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1.  The evolution of colorectal cancer genetics—Part 2: clinical implications and applications 
The genetic understanding of colorectal cancer (CRC) continues to grow, and it is now estimated that 10% of the population has a known hereditary CRC syndrome. This article will examine the evolving surgical and medical management of hereditary CRC syndromes, and the impact of tumor genetics on therapy. This review will focus on the most common hereditary CRC-prone diseases seen in clinical practice, which include Lynch syndrome (LS), familial adenomatous polyposis (FAP) & attenuated FAP (AFAP), MutYH-associated polyposis (MAP), and serrated polyposis syndrome (SPS). Each section will review the current recommendations in the evaluation and treatment of these syndromes, as well as review surgical management and operative planning. A highly detailed multigeneration cancer family history with verified genealogy and pathology documentation whenever possible, coupled with germline mutation testing when indicated, is critically important to management decisions. Although caring for patients with these syndromes remains complex, the application of this knowledge facilitates better treatment of both individuals and their affected family members for generations to come.
doi:10.3978/j.issn.2078-6891.2014.068
PMCID: PMC4173046  PMID: 25276406
Surgical oncologic management; medical oncologic management; hereditary colorectal cancer (hereditary CRC)
2.  The evolution of colorectal cancer genetics—Part 1: from discovery to practice 
Colorectal cancer (CRC) is an increasing burden on our society. Identifying those who are at the greatest risk and improving triage for treatment will have the greatest impact on healthcare. CRC is a prime paradigm for cancer genetics: the majority of disease results from stages of progression lending itself to prevention by early detection of the pre-disease (neoplastic) state. Approximately 10% represent well defined hereditary cancer syndromes. Hereditary CRC has the added benefit that many are slow growing and family members are armed with the knowledge of potential risk of associated carcinomas and empowerment to reduce the disease burden. This knowledge provides the indication for early endoscopic and/or surgical intervention for prevention or treatment of an entire family cohort. The molecular basis of CRC allows enhanced characterization of carcinomas, leading to targeted therapies.
doi:10.3978/j.issn.2078-6891.2014.069
PMCID: PMC4173047  PMID: 25276405
Colorectal cancer (CRC); genetics; prevention; CRC syndromes; Lynch syndrome (LS)
3.  Absence of Evidence for an Association Between Resistin Gene Variants and Insulin Resistance in an Asian Population with Low and High Blood Pressure 
Aims
Although the function of resistin in human biology is unclear, some evidence suggests resistin gene variants influence insulin resistance, and insulin resistance-related hypertension. We searched for associations between common resistin gene variants and factors related to insulin resistance in Asian individuals with high or low blood pressure.
Methods
Non-diabetic Chinese or Japanese sibling pairs were included if one had extreme hypertension and the other was either hypertensive or hypotensive. Four common, non-coding single nucleotide polymorphisms (SNPs) were identified by sequencing the resistin gene in 24 hypertensive probands. Generalized estimating equations-based regressions were then performed to test for SNP associations using the entire study population (n=1556).
Results
Of 72 tests, only one was significant at the 0.05 level; 3.5 significant tests were expected by chance alone. High variability in insulin and triglyceride levels created wide confidence intervals, thus the negative results are not conclusive for these phenotypes. However, the large sample size resulted in narrow confidence intervals for BMI, fasting and 120 minute post-load glucose, and high and low density lipoprotein cholesterol.
Conclusion
Factors associated with insulin resistance are not likely influenced by the resistin gene in non-diabetic Asian individuals with high and low blood pressure.
doi:10.1016/j.diabres.2008.04.001
PMCID: PMC4156032  PMID: 18501464
resistin; hypertension; Asian population; insulin resistance; single nucleotide polymorphisms
4.  Shorter Men Live Longer: Association of Height with Longevity and FOXO3 Genotype in American Men of Japanese Ancestry 
PLoS ONE  2014;9(5):e94385.
Objectives
To determine the relation between height, FOXO3 genotype and age of death in humans.
Methods
Observational study of 8,003 American men of Japanese ancestry from the Honolulu Heart Program/Honolulu-Asia Aging Study (HHP/HAAS), a genetically and culturally homogeneous cohort followed for over 40 years. A Cox regression model with age as the time scale, stratified by year of birth, was used to estimate the effect of baseline height on mortality during follow-up. An analysis of height and longevity-associated variants of the key regulatory gene in the insulin/IGF-1 signaling (IIS) pathway, FOXO3, was performed in a HHP-HAAS subpopulation. A study of fasting insulin level and height was conducted in another HHP-HAAS subpopulation.
Results
A positive association was found between baseline height and all-cause mortality (RR = 1.007; 95% CI 1.003–1.011; P = 0.002) over the follow-up period. Adjustments for possible confounding variables reduced this association only slightly (RR = 1.006; 95% CI 1.002–1.010; P = 0.007). In addition, height was positively associated with all cancer mortality and mortality from cancer unrelated to smoking. A Cox regression model with time-dependent covariates showed that relative risk for baseline height on mortality increased as the population aged. Comparison of genotypes of a longevity-associated single nucleotide polymorphism in FOXO3 showed that the longevity allele was inversely associated with height. This finding was consistent with prior findings in model organisms of aging. Height was also positively associated with fasting blood insulin level, a risk factor for mortality. Regression analysis of fasting insulin level (mIU/L) on height (cm) adjusting for the age both data were collected yielded a regression coefficient of 0.26 (95% CI 0.10–0.42; P = 0.001).
Conclusion
Height in mid-life is positively associated with mortality, with shorter stature predicting longer lifespan. Height was, moreover, associated with fasting insulin level and the longevity genotype of FOXO3, consistent with a mechanistic role for the IIS pathway.
doi:10.1371/journal.pone.0094385
PMCID: PMC4013008  PMID: 24804734
5.  FOXO3 Gene Variants and Human Aging: Coding Variants May Not Be Key Players 
FOXO3 is generally recognized as a “master” gene in aging since its association with longevity has been replicated in multiple organisms and human populations. A group of single nucleotide polymorphisms in linkage disequilibrium with a coding region has been associated with human longevity, but the actual functional variant is unidentified. Therefore, we sequenced the coding region in our long-lived Japanese American population in order to enhance resources for fine mapping this region. We demonstrate that of 38 published variants, 6 are misalignments with homologous nonallelic sequences from FOXO3B (ZNF286B), a pseudogene on a different chromosome; 2 are attributable to ZNF286B only, and the remaining 30 were unconfirmed, indicating that they are very rare and not likely involved in longevity. Furthermore, we identified a novel, unique, nonsynonymous coding variant in exon 3 (Gly566Ala; rs138174682) that is prevalent in multiple ethnic groups but appeared too rare for major longevity effects in our study populations.
doi:10.1093/gerona/gls067
PMCID: PMC3668389  PMID: 22459618
Aging; FOXO3; Genetic; Human longevity
6.  Common ALDH2 genetic variants predict development of hypertension in the SAPPHIRe prospective cohort: Gene-environmental interaction with alcohol consumption 
Background
Genetic variants near/within the ALDH2 gene encoding the mitochondrial aldehyde dehydrogenase 2 have been associated with blood pressure and hypertension in several case–control association studies in East Asian populations.
Methods
Three common tag single nucleotide polymorphisms (tagSNP) in the ALDH2 gene were genotyped in 1,134 subjects of Chinese origin from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family cohort. We examined whether the ALDH2 SNP genotypes predicted the development of hypertension in the prospective SAPPHIRe cohort.
Results
Over an average follow-up period of 5.7 years, carriers homozygous for the rs2238152 T allele in the ALDH2 gene were more likely to progress to hypertension than were non-carriers (hazard ratio [HR], 2.88, 95% confidence interval [CI], 1.06-7.84, P = 0.03), corresponding to a population attributable risk of ~7.1%. The risk associated with the rs2238152 T allele were strongest in heavy/moderate alcohol drinkers and was reduced in non-drinkers, indicating an interaction between ALDH2 genetic variants and alcohol intake on the risk of hypertension (P for interaction = 0.04). The risk allele was associated with significantly lower ALDH2 gene expression levels in human adipose tissue.
Conclusion
ALDH2 genetic variants were associated with progression to hypertension in a prospective Chinese cohort. The association was modified by alcohol consumption.
doi:10.1186/1471-2261-12-58
PMCID: PMC3476438  PMID: 22839215
ALDH2; Hypertension; SNP; Chinese

Results 1-6 (6)