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BACKGROUND: Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles. METHODS: We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs. RESULTS: Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p < 0(-6) level. Twenty of these regions contained defined genes, including one already associated with breast cancer risk: TOX3. With a lower threshold for preliminary significance to p < 10(-5), we identified 11 additional SNPs in FGFR2, a well-established breast cancer-associated gene. Ten candidate SNPs were selected, excluding those already associated with breast cancer, for technical validation as well as replication in 1668 samples from the same population. Only SNP rs345299, located in intron 1 of VAV3, remained suggestively associated (p-value, 1.16 x 10(-5)), but it did not associate with breast cancer risk in pooled data from two large, mixed-population cohorts. CONCLUSIONS: This study indicated the role of TOX3 and FGFR2 as breast cancer susceptibility genes in BRCA1/2-wild-type breast cancer patients from Sardinian population.

BACKGROUND: Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles. METHODS: We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs. RESULTS: Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p

OBJECTIVE Glycated hemoglobin (HbA1c), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA1c. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA1c levels.\ud \ud RESEARCH DESIGN AND METHODS We studied associations with HbA1c in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA1c loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening.\ud \ud RESULTS Ten loci reached genome-wide significant association with HbA1c, including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10−26), HFE (rs1800562/P = 2.6 × 10−20), TMPRSS6 (rs855791/P = 2.7 × 10−14), ANK1 (rs4737009/P = 6.1 × 10−12), SPTA1 (rs2779116/P = 2.8 × 10−9) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10−9), and four known HbA1c loci: HK1 (rs16926246/P = 3.1 × 10−54), MTNR1B (rs1387153/P = 4.0 × 10−11), GCK (rs1799884/P = 1.5 × 10−20) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10−18). We show that associations with HbA1c are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA1c) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA1c.\ud \ud CONCLUSIONS GWAS identified 10 genetic loci reproducibly associated with HbA1c. Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA1c levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA1c.

Identifying the genetic variants that regulate fasting glucose concentrations may further our understanding of the pathogenesis of diabetes. We therefore investigated the association of fasting glucose levels with SNPs in 2 genome-wide scans including a total of 5,088 nondiabetic individuals from Finland and Sardinia. We found a significant association between the SNP rs563694 and fasting glucose concentrations (P = 3.5 × 10–7). This association was further investigated in an additional 18,436 nondiabetic individuals of mixed European descent from 7 different studies. The combined P value for association in these follow-up samples was 6.9 × 10–26, and combining results from all studies resulted in an overall P value for association of 6.4 × 10–33. Across these studies, fasting glucose concentrations increased 0.01–0.16 mM with each copy of the major allele, accounting for approximately 1% of the total variation in fasting glucose. The rs563694 SNP is located between the genes glucose-6-phosphatase catalytic subunit 2 (G6PC2) and ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11). Our results in combination with data reported in the literature suggest that G6PC2, a glucose-6-phosphatase almost exclusively expressed in pancreatic islet cells, may underlie variation in fasting glucose, though it is possible that ABCB11, which is expressed primarily in liver, may also contribute to such variation.

Supplemental material, MSJ963937_supplemental_material for PRF1 mutation alters immune system activation, inflammation, and risk of autoimmunity by Carlo Sidore, Valeria Orrù, Eleonora Cocco, Maristella Steri, Jamie RJ Inshaw, Maristella Pitzalis, Antonella Mulas, Stuart McGurnaghan, Jessica Frau, Eleonora Porcu, Fabio Busonero, Mariano Dei, Sandra Lai, Gabriella Sole, Francesca Virdis, Valentina Serra, Fausto Poddie, Alessandro Delitala, Michele Marongiu, Francesca Deidda, Mauro Pala, Matteo Floris, Marco Masala, Suna Onengut-Gumuscu, Catherine C Robertson, Lidia Leoni, Annapaola Frongia, Maria Rossella Ricciardi, Margherita Chessa, Nazario Olla, Mario Lovicu, Annalisa Loizedda, Andrea Maschio, Luisa Mereu, Paola Ferrigno, Nicolo Curreli, Lenuta Balaci, Francesco Loi, Liana AP Ferreli, Maria Grazia Pilia, Antonello Pani, Maria Giovanna Marrosu, Goncalo R Abecasis, Stephen S Rich, Helen Colhoun, John A Todd, David Schlessinger, Edoardo Fiorillo, Francesco Cucca and Magdalena Zoledziewska in Multiple Sclerosis Journal

Supplemental material, MSJ963937_supplemental_material for PRF1 mutation alters immune system activation, inflammation, and risk of autoimmunity by Carlo Sidore, Valeria Orrù, Eleonora Cocco, Maristella Steri, Jamie RJ Inshaw, Maristella Pitzalis, Antonella Mulas, Stuart McGurnaghan, Jessica Frau, Eleonora Porcu, Fabio Busonero, Mariano Dei, Sandra Lai, Gabriella Sole, Francesca Virdis, Valentina Serra, Fausto Poddie, Alessandro Delitala, Michele Marongiu, Francesca Deidda, Mauro Pala, Matteo Floris, Marco Masala, Suna Onengut-Gumuscu, Catherine C Robertson, Lidia Leoni, Annapaola Frongia, Maria Rossella Ricciardi, Margherita Chessa, Nazario Olla, Mario Lovicu, Annalisa Loizedda, Andrea Maschio, Luisa Mereu, Paola Ferrigno, Nicolo Curreli, Lenuta Balaci, Francesco Loi, Liana AP Ferreli, Maria Grazia Pilia, Antonello Pani, Maria Giovanna Marrosu, Goncalo R Abecasis, Stephen S Rich, Helen Colhoun, John A Todd, David Schlessinger, Edoardo Fiorillo, Francesco Cucca and Magdalena Zoledziewska in Multiple Sclerosis Journal