histology‐specific incidence patterns of esophagogastric carcinoma among APIs differ from those among whites and blacks. The reasons for significantly higher rates of noncardia adenocarcinoma among APIs compared with whites and blacks need further investigation. Cancer 2006. © 2005 American Cancer Society.

Prostate cancer (PCa) is one of the most common cancers in the world. Inflammation has been described as a risk factor for PCa and depends on the production of cytokines in response to tissue damage or the presence of stimuli that induces cellular stress. Interindividual variation in cytokine production is partially controlled by single-nucleotide polymorphisms (SNPs) that have been associated with differential production of cytokines. We have recently showed that SNP-SNP interactions of cytokine genes are associated with PCa risk. However, little is known about the association of cytokine SNPs and PCa aggressiveness. In this study, we evaluated the association of 15 SNPs in five cytokine genes and aggressiveness of PCa in African- and Caucasian-American individuals. Caucasian Americans with the genotypes IL10-1082GG or IL1B+3954TT had 2.31-fold [95% confidence interval (CI) = 1.13-4.72] and 3.11 (95% CI = 1.20-8.06)-fold risk, respectively, of developing aggressive PCa, as compared with individuals without those genotypes. We did not find any associations in the African-American group. Using Multivariate Adaptive Regression Splines modeling for exploratory SNP-SNP interactions, our results showed that more aggressive PCa in Caucasians Americans is associated with the CT genotype at IL8-47 [odds ratios (OR) = 3.50; 95% CI = 1.13-10.88] or combined genotypes of IL1B-511CC and IL10-1082GG (OR = 3.38; 95% CI = 1.70-6.71). Unfortunately, the same analysis could not be performed in the African-Americans due to limited number of individuals. With limited sample size, the results from this study suggest that SNPs in cytokine genes may be associated with PCa aggressiveness. More extensive studies are warranted to validate our findings.