Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility.

We analyzed 1,900 Turkish Behçet's disease cases and 1,779 controls genotyped with the Immunochip. The most significantly associated SNP was rs1050502, a tag SNP for HLA-B*51. In the Turkish discovery set, we identified three new risk loci, IL1A-IL1B, IRF8, and CEBPB-PTPN1, with genome-wide significance (P < 5 × 10-8) by direct genotyping and ADO-EGR2 by imputation. We replicated the ADO-EGR2, IRF8, and CEBPB-PTPN1 loci by genotyping 969 Iranian cases and 826 controls. Imputed data in 608 Japanese cases and 737 controls further replicated ADO-EGR2 and IRF8, and meta-analysis additionally identified RIPK2 and LACC1. The disease-associated allele of rs4402765, the lead marker at IL1A-IL1B, was associated with both decreased IL-1α and increased IL-1ß production. ABO non-secretor genotypes for two ancestry-specific FUT2 SNPs showed strong disease association (P = 5.89 × 10-15). Our findings extend the list of susceptibility genes shared with Crohn's disease and leprosy and implicate mucosal factors and the innate immune response to microbial exposure in Behçet's disease susceptibility.

Mitochondrial genome association study with peripheral arterial disease and venous thromboembolism.

BACKGROUND AND AIMS: Peripheral arterial disease (PAD) and venous thromboembolism (VTE) are vascular traits sharing common modifiable and non-modifiable risk factors. These vascular pathologies have known nuclear-encoded genetic risk factors and the mitochondrial DNA may account for part of the missing heritability. To determine if PAD and VTE have a dual genetic control (mitochondrial and nuclear), we hereby investigated the association of mitochondrial DNA polymorphisms and haplogroups with these vascular traits. METHODS: The association of mitochondrial single nucleotide polymorphisms (mtSNPs) and haplogroups was tested in 1652 PAD cases and 1629 controls from the eMERGE PAD genome-wide association study (GWAS), and 1241 VTE cases and 1278 controls from the GENEVA GWAS of venous thrombosis (dbGaP accession numbers phs000203.v1.p1 and phs000289.v2.p1, respectively). RESULTS: 66 and 72 mtSNPs passed quality control filters and were tested for association with PAD and VTE, respectively. Significant evidence of population stratification could not be detected in both datasets. Three mtSNPs (m.477T > C, m.9667A > G, and m.10915T > C) were nominally associated (3.01 × 10(-3) ≤ pa ≤ 3.96 × 10(-2)) with PAD in the logistic regression adjusted for confounding factors, and m.11914G > A was nominally associated (pa = 4.14 × 10(-2)) with VTE. None of the nine major mitochondrial haplogroups were associated with either PAD or VTE. CONCLUSION: Unlike other vascular diseases such as stroke and diabetes, these results suggest that common mitochondrial variants individually or in combination do not play a major role in PAD and VTE susceptibility.

Multicentric Genome-Wide Association Study for Primary Spontaneous Pneumothorax.

Despite elevated incidence and recurrence rates for Primary Spontaneous Pneumothorax (PSP), little is known about its etiology, and the genetics of idiopathic PSP remains unexplored. To identify genetic variants contributing to sporadic PSP risk, we conducted the first PSP genome-wide association study. Two replicate pools of 92 Portuguese PSP cases and of 129 age- and sex-matched controls were allelotyped in triplicate on the Affymetrix Human SNP Array 6.0 arrays. Markers passing quality control were ranked by relative allele score difference between cases and controls (|RASdiff|), by a novel cluster method and by a combined Z-test. 101 single nucleotide polymorphisms (SNPs) were selected using these three approaches for technical validation by individual genotyping in the discovery dataset. 87 out of 94 successfully tested SNPs were nominally associated in the discovery dataset. Replication of the 87 technically validated SNPs was then carried out in an independent replication dataset of 100 Portuguese cases and 425 controls. The intergenic rs4733649 SNP in chromosome 8 (between LINC00824 and LINC00977) was associated with PSP in the discovery (P = 4.07E-03, ORC[95% CI] = 1.88[1.22-2.89]), replication (P = 1.50E-02, ORC[95% CI] = 1.50[1.08-2.09]) and combined datasets (P = 8.61E-05, ORC[95% CI] = 1.65[1.29-2.13]). This study identified for the first time one genetic risk factor for sporadic PSP, but future studies are warranted to further confirm this finding in other populations and uncover its functional role in PSP pathogenesis.

Ulcerative Colitis Is Under Dual (Mitochondrial and Nuclear) Genetic Control.

BACKGROUND: Cellular oxidative stress and genetic susceptibility have been implicated in the multifactorial etiology of ulcerative colitis (UC). The nuclear genome association with UC has been intensely investigated, but the role of the mitochondrial DNA (mtDNA) has received far less attention and may account for part of the missing heritability. This study is a comprehensive analysis of the mtDNA contribution to UC susceptibility. METHODS: The association of mitochondrial single-nucleotide polymorphisms (mtSNPs) and haplogroups with UC was tested in 488 cases and 833 controls of European ancestry from the NIDDK IBD Genetics Consortium Ulcerative Colitis Genome-Wide Association Study available through dbGaP and from the Illumina Genotype Control Database (studies 64 and 65). RESULTS: No evidence of population stratification could be detected using 218 ancestry informative markers for European Americans. Seven of the 58 tested mtSNPs were nominally associated with UC, and A10550G in MT-ND4L withstands the Bonferroni correction (P = 1.29E-06, odds ratio [ORG] [95% confidence interval (CI)] = 4.80 [2.54-9.05], 10550G allele: 8.1% of patients and 1.9% of controls). A10550G remains equally associated after conditional analyses on the 11 UC genome-wide association studies (GWAS) top SNPs (6.35E-07 < Pcond < 4.58E-06), which suggests that it constitutes an independent risk factor from nuclear-encoded susceptibility loci. We detected additive (but not multiplicative) epistatic interactions between A10550G and all 11 top GWAS hits. Subhaplogroup K1 (P = 0.021, OR [95% CI] = 1.71 [1.08-2.69]) increased the risk for UC, whereas the U5b lineage conferred protection (P = 0.016, OR [95% CI] = 0.34 [0.14-0.82]). CONCLUSIONS: These results suggest that UC has a dual mitochondrial and nuclear genetic control that warrants further replication in independent data sets and reinforces its etiopathogenic complexity.

Genetic Variants Underlying Risk of Intracranial Aneurysms: Insights from a GWAS in Portugal.

Subarachnoid hemorrhage (SAH) is a life-threatening event that most frequently leads to severe disability and death. Its most frequent cause is the rupture of a saccular intracranial aneurysm (IA), which is a blood vessel dilation caused by disease or weakening of the vessel wall. Although the genetic contribution to IA is well established, to date no single gene has been unequivocally identified as responsible for IA formation or rupture. We aimed to identify IA susceptibility genes in the Portuguese population through a pool-based multistage genome-wide association study. Replicate pools were allelotyped in triplicate in a discovery dataset (100 IA cases and 92 gender-matched controls) using the Affymetrix Human SNP Array 6.0. Top SNPs (absolute value of the relative allele score difference between cases and controls |RASdiff|≥13.0%) were selected for technical validation by individual genotyping in the discovery dataset. From the 101 SNPs successfully genotyped, 99 SNPs were nominally associated with IA. Replication of technically validated SNPs was conducted in an independent replication dataset (100 Portuguese IA cases and 407 controls). rs4667622 (between UBR3 and MYO3B), rs6599001 (between SCN11A and WDR48), rs3932338 (214 kilobases downstream of PRDM9), and rs10943471 (96 kilobases upstream of HTR1B) were associated with IA (unadjusted allelic chi-square tests) in the datasets tested (discovery: 6.84E-04≤P≤1.92E-02, replication: 2.66E-04≤P≤2.28E-02, and combined datasets: 6.05E-05≤P≤5.50E-04). Additionally, we confirmed the known association with IA of rs1333040 at the 9p21.3 genomic region, thus validating our dataset. These novel findings in the Portuguese population warrant further replication in additional independent studies, and provide additional candidates to more comprehensively understand IA etiopathogenesis.

Characterization of the major histocompatibility complex locus association with Behçet's disease in Iran.

INTRODUCTION: The aim of this study was to characterize the association of human leukocyte antigen (HLA) B alleles and major histocompatibility complex (MHC) single nucleotide polymorphisms (SNPs) with Behçet's disease (BD) in an Iranian dataset. METHODS: The association of three SNPs in the MHC region previously identified as the most associated in high-density genotyping studies was tested in a case-control study on 973 BD patients and 825 controls from Iran, and the association of HLA-B alleles was tested in a subset of 681 patients and 414 controls. RESULTS: We found that HLA-B*51 (P = 4.11 × 10(-41), OR [95% CI] = 4.63[3.66-5.85]) and B*15 confer risk for BD (P = 2.83 × 10(-2), OR [95% CI] = 1.75[1.08-2.84]) in Iranian, and in B*51 negative individuals, only the B*15 allele is significantly associated with BD (P = 2.51 × 10(-3), OR [95% CI] = 2.40[1.37-4.20]). rs76546355, formerly known as rs116799036, located between HLA-B and MICA (MHC class I polypeptide-related sequence A), demonstrated the same level of association with BD as HLA-B*51 (P adj = 1.78 × 10(-46), OR [95% CI] = 5.46[4.21-7.09], and P adj = 8.34 × 10(-48), OR [95% CI] = 5.44[4.20-7.05], respectively) in the HLA-B allelotyped subset, while rs2848713 was less associated (P adj = 7.14 × 10(-35), OR [95% CI] = 3.73[2.97-4.69]) and rs9260997 was not associated (P adj = 1.00 × 10(-1)). Additionally, we found that B*51 genotype-phenotype correlations do not survive Bonferroni correction, while carriers of the rs76546355 risk allele predominate in BD cases with genital ulcers, positive pathergy test and positive BD family history (2.31 × 10(-4) ≤ P ≤ 1.59 × 10(-3)). CONCLUSIONS: We found that the HLA-B*51 allele and the rs76546355/rs116799036 MHC SNP are independent genetic risk factors for BD in Iranian, and that positivity for the rs76546355/rs116799036 risk allele, but not for B*51, does correlate with specific demographic characteristics or clinical manifestations in BD patients.

Cardiovascular risk profile of high school students: a cross-sectional study.

INTRODUCTION: Disease prevention should begin in childhood and lifestyles are important risk determinants of cardiovascular disease. Awareness and monitoring of risk is essential in preventive strategies. AIM: To characterize cardiovascular risk and the relationships between certain variables in adolescents. METHODS: In a cross-sectional study, 854 adolescent schoolchildren were surveyed, mean age 16.3 ± 0.9 years. Data collection included questionnaires, physical examination, charts for 10-year relative risk of mortality, and biochemical assays. In the statistical analysis continuous variables were studied by the Student's t test and categorical variables by the chi-square test and Fisher's exact test, and each risk factor was entered as a dependent variable in logistic regression analysis. RESULTS: Physical activity was insufficient in 81% of students. The daily consumption of soup, salad or vegetables, and fruit was, respectively, 37%, 39% and 21%. A minority (6%) took ≤ 3 and 77% took ≥ 5 meals a day. The prevalence of each risk factor was as follows: overweight 16%; smoking 13%; hypertension 11%; impaired glucose metabolism 9%; hypertriglyceridemia 9%; and hypercholesterolemia 5%. Out-of-school physical activity, hypertension and overweight were more prevalent in males (p<0.001). Females had higher levels of cholesterol (p<0.005) and triglycerides (p<0.001). A quarter of the adolescents had a relative risk score for 10-year cardiovascular mortality of ≥ 2. Overweight showed a positive association with blood pressure, changes in glucose metabolism and triglycerides, and a negative association with number of daily meals. CONCLUSIONS: The results demonstrate the need for action in providing and encouraging healthy choices for adolescents, with an emphasis on behavioral and lifestyle changes aimed at individuals, families and communities.