Study of a single BRCA2 mutation with high carrier frequency in a small population.

Germ-line changes in the cancer-predisposition gene BRCA2 are found in a small proportion of breast cancers. Mutations in the BRCA2 gene have been studied mainly in families with high risk of breast cancer in females, and male breast cancer also has been associated with BRCA2 mutations. The importance of germ-line BRCA2 mutations in individuals without a family history of breast cancer is unknown. The same BRCA2 mutation has been found in 16/21 Icelandic breast cancer families, indicating a founder effect. We determined the frequency of this mutation, 999del5, in 1,182 Icelanders, comprising 520 randomly selected individuals from the population and a series of 632 female breast cancer patients (61.4% of patients diagnosed during the study period) and all male breast cancer patients diagnosed during the past 40 years. We detected the 999del5 germ-line mutation in 0.6% of the population, in 7.7% of female breast cancer patients, and in 40% of males with breast cancer. The mutation was strongly associated with onset of female breast cancer at age <50 years, but its penetrance and expression are varied. A number of cancers other than breast cancer were found to be increased in relatives of mutation carriers, including those with prostate and pancreatic cancer. Furthermore, germ-line BRCA2 mutation can be present without a strong family history of breast cancer. Comparison of the age at onset for mother/daughter pairs with the 999del5 mutation and breast cancer indicates that age at onset is decreasing in the younger generation. Increase in breast cancer incidence and lower age at onset suggest a possible contributing environmental factor.     

Inferred expression regulator activities suggest genes mediating cardiometabolic genetic signals

Expression QTL (eQTL) analyses have suggested many genes mediating genome-wide association study (GWAS) signals but most GWAS signals still lack compelling explanatory genes. We have leveraged an adipose-specific gene regulatory network to infer expression regulator activities and phenotypic master regulators (MRs), which were used to detect activity QTLs (aQTLs) at cardiometabolic trait GWAS loci. Regulator activities were inferred with the VIPER algorithm that integrates enrichment of expected expression changes among a regulator’s target genes with confidence in their regulator-target network interactions and target overlap between different regulators (i.e., pleiotropy). Phenotypic MRs were identified as those regulators whose activities were most important in predicting their respective phenotypes using random forest modeling. While eQTLs were typically more significant than aQTLs in cis, the opposite was true among candidate MRs in trans. Several GWAS loci colocalized with MR trans-eQTLs/aQTLs in the absence of colocalized cis-QTLs. Intriguingly, at the 1p36.1 BMI GWAS locus the EPHB2 cis-aQTL was stronger than its cis-eQTL and colocalized with the GWAS signal and 35 BMI MR trans-aQTLs, suggesting the GWAS signal may be mediated by effects on EPHB2 activity and its downstream effects on a network of BMI MRs. These MR and aQTL analyses represent systems genetic methods that may be broadly applied to supplement standard eQTL analyses for suggesting molecular effects mediating GWAS signals.     

Serum levels of marine-derived n-3 fatty acids in Icelanders, Japanese, Koreans, and Americans--a descriptive epidemiologic study

In the 1990s Iceland and Japan were known as countries with high fish consumption whereas coronary heart disease (CHD) mortality in Iceland was high and that in Japan was low among developed countries. We described recent data fish consumption and CHD mortality from publicly available data. We also measured CHD risk factors and serum levels of marine-derived n-3 and other fatty acids from population-based samples of 1324 men in Iceland, Japan, South Korea, and the US. CHD mortality in men in Iceland was almost 3 times as high as that in Japan and South Korea. Generally, a profile of CHD risk factors in Icelanders compared to Japanese was more favorable. Serum marine-derived n-3 fatty acids in Iceland were significantly lower than in Japan and South Korea but significantly higher than in the US.     

Fine mapping the KLK3 locus on chromosome 19q13.33 associated with prostate cancer susceptibility and PSA levels

Measurements of serum prostate-specific antigen (PSA) protein levels form the basis for a widely used test to screen men for prostate cancer. Germline variants in the gene that encodes the PSA protein (KLK3) have been shown to be associated with both serum PSA levels and prostate cancer. Based on a resequencing analysis of a 56?kb region on chromosome 19q13.33, centered on the KLK3 gene, we fine mapped this locus by genotyping tag SNPs in 3,522 prostate cancer cases and 3,338 controls from five case?Ccontrol studies. We did not observe a strong association with the KLK3 variant, reported in previous studies to confer risk for prostate cancer (rs2735839; P?=?0.20) but did observe three highly correlated SNPs (rs17632542, rs62113212 and rs62113214) associated with prostate cancer [P?=?3.41?×?10^?4, per-allele trend odds ratio (OR)?=?0.77, 95% CI?=?0.67?C0.89]. The signal was apparent only for nonaggressive prostate cancer cases with Gleason score <7 and disease stage <III (P?=?4.72?×?10^?5, per-allele trend OR?=?0.68, 95% CI?=?0.57?C0.82) and not for advanced cases with Gleason score >8 or stage ??III (P?=?0.31, per-allele trend OR?=?1.12, 95% CI?=?0.90?C1.40). One of the three highly correlated SNPs, rs17632542, introduces a non-synonymous amino acid change in the KLK3 protein with a predicted benign or neutral functional impact. Baseline PSA levels were 43.7% higher in control subjects with no minor alleles (1.61?ng/ml, 95% CI?=?1.49?C1.72) than in those with one or more minor alleles at any one of the three SNPs (1.12?ng/ml, 95% CI?=?0.96?C1.28) (P?=?9.70?×?10^?5). Together our results suggest that germline KLK3 variants could influence the diagnosis of nonaggressive prostate cancer by influencing the likelihood of biopsy.     

Pancreatic Cancer Genetics

Although relatively rare, pancreatic tumors are highly lethal [1]. In the United States, an estimated 48,960 individuals will be diagnosed with pancreatic cancer and 40,560 will die from this disease in 2015 [1]. Globally, 337,872 new pancreatic cancer cases and 330,391 deaths were estimated in 2012 [2]. In contrast to most other cancers, mortality rates for pancreatic cancer are not improving; in the US, it is predicted to become the second leading cause of cancer related deaths by 2030 [3, 4]. The vast majority of tumors arise in the exocrine pancreas, with pancreatic ductal adenocarcinoma (PDAC) accounting for approximately 95% of tumors. Tumors arising in the endocrine pancreas (pancreatic neuroendocrine tumors) represent less than 5% of all pancreatic tumors [5]. Smoking, type 2 diabetes mellitus (T2D), obesity and pancreatitis are the most consistent epidemiological risk factors for pancreatic cancer [5]. Family history is also a risk factor for developing pancreatic cancer with odds ratios (OR) ranging from 1.7-2.3 for first-degree relatives in most studies, indicating that shared genetic factors may play a role in the etiology of this disease [6-9]. This review summarizes the current knowledge of germline pancreatic cancer risk variants with a special emphasis on common susceptibility alleles identified through Genome Wide Association Studies (GWAS).     

Analysing the large decline in coronary heart disease mortality in the Icelandic population aged 25-74 between the years 1981 and 2006

Background

Coronary heart disease (CHD) mortality rates have been decreasing in Iceland since the 1980s. We examined how much of the decrease between 1981 and 2006 could be attributed to medical and surgical treatments and how much to changes in cardiovascular risk factors.

Methodology

The previously validated IMPACT CHD mortality model was applied to the Icelandic population. The data sources were official statistics, national quality registers, published trials and meta-analyses, clinical audits and a series of national population surveys.

Principal Findings

Between 1981 and 2006, CHD mortality rates in Iceland decreased by 80% in men and women aged 25 to 74 years, which resulted in 295 fewer deaths in 2006 than if the 1981 rates had persisted. Incidence of myocardial infarction (MI) decreased by 66% and resulted in some 500 fewer incident MI cases per year, which is a major determinant of possible deaths from MI. Based on the IMPACT model approximately 73% (lower and upper bound estimates: 54%–93%) of the mortality decrease was attributable to risk factor reductions: cholesterol 32%; smoking 22%; systolic blood pressure 22%, and physical inactivity 5% with adverse trends for diabetes (−5%), and obesity (−4%). Approximately 25% (lower and upper bound estimates: 8%–40%) of the mortality decrease was attributable to treatments in individuals: secondary prevention 8%; heart failure treatments 6%; acute coronary syndrome treatments 5%; revascularisation 3%; hypertension treatments 2%, and statins 0.5%.

Conclusions

Almost three quarters of the large CHD mortality decrease in Iceland between 1981 and 2006 was attributable to reductions in major cardiovascular risk factors in the population. These findings emphasize the value of a comprehensive prevention strategy that promotes tobacco control and a healthier diet to reduce incidence of MI and highlights the potential importance of effective, evidence based medical treatments.     

A comprehensive resequence analysis of the KLK15–KLK3–KLK2 locus on chromosome 19q13.33

Single nucleotide polymorphisms (SNPs) in the KLK3 gene on chromosome 19q13.33 are associated with serum prostate-specific antigen (PSA) levels. Recent genome wide association studies of prostate cancer have yielded conflicting results for association of the same SNPs with prostate cancer risk. Since the KLK3 gene encodes the PSA protein that forms the basis for a widely used screening test for prostate cancer, it is critical to fully characterize genetic variation in this region and assess its relationship with the risk of prostate cancer. We have conducted a next-generation sequence analysis in 78 individuals of European ancestry to characterize common (minor allele frequency, MAF >1%) genetic variation in a 56 kb region on chromosome 19q13.33 centered on the KLK3 gene (chr19:56,019,829–56,076,043 bps). We identified 555 polymorphic loci in the process including 116 novel SNPs and 182 novel insertion/deletion polymorphisms (indels). Based on tagging analysis, 144 loci are necessary to tag the region at an r ² threshold of 0.8 and MAF of 1% or higher, while 86 loci are required to tag the region at an r ² threshold of 0.8 and MAF >5%. Our sequence data augments coverage by 35 and 78% as compared to variants in dbSNP and HapMap, respectively. We observed six non-synonymous amino acid or frame shift changes in the KLK3 gene and three changes in each of the neighboring genes, KLK15 and KLK2. Our study has generated a detailed map of common genetic variation in the genomic region surrounding the KLK3 gene, which should be useful for fine-mapping the association signal as well as determining the contribution of this locus to prostate cancer risk and/or regulation of PSA expression.     

Y chromosome haplogroups and prostate cancer in populations of European and Ashkenazi Jewish ancestry

Genetic variation on the Y chromosome has not been convincingly implicated in prostate cancer risk. To comprehensively analyze the role of inherited Y chromosome variation in prostate cancer risk in individuals of European ancestry, we genotyped 34 binary Y chromosome markers in 3,995 prostate cancer cases and 3,815 control subjects drawn from four studies. In this set, we identified nominally significant association between a rare haplogroup, E1b1b1c, and prostate cancer in stage I (P = 0.012, OR = 0.51; 95% confidence interval 0.30-0.87). Population substructure of E1b1b1c carriers suggested Ashkenazi Jewish ancestry, prompting a replication phase in individuals of both European and Ashkenazi Jewish ancestry. The association was not significant for prostate cancer overall in studies of either Ashkenazi Jewish (1,686 cases and 1,597 control subjects) or European (686 cases and 734 control subjects) ancestry (P(meta) = 0.078), but a meta-analysis of stage I and II studies revealed a nominally significant association with prostate cancer risk (P(meta) = 0.010, OR = 0.77; 95% confidence interval 0.62-0.94). Comparing haplogroup frequencies between studies, we noted strong similarities between those conducted in the US and France, in which the majority of men carried R1 haplogroups, resembling Northwestern European populations. On the other hand, Finns had a remarkably different haplogroup distribution with a preponderance of N1c and I1 haplogroups. In summary, our results suggest that inherited Y chromosome variation plays a limited role in prostate cancer etiology in European populations but warrant follow-up in additional large and well characterized studies of multiple ethnic backgrounds.