A genome-wide association study of essential hypertension in an Australian population using a DNA pooling approach.

Despite the success of genome-wide association studies (GWAS) in detecting genetic loci involved in complex traits, few susceptibility genes have been detected for essential hypertension (EH). We aimed to use pooled DNA GWAS approach to identify and validate novel genomic loci underlying EH susceptibility in an Australian case-control population. Blood samples and questionnaires detailing medical history, blood pressure, and prescribed medications were collected for 409 hypertensives and 409 age-, sex- and ethnicity-matched normotensive controls. Case and control DNA were pooled in quadruplicate and hybridized to Illumina 1 M-Duo arrays. Allele frequencies agreed with those reported in reference data and known EH association signals were represented in the top-ranked SNPs more frequently than expected by chance. Validation showed that pooled DNA GWAS gave reliable estimates of case and control allele frequencies. Although no markers reached Bonferroni-corrected genome-wide significance levels (5.0 × 10-8), the top marker rs34870220 near ASGR1 approached significance (p = 4.32 × 10-7), as did several candidate loci (p < 1 × 10-6) on chromosomes 2, 4, 6, 9, 12, and 17. Four markers (located in or near genes NHSL1, NKFB1, GLI2, and LRRC10) from the top ten ranked SNPs were individually genotyped in pool samples and were tested for association between cases and controls using the χ 2 test. Of these, rs1599961 (NFKB1) and rs12711538 (GLI2) showed significant difference between cases and controls (p < 0.01). Additionally, four top-ranking markers within NFKB1 were found to be in LD, suggesting a single strong association signal for this gene.

Evaluation of a 7-Gene Genetic Profile for Athletic Endurance Phenotype in Ironman Championship Triathletes.

Polygenic profiling has been proposed for elite endurance performance, using an additive model determining the proportion of optimal alleles in endurance athletes. To investigate this model's utility for elite triathletes, we genotyped seven polymorphisms previously associated with an endurance polygenic profile (ACE Ins/Del, ACTN3 Arg577Ter, AMPD1 Gln12Ter, CKMM 1170bp/985+185bp, HFE His63Asp, GDF8 Lys153Arg and PPARGC1A Gly482Ser) in a cohort of 196 elite athletes who participated in the 2008 Kona Ironman championship triathlon. Mean performance time (PT) was not significantly different in individual marker analysis. Age, sex, and continent of origin had a significant influence on PT and were adjusted for. Only the AMPD1 endurance-optimal Gln allele was found to be significantly associated with an improvement in PT (model p = 5.79 x 10-17, AMPD1 genotype p = 0.01). Individual genotypes were combined into a total genotype score (TGS); TGS distribution ranged from 28.6 to 92.9, concordant with prior studies in endurance athletes (mean±SD: 60.75±12.95). TGS distribution was shifted toward higher TGS in the top 10% of athletes, though the mean TGS was not significantly different (p = 0.164) and not significantly associated with PT even when adjusted for age, sex, and origin. Receiver operating characteristic curve analysis determined that TGS alone could not significantly predict athlete finishing time with discriminating sensitivity and specificity for three outcomes (less than median PT, less than mean PT, or in the top 10%), though models with the age, sex, continent of origin, and either TGS or AMPD1 genotype could. These results suggest three things: that more sophisticated genetic models may be necessary to accurately predict athlete finishing time in endurance events; that non-genetic factors such as training are hugely influential and should be included in genetic analyses to prevent confounding; and that large collaborations may be necessary to obtain sufficient sample sizes for powerful and complex analyses of endurance performance.

The genetics of endurance: frequency of the ACTN3 R577X variant in Ironman World Championship athletes.

OBJECTIVES: To investigate the frequency of the ACTN3 R577X polymorphism in elite endurance triathletes, and whether ACTN3 R577X is significantly associated with performance time. DESIGN: Cross-sectional study. METHODS: Saliva samples, questionnaires, and performance times were collected for 196 elite endurance athletes who participated in the 2008 Kona Ironman championship triathlon. Athletes were of predominantly North American, European, and Australian origin. A one-way analysis of variance was conducted to compare performance times between genotype groups. Multiple linear regression analysis was performed to model the effect of questionnaire variables and genotype on performance time. Genotype and allele frequencies were compared to results from different populations using the chi-square test. RESULTS: Performance time did not significantly differ between genotype groups, and age, sex, and continent of origin were significant predictors of finishing time (age and sex: p<5×10(-6); continent: p=0.003) though genotype was not. Genotype and allele frequencies obtained (RR 26.5%, RX 50.0%, XX 23.5%, R 51.5%, X 48.5%) were found to be not significantly different from Australian, Spanish, and Italian endurance athletes (p>0.05), but were significantly different from Kenyan, Ethiopian, and Finnish endurance athletes (p<0.01). CONCLUSIONS: Genotype and allele frequencies agreed with those reported for endurance athletes of similar ethnic origin, supporting previous findings for an association between 577X allele and endurance. However, analysis of performance time suggests that ACTN3 does not alone influence endurance performance, or may have a complex effect on endurance performance due to a speed/endurance trade-off.

Investigation of the role of the GABRG2 gene variant in migraine.

Migraine is the most common neurological disorder worldwide affecting about 12% of the worldwide population. This disorder has been classed into two main types of migraine-with and without aura. While a number of factors can influence the onset of migraine, a major factor is that of genetics. The GABAA gene encodes for the GABAA receptor. Along with other receptors, the GABAA receptor is involved in the mediation of neuronal activities. In this study, a GABRG2 gene (GABAA receptor gamma-2-subunit) SNP (rs211037) was genotyped on a migraine case-control population of 546 (273 affected and an equal number of healthy) individuals. Using specifically designed primers, a high resolution melt (HRM) assay was carried out in the genotyping process. After genotyping, results were compared in the case and control populations. Analysis of results showed no significant differences in the allele frequencies between case and control populations. Similarly no differences were detected for subtypes or for a specific gender of migraine (p>0.05). Although this gene has been previously found to be involved in febrile seizures and there is some co-morbidity between epilepsy and migraine, we decided to investigate this marker for involvement in migraine. The results did not support a role for the tested GABRG2 variant in migraine.

Current status of pharmacogenomics testing for anti-tumor drug therapies: approaches to non-melanoma skin cancer.

Skin cancer is one of the most commonly occurring cancer types, with substantial social, physical, and financial burdens on both individuals and societies. Although the role of UV light in initiating skin cancer development has been well characterized, genetic studies continue to show that predisposing factors can influence an individual's susceptibility to skin cancer and response to treatment. In the future, it is hoped that genetic profiles, comprising a number of genetic markers collectively involved in skin cancer susceptibility and response to treatment or prognosis, will aid in more accurately informing practitioners' choices of treatment. Individualized treatment based on these profiles has the potential to increase the efficacy of treatments, saving both time and money for the patient by avoiding the need for extensive or repeated treatment. Increased treatment responses may in turn prevent recurrence of skin cancers, reducing the burden of this disease on society. Currently existing pharmacogenomic tests, such as those that assess variation in the metabolism of the anticancer drug fluorouracil, have the potential to reduce the toxic effects of anti-tumor drugs used in the treatment of non-melanoma skin cancer (NMSC) by determining individualized appropriate dosage. If the savings generated by reducing adverse events negate the costs of developing these tests, pharmacogenomic testing may increasingly inform personalized NMSC treatment.