A Whole-Genome SNP Association Study of NCI60 Cell Line Panel Indicates a Role of Ca2+ Signaling in Selenium Resistance

Epidemiological studies have suggested an association between selenium intake and protection from a variety of cancer. Considering this clinical importance of selenium, we aimed to identify the genes associated with resistance to selenium treatment. We have applied a previous methodology developed by our group, which is based on the genetic and pharmacological data publicly available for the NCI60 cancer cell line panel. In short, we have categorized the NCI60 cell lines as selenium resistant and sensitive based on their growth inhibition (GI50) data. Then, we have utilized the Affymetrix 125K SNP chip data available and carried out a genome-wide case-control association study for the selenium sensitive and resistant NCI60 cell lines. Our results showed statistically significant association of four SNPs in 5q33–34, 10q11.2, 10q22.3 and 14q13.1 with selenium resistance. These SNPs were located in introns of the genes encoding for a kinase-scaffolding protein (AKAP6), a membrane protein (SGCD), a channel protein (KCNMA1), and a protein kinase (PRKG1). The knock-down of KCNMA1 by siRNA showed increased sensitivity to selenium in both LNCaP and PC3 cell lines. Furthermore, SNP-SNP interaction (epistasis) analysis indicated the interactions of the SNPs in AKAP6 with SGCD as well as SNPs in AKAP6 with KCNMA1 with each other, assuming additive genetic model. These genes were also all involved in the Ca2+ signaling, which has a direct role in induction of apoptosis and induction of apoptosis in tumor cells is consistent with the chemopreventive action of selenium. Once our findings are further validated, this knowledge can be translated into clinics where individuals who can benefit from the chemopreventive characteristics of the selenium supplementation will be easily identified using a simple DNA analysis

Polymorphisms in the selectin gene cluster are associated with fertility and survival time in a population of Holstein Friesian cows

Selectins are adhesion molecules, which mediate attachment between leucocytes and endothelium. They aid extravasation of leucocytes from blood into inflamed tissue during the mammary gland’s response to infection. Selectins are also involved in attachment of the conceptus to the endometrium and subsequent placental development. Poor fertility and udder health are major causes for culling dairy cows. The three identified bovine selectin genes SELP, SELL and SELE are located in a gene cluster. SELP is the most polymorphic of these genes. Several SNP in SELP and SELE are associated with human vascular disease, while SELP SNP rs6127 has been associated with recurrent pregnancy loss in women. This study describes the results of a gene association study for SNP in SELP (n = 5), SELL (n = 2) and SELE (n = 1) with fertility, milk production and longevity traits in a population of 337 Holstein Friesian dairy cows. Blood samples for PCR-RFLP were collected at 6 months of age and animals were monitored until either culling or 2,340 days from birth. Three SNP in SELPEx4-6 formed a haplotype block containing a Glu/Ala substitution at rs42312260. This region was associated with poor fertility and reduced survival times. SELPEx8 (rs378218397) coded for a Val475Met variant locus in the linking region between consensus repeats 4 and 5, which may influence glycosylation. The synonymous SNP rs110045112 in SELEEx14 deviated from Hardy Weinberg equilibrium. For both this SNP and rs378218397 there were too few AA homozygotes present in the population and AG heterozygotes had significantly worse fertility than GG homozygotes. Small changes in milk production associated with some SNP could not account for the reduced fertility and only SELPEx6 showed any association with somatic cell count. These results suggest that polymorphisms in SELP and SELE are associated with the likelihood of successful pregnancy, potentially through compromised implantation and placental development

Influences of diet during gestation on potential postpartum reproductive performance and milk production of beef heifers

The influences of nutritional protein and energy during early and mid pregnancy on milk production and postpartum reproductive parameters were determined in 70 beef heifers of two composite breeds (Bos indicus X Bos taurus). At artificial insemination (AI), heifers were divided into four dietary treatment groups identified by the level of protein, and to a lesser extent energy, fed during the first and second trimesters: high/high (HH), high/low (HL), low/high (LH), and low/low (LL). Milk production was lower in the heifers receiving high treatment in first trimester than that in heifers receiving the low treatment (P = 0.01). Milk production was negatively associated with dam body condition score (BCS; P = 0.01), nonesterified fatty acids (P = 0.001), and leptin (P = 0.02) and positively associated with urea (P < 0.001) concentrations during lactation. Increased dietary protein in the first trimester increased or decreased concentrations of colostral protein dependent upon genotype (P = 0.03). Colostral protein was positively associated with bovine pregnancy associated glycoprotein from late gestation (P = 0.007). Milk fat was negatively associated with BCS (P = 0.007) and influenced by genotype (P = 0.003). Dietary treatment did not affect the postpartum reproductive performance of beef heifers. Gestation length (P < 0.001) and the postpartum interval to first estrus (PPI; P = 0.02) were positively associated with calf size. Placental size was negatively associated with placental expulsion time (P < 0.01). Prepartum BCS of the heifers was negatively associated with PPI (P = 0.01). Overall, high levels of nutrition during early gestation are detrimental to milk production in beef heifers

Nutrient intake in the bovine during early and mid-gestation causes sex-specific changes in progeny plasma IGF-I, liveweight, height and carcass traits

Fetal and postnatal growth are mediated by insulin-like growth factors (IGFs) and their binding proteins (IGFBPs). Maternal nutrient intake during gestation can program the postnatal IGF-axis. This may have significant economic implications for beef cattle production. We investigated the effect of high (H=240%) and low (L=70%) levels of recommended daily crude protein (CP) intake for heifers during the first and second trimesters of gestation in a two-by-two factorial design on progeny (n=68) plasma IGF-I, IGF-II, total IGFBP (tIGFBP), postnatal growth and carcass traits. Calves were heavier at birth following high CP diets during the second trimester (P=0.03) and this persisted to 29d. Plasma IGF-I concentrations of males were greater for HL compared to LL (P0.04) from 29 to 657d, and for LH compared to LL from 29 until 379d (P=0.02). Exposure to low CP diets during the first trimester resulted in heavier males from 191d onwards (P=0.04) but a tendency for lighter females from 552d onwards (P=0.07) that had lighter carcass weights (P=0.04). Longissimus dorsi cross-sectional area of all carcasses was greater following exposure to low CP diets during the second trimester (P=0.04). Heifer nutrient intake during the first and second trimesters causes persistent and sex-specific programming of progeny plasma IGF-I, postnatal liveweight and carcass weight. Refining heifer nutritional programs during early gestation may optimize production objectives in progeny.G.C. Micke, T.M. Sullivan, K.L. Gatford, J.A. Owens and V.E.A. Perr