Circulating glucose levels are tightly regulated. To identify novel glycemic loci, we performed meta-analyses of 21 genome-wide associations studies informative for fasting glucose (FG), fasting insulin (FI) and indices of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 non-diabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with FG/HOMA-B and two associated with FI/HOMA-IR. These include nine new FG loci (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and FAM148B) and one influencing FI/HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB/TMEM195 with type 2 diabetes (T2D). Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify T2D risk loci, as well as loci that elevate FG modestly, but do not cause overt diabetes.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10−8). SNP rs7560163 (P = 7.0×10−9, OR (95% CI) = 0.75 (0.67–0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10−5) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.

These preliminary results suggest, for the first time, an association between MBL level and respiratory tract infections in young men and a possible association between infections and MBL2 polymorphisms.

Matrix metalloproteinases are responsible for degradation and remodelling of extracellular matrix and exert important roles in initiation and progression of inflammatory diseases. We aimed to examine the role of Matrix metalloproteinases (MMPs) and their regulators in degenerative arterial diseases. Serum samples were collected from patients with arterial disease (n = 126), who underwent surgery because of symptomatic aorto‐occlusive disease (AOD, n = 18), carotid artery stenosis (n = 67) or abdominal arotic aneurysm (n = 41). Serum MMP‐1, MMP‐8, MMP‐13, TIMP‐1, myeloperoxidase (MPO) and neutrophil elastase (HNE) concentrations were determined by ELISA, and the molar ratio of MMP‐8 and TIMP‐1 was calculated. To get reference values, the determinations were done on samples of healthy blood donors (n = 100). In univariate analyses, the patients had higher MMP‐8 (P < 0.001), TIMP‐1 (P = 0.045), and MMP‐8/TIMP‐1 (P < 0.001), and lower MPO (P < 0.001) when compared with the blood donors. All three subgroups had higher MMP‐8 (P < 0.001) and MMP‐8/TIMP‐1 (P < 0.001), and lower MPO (P < 0.01, except AOD) levels when compared with the references. In multiple logistic regression analyses, the male gender (P < 0.01), age (P < 0.001), elevated MMP‐8 (P < 0.001) and decreased MPO (P < 0.001) concentrations associated significantly with the risk for arterial disease, and provided an area under curve (AUC) of 0.97 in the Receiver operating characteristics analyses. In multiple linear regression analyses, HNE correlated with both MMP‐8 (P < 0.001) and MPO (P = 0.008) concentrations. Combination of high MMP‐8 and low MPO level in serum eventually reflecting selectively modified neutrophil degranulation may indicate increased risk for arterial disease.

Elevated serum cLPS levels were associated with an elevated BMI. This is a novel finding and it strengthens the link between chlamydial infection and obesity. A lack of association between totLPS and BMI suggests that the association between infection and an elevated BMI may be specific to certain pathogens.

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IntroductionSmoking increases the risk of asthma and reduces lung function among subjects with and without asthma. We assessed the effects of smoking on lung function reflecting both central and small airways among adults with newly onset asthma.MethodsIn a population-based study, 521 (response rate 86%) working-aged adults with clinically defined newly diagnosed asthma answered a questionnaire on personal smoking and other factors potentially influencing lung function, and performed spirometry. We applied multiple linear regression analysis to estimate the relations between smoking and lung function adjusting for confounding.ResultsAmong asthmatics, FEV1 level was reduced significantly, on average 208 mL, related to regular smoking (adjusted effect estimate −0.208, 95% CI −0.355 to −0.061) and 245 mL in relation to former smoking, that is, among those who quit less than a year ago (−0.245, 95% CI −0.485 to −0.004). In contrast, FEV1 was not significantly related to occasional smoking or former smoking among those who quit over a year ago. Forced expiratory flow (FEF) levels (L/s) were also significantly reduced among regular smokers (FEF25–75%: −0.372, 95% CI −0.607 to −0.137; FEF50%: −0.476, 95% CI −0.750 to −0.202). An exposure–response pattern related to both daily smoking rate and lifetime cumulative smoking was seen both among men and women.ConclusionsThis study provides new evidence that among working-aged adults with new asthma, regular smoking and former smoking reduce lung function levels with a dose–response pattern. The lung function parameters applied as outcomes reflect both larger and smaller airways.

PURPOSE OF THE STUDY. The goal of this study was to evaluate the risk of a child developing asthma if 1 or both parents has asthma. METHODS. A random sample of 1623 children was followed up over 20 years. The outcome of interest was physiciandiagnosed asthma in parents or children determined by telephone interview at baseline and follow-up surveys. RESULTS. If either of the parents had asthma, the risk of the child developing asthma was significantly increased throughout the study period: the maternal asthma hazard ratio (HR) was 1.91 (95% confidence interval [CI]: 1.36-2.69), and the paternal asthma HR was 2.01 (95% CI: 1.37-2.96). The risk was higher still if both parents had asthma (HR: 3.83 [95% CI: 2.03-7.24]). Siblings conveyed a strong independent risk for the study subject to develop asthma (HR: 2.33 [95% CI: 1.73-3.14]). This risk was even higher when more than one-half of the subject's siblings had asthma, indicating a dose-response pattern (HR: 2.92 [95% CI: 1.94-4.41]). CONCLUSIONS. The results underline the usefulness of asking about asthma in siblings in addition to parental asthma in clinical practice. REVIEWER COMMENTS. We have long known that asthma runs in families. This study helps clarify the risk. If both parents have asthma, the child's risk of developing asthma is greater than if only 1 parent has asthma, and, furthermore, this risk of developing asthma continues into adolescence and young adulthood. Having siblings with asthma also increases the risk even if neither parent has asthma.