Iron and hepcidin as risk factors in atherosclerosis: what do the genes say?

BACKGROUND: Previous reports suggested a role for iron and hepcidin in atherosclerosis. Here, we evaluated the causality of these associations from a genetic perspective via (i) a Mendelian randomization (MR) approach, (ii) study of association of atherosclerosis-related single nucleotide polymorphisms (SNPs) with iron and hepcidin, and (iii) estimation of genomic correlations between hepcidin, iron and atherosclerosis. RESULTS: Analyses were performed in a general population sample. Iron parameters (serum iron, serum ferritin, total iron-binding capacity and transferrin saturation), serum hepcidin and genome-wide SNP data were available for N = 1,819; non-invasive measurements of atherosclerosis (NIMA), i.e., presence of plaque, intima media thickness and ankle-brachial index (ABI), for N = 549. For the MR, we used 12 iron-related SNPs that were previously identified in a genome-wide association meta-analysis on iron status, and assessed associations of individual SNPs and quartiles of a multi-SNP score with NIMA. Quartile 4 versus quartile 1 of the multi-SNP score showed directionally consistent associations with the hypothesized direction of effect for all NIMA in women, indicating that increased body iron status is a risk factor for atherosclerosis in women. We observed no single SNP associations that fit the hypothesized directions of effect between iron and NIMA, except for rs651007, associated with decreased ferritin concentration and decreased atherosclerosis risk. Two of six NIMA-related SNPs showed association with the ratio hepcidin/ferritin, suggesting that an increased hepcidin/ferritin ratio increases atherosclerosis risk. Genomic correlations were close to zero, except for hepcidin and ferritin with ABI at rest [-0.27 (SE 0.34) and -0.22 (SE 0.35), respectively] and ABI after exercise [-0.29 (SE 0.34) and -0.30 (0.35), respectively]. The negative sign indicates an increased atherosclerosis risk with increased hepcidin and ferritin concentrations. CONCLUSIONS: Our results suggest a potential causal role for hepcidin and ferritin in atherosclerosis, and may indicate that iron status is causally related to atherosclerosis in women

Empirical evaluation of prediction intervals for cancer incidence

BACKGROUND: Prediction intervals can be calculated for predicting cancer incidence on the basis of a statistical model. These intervals include the uncertainty of the parameter estimates and variations in future rates but do not include the uncertainty of assumptions, such as continuation of current trends. In this study we evaluated whether prediction intervals are useful in practice. METHODS: Rates for the period 1993–97 were predicted from cancer incidence rates in the five Nordic countries for the period 1958–87. In a Poisson regression model, 95% prediction intervals were constructed for 200 combinations of 20 cancer types for males and females in the five countries. The coverage level was calculated as the proportion of the prediction intervals that covered the observed number of cases in 1993–97. RESULTS: Overall, 52% (104/200) of the prediction intervals covered the observed numbers. When the prediction intervals were divided into quartiles according to the number of cases in the last observed period, the coverage level was inversely proportional to the frequency (84%, 52%, 46% and 26%). The coverage level varied widely among the five countries, but the difference declined after adjustment for the number of cases in each country. CONCLUSION: The coverage level of prediction intervals strongly depended on the number of cases on which the predictions were based. As the sample size increased, uncertainty about the adequacy of the model dominated, and the coverage level fell far below 95%. Prediction intervals for cancer incidence must therefore be interpreted with caution

Sequence variants in the PTCH1 gene associate with spine bone mineral density and osteoporotic fractures

Bone mineral density (BMD) is a measure of osteoporosis and is useful in evaluating the risk of fracture. In a genome-wide association study of BMD among 20,100 Icelanders, with follow-up in 10,091 subjects of European and East-Asian descent, we found a new BMD locus that harbours the PTCH1 gene, represented by rs28377268 (freq. 11.4–22.6%) that associates with reduced spine BMD (P=1.0 × 10−11, β=−0.09). We also identified a new spine BMD signal in RSPO3, rs577721086 (freq. 6.8%), that associates with increased spine BMD (P=6.6 × 10−10, β=0.14). Importantly, both variants associate with osteoporotic fractures and affect expression of the PTCH1 and RSPO3 genes that is in line with their influence on BMD and known biological function of these genes. Additional new BMD signals were also found at the AXIN1 and SOST loci and a new lead SNP at the EN1 locus

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Sequence variant at 4q25 near PITX2 associates with appendicitis.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesAppendicitis is one of the most common conditions requiring acute surgery and can pose a threat to the lives of affected individuals. We performed a genome-wide association study of appendicitis in 7,276 Icelandic and 1,139 Dutch cases and large groups of controls. In a combined analysis of the Icelandic and Dutch data, we detected a single signal represented by an intergenic variant rs2129979 [G] close to the gene PITX2 associating with increased risk of appendicitis (OR = 1.15, P = 1.8 × 10(-11)). We only observe the association in patients diagnosed in adulthood. The marker is close to, but distinct from, a set of markers reported to associate with atrial fibrillation, which have been linked to PITX2. PITX2 has been implicated in determination of right-left symmetry during development. Anomalies in organ arrangement have been linked to increased prevalence of gastrointestinal and intra-abdominal complications, which may explain the effect of rs2129979 on appendicitis risk

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis