Comparison of Exact Methods for Analyzing Family-Based Samples

Family-based association tests are used to identify genes that increase the risk of developing a disease, while controlling for spurious associations caused by population structure. The exact family-based association test, exact FBAT, is a unified approach which can be app lied to tests of different genetic models, sampling designs, null hypotheses , and missing parental information. The purpose of this report is to compare the power of the exact FBAT with two other tests, exact conditional logistic regression (CLR) and the exact trend test for clustered data (QEM). Pedigrees of sibships were simulated based upon a variety of different parameters, and then the test statistic was calculated for each. Examining the power for each test, we find that QE 1 is clearly the most powerful test among the three in detecting linkage among data from sampled sibships. The difference in power among exact FBAT and exact CLR is small, with exact CLR demonstrating a slight advantage over exact FBAT. While the relative differences in power is substantial for small sample size8, the gaps shrink as the number of families increases

Genetic Variation in Selenoprotein Genes, Lifestyle, and Risk of Colon and Rectal Cancer

BACKGROUND: Associations between selenium and cancer have directed attention to role of selenoproteins in the carcinogenic process. METHODS: We used data from two population-based case-control studies of colon (n = 1555 cases, 1956 controls) and rectal (n = 754 cases, 959 controls) cancer. We evaluated the association between genetic variation in TXNRD1, TXNRD2, TXNRD3, C11orf31 (SelH), SelW, SelN1, SelS, SepX, and SeP15 with colorectal cancer risk. RESULTS: After adjustment for multiple comparisons, several associations were observed. Two SNPs in TXNRD3 were associated with rectal cancer (rs11718498 dominant OR 1.42 95% CI 1.16,1.74 pACT 0.0036 and rs9637365 recessive 0.70 95% CI 0.55,0.90 pACT 0.0208). Four SNPs in SepN1 were associated with rectal cancer (rs11247735 recessive OR 1.30 95% CI 1.04,1.63 pACT 0.0410; rs2072749 GGvsAA OR 0.53 95% CI 0.36,0.80 pACT 0.0159; rs4659382 recessive OR 0.58 95% CI 0.39,0.86 pACT 0.0247; rs718391 dominant OR 0.76 95% CI 0.62,0.94 pACT 0.0300). Interaction between these genes and exposures that could influence these genes showed numerous significant associations after adjustment for multiple comparisons. Two SNPs in TXNRD1 and four SNPs in TXNRD2 interacted with aspirin/NSAID to influence colon cancer; one SNP in TXNRD1, two SNPs in TXNRD2, and one SNP in TXNRD3 interacted with aspirin/NSAIDs to influence rectal cancer. Five SNPs in TXNRD2 and one in SelS, SeP15, and SelW1 interacted with estrogen to modify colon cancer risk; one SNP in SelW1 interacted with estrogen to alter rectal cancer risk. Several SNPs in this candidate pathway influenced survival after diagnosis with colon cancer (SeP15 and SepX1 increased HRR) and rectal cancer (SepX1 increased HRR). CONCLUSIONS: Findings support an association between selenoprotein genes and colon and rectal cancer development and survival after diagnosis. Given the interactions observed, it is likely that the impact of cancer susceptibility from genotype is modified by lifestyle

The influence of the CHIEF pathway on colorectal cancer-specific mortality.

Many components of the CHIEF (Convergence of Hormones, Inflammation, and Energy Related Factors) pathway could influence survival given their involvement in cell growth, apoptosis, angiogenesis, and tumor invasion stimulation. We used ARTP (Adaptive Rank Truncation Product) to test if genes in the pathway were associated with colorectal cancer-specific mortality. Colon cancer (n = 1555) and rectal cancer (n = 754) cases were followed over five years. Age, center, stage at diagnosis, and tumor molecular phenotype were considered when calculating ARTP p values. A polygenic risk score was used to summarize the magnitude of risk associated with this pathway. The JAK/STAT/SOC was significant for colon cancer survival (PARTP = 0.035). Fifteen genes (DUSP2, INFGR1, IL6, IRF2, JAK2, MAP3K10, MMP1, NFkB1A, NOS2A, PIK3CA, SEPX1, SMAD3, TLR2, TYK2, and VDR) were associated with colon cancer mortality (PARTP < 0.05); JAK2 (PARTP  = 0.0086), PIK3CA (PARTP = 0.0098), and SMAD3 (PARTP = 0.0059) had the strongest associations. Over 40 SNPs were significantly associated with survival within the 15 significant genes (PARTP < 0.05). SMAD3 had the strongest association with survival (HRGG 2.46 95% CI 1.44,4.21 PTtrnd = 0.0002). Seven genes (IL2RA, IL8RA, IL8RB, IRF2, RAF1, RUNX3, and SEPX1) were significantly associated with rectal cancer (PARTP < 0.05). The HR for colorectal cancer-specific mortality among colon cancer cases in the upper at-risk alleles group was 11.81 (95% CI 7.07, 19. 74) and was 10.99 (95% CI 5.30, 22.78) for rectal cancer. These results suggest that several genes in the CHIEF pathway are important for colorectal cancer survival; the risk associated with the pathway merits validation in other studies

Polygenic summary score associated with CHIEF pathway for colorectal cancer survival.

<p>¹SNPs included in score: <i>BMP2</i> rs1979855, rs3178250, <i>BMPR1A</i> rs7895217, rs10887668, <i>BMPR1B</i> rs10049681, rs4699673, rs12508087, rs9307147, rs4490463, rs2120834, <i>DUSP2</i> rs1724120, EIF4EBP3 rs250425, <i>IFNGR1</i> rs3799488, rs9376267, rs1327474, <i>IGF1</i>, <i>IKBKB</i> rs5029748, rs10958713, <i>IL1B</i> rs1143627, rs1143623, <i>IL6</i> rs1800796, <i>IRF2</i> rs6856910, rs793777, rs2797507, rs12504466, rs793814, rs7655800, rs9684244, rs13139310, rs13116389, rs793801, rs3775582, <i>IRF8</i> rs305083, rs305080, rs11649318, rs13338943, rs10514611, rs1044873, <i>JAK2</i> rs1887429, rs7043371, rs10974947, rs3780379, rs10815160, <i>JUNB</i> rs2229510, <i>MAP3K10</i> rs1129156, <i>MMP1</i> rs470215, <i>MMP3</i> rs3025066, <i>NFKBIA</i> rs696, rs2233409, rs3138053, <i>NOS2A</i> rs7406657, rs2297516, <i>PIK3CA</i> rs2699905, rs7640662, rs2677760, rs1607237, <i>RPS6KA2</i> rs2049956, rs1894660, rs6918886, rs932356, rs9459715, rs1883361, rs4710090, rs661325, rs2345067, rs2072638, rs1309150, rs7745781, <i>SEP15</i> rs9433110, <i>SEPX1</i> rs732510, <i>SMAD3</i> rs1498506, rs9972423, rs2118611, rs11071933, rs7163381, rs4776892, rs2414937, rs745103, rs893473, rs1866317, rs4601989, rs11639295, rs12708492, <i>SOCS1</i> rs4780355, <i>STAT3</i> rs1053005, rs2293152, rs8069645, <i>STAT5A</i> rs12601982, <i>TLR2</i> rs5743704, rs5743708, <i>TYK2</i> rs12720356, rs280521, rs280523, <i>VDR</i>_Fok1, <i>VDR</i>_Poly. 2SNPs included in score: <i>BMP1</i> rs12114940, rs3924229, rs3857979, <i>BMPR1A</i> rs7088641, rs2168730, rs7895217, rs4934275, <i>ESR2</i>_Rsa, <i>IL1A</i> rs3783546, <i>IL2RA</i> rs2386841, rs7072398, rs11256456, rs11256457, rs6602398, rs11256497, rs791587, rs10905669, rs2476491, rs2256774, rs706779, rs706778, rs3118470, <i>IL3</i> rs181781, <i>IL8RA</i> rs1008563, rs1008562, rs16858811, <i>IL8RB</i> rs1126579, <i>IRF2</i> rs809909, rs10009261, rs1425551, rs807684, rs3756094, <i>PRKAG2</i> rs1541538, rs2536082, rs6947064, rs7805747, rs1860743, rs10278273, rs7801616, rs7784818, rs3934597, <i>RAF1</i> rs3729931, rs9809501, rs11923427, rs4684871, rs904453, <i>RUNX3</i> rs7517302, rs2135756, <i>SEPX1</i> rs13331553, rs732510, <i>SOCS1</i> rs193779, <i>STK11</i> rs8111699, rs741765, <i>TSC2</i> rs2074968.</p

Overall pathway P_ARTP¹.

1<p>Adjusted for age, study center, race/ethnicity, sex, AJCC stage, and tumor markers: CIMP, <i>KRAS</i>, <i>TP53</i>; MSI for colon only. ARTP p values based on 10,000 permutations.</p><p>Overall pathway P_ARTP^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116169#nt104" target="_blank">1</a>}.</p

Genes and related SNPs associated with colorectal cancer-specific mortality among patients diagnosed with colon cancer (gene P_ARTP≤0.05; SNP P_trend≤0.10).

1<p>Hazard Ratio (HR) and 95% Confidence Intervals (CI) adjusted for age, study center, race/ethnicity, sex, AJCC stage, and tumor molecular phenotype: MSI, CIMP, <i>KRAS</i>, and <i>TP53</i>. P_ARTP based on 10,000 permutations.</p><p>Genes and related SNPs associated with colorectal cancer-specific mortality among patients diagnosed with colon cancer (gene P_ARTP≤0.05; SNP P_trend≤0.10).</p

Description of study population.

1<p>Includes cases lost to follow-up within five years of diagnosis.</p>2<p>Excludes cases lost to follow-up within five years of diagnosis.</p>3<p>Time from diagnosis to death or last follow-up.</p><p>Description of study population.</p

IJMEG1205002a

Abstract: Background: Telomeres cap the ends of chromosomes and help maintain genomic stability and integrity. Telomere length (TL) has been linked to a number of diseases, including a variety of cancers; however, the association between TL and risk for colorectal cancer is unclear. Methods: We investigate the association between genetic, diet, and lifestyle factors and TL and the association between TL and colorectal cancer using data from a populationbased case-control study of colon (249 cases and 371 controls) and rectal cancer (276 cases and 372 controls) conducted in Utah. DNA samples came from immortalized cell lines for colon cancer and directly from whole blood for rectal cancer. We genotyped 11 single nucleotide polymorphisms in five genes associated with telomeres, TERT, MEN1, MRE11A, RECQL5, and TNKS. Results: TL was measured using quantitative PCR. TERT rs2853676 (p=0.044) and RECQL5 rs820152 (p=0.001) were associated with TL at &lt;0.05 level of significance. After adjusting for age and sex, BMI and cigarette smoking were significantly inversely associated with TL among controls. Use of aspirin/NSAIDs interacted significantly with TERT rs10069690 and rs2242652 to alter TL. Longer TL was significantly associated with reduced colon cancer risk after adjusting for age and sex (OR = 0.94 95% confidence intervals 0.89-0.99 per decile of TL). Further adjustment for BMI and cigarette smoking attenuated the association so that it was no longer significant. Conclusions: In summary several genetic and lifestyle factors were observed to influence TL. These factors also appear to confound associations between TL and colon cancer