CHI3L1 is a susceptibility gene for asthma, bronchial hyperresponsiveness, and reduced lung function, and elevated circulating YKL-40 levels are a biomarker for asthma and decline in lung function.

Plasma lipoprotein(a) (Lp[a]) level is an independent risk factor of cardiovascular disease that is under strong genetic control. We conducted a genome-wide association study of plasma Lp(a) in 386 members of a founder population that adheres to a communal lifestyle, proscribes cigarette smoking, and prepares and eats meals communally. We identified associations with 77 single nucleotide polymorphisms (SNPs) spanning 12.5 Mb on chromosome 6q26-q27 that met criteria for genome-wide significance (P # 1.3 3 10 27 ) and were within or flanking nine genes, including LPA. We show that variation in at least six genes in addition to LPA are significantly associated with Lp(a) levels independent of each other and of the kringle IV repeat polymorphism in the LPA gene. One novel SNP in intron 37 of the LPA gene was also associated with Lp(a) levels and carotid artery disease number in unrelated Caucasians (P 5 7.3 3 10 212 and 0.024, respectively), also independent of kringle IV number. This study suggests a complex genetic architecture of Lp(a) levels that may involve multiple loci on chromosome 6q26-q27. Lipoprotein (a) [Lp(a)] is recognized as an independent risk factor for atherosclerotic cardiovascular disease (1, 2). The mechanisms underlying this pathogenesis are poorly understood, although proatherogenic, prothrombotic, and inflammatory pathways contribute. Moreover, plasma Lp(a) levels are not responsive to statins and other cholesterol-lowering drugs, except for niacin, for which the long-term efficacy and safety is not yet established (3). Lp(a) is produced in the liver (4) and circulates in the plasma as an LDL particle having as a protein moiety apolipoprotein(a) [apo(a)], encoded by the LPA gene, linked by a disulfide bond to an apolipoprotein B-100 particle, on a 1:1 molecular basis (5). While apolipoprotein B-100 remains relatively constant in size, apo(a) varies in size due to polymorphism in the number of tandemly repeated kringle IV type 2 domains encoded by sequences in exons 1 and 2 of the LPA gene (6).The human LPA gene arose as a duplication of the PLG gene in the primate lineage and retains 80% sequence identity to PLG (7), which has only a single kringle IV structure. The number of kringle IV repeats in Lp(a) is under genetic control and inversely correlates with plasma levels of Lp(a), likely as result of the lower secretion rate in hepatocytes of apo(a) isoforms with larger numbers of kringle IV repeats (8, 9). The LPA locus accounts for 70-90% of the variability in Lp(a) levels in worldwide Abbreviations: apo(a), apolipoprotein(a); BMI, body mass index; LD, linkage disequilibrium; Lp(a), lipoprotein (a); SNP, single nucleotide polymorphism; RSS, residual sum of squares.

OBJECTIVE-The objective of this study was to identify DNA polymorphisms associated with type 2 diabetes in a MexicanAmerican population.RESEARCH DESIGN AND METHODS-We genotyped 116,204 single nucleotide polymorphisms (SNPs) in 281 Mexican Americans with type 2 diabetes and 280 random Mexican Americans from Starr County, Texas, using the Affymetrix GeneChip Human Mapping 100K set. Allelic association exact tests were calculated. Our most significant SNPs were compared with results from other type 2 diabetes genome-wide association studies (GWASs). Proportions of African, European, and Asian ancestry were estimated from the HapMap samples using structure for each individual to rule out spurious association due to population substructure.RESULTS-We observed more significant allelic associations than expected genome wide, as empirically assessed by permutation (14 below a P of 1 ϫ 10 Ϫ4 [8.7 expected]). No significant differences were observed between the proportion of ancestry estimates in the case and random control sets, suggesting that the association results were not likely confounded by substructure. A query of our top ϳ1% of SNPs (P Ͻ 0.01) revealed SNPs in or near four genes that showed evidence for association (P Ͻ 0.05) in multiple other GWAS interrogated: rs979752 and rs10500641 near UBQLNL and OR52H1 on chromosome 11, rs2773080 and rs3922812 in or near RALGPS2 on chromosome 1, and rs1509957 near EGR2 on chromosome 10. CONCLUSIONS-We

Background Lung function is a long-term predictor of mortality and morbidity. Objective We sought to identify single nucleotide polymorphisms (SNPs) associated with lung function. Methods We performed a genome-wide association study (GWAS) of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC in 1,144 Hutterites aged 6–89 years, who are members of a founder population of European descent. We performed least absolute shrinkage and selection operation (LASSO) regression to select the minimum set of SNPs that best predict FEV1/FVC in the Hutterites and used the GRAIL algorithm to mine the Gene Ontology database for evidence of functional connections between genes near the predictive SNPs. Results Our GWAS identified significant associations between FEV1/FVC and SNPs at the THSD4-UACA-TLE3 locus on chromosome 15q23 (P = 5.7x10−8 ~ 3.4x10−9). Nine SNPs at or near four additional loci had P-values < 10−5 with FEV1/FVC. There were only two SNPs with P-values < 10−5 for FEV1 or FVC. We found nominal levels of significance with SNPs at 9 of the 27 previously reported loci associated with lung function measures. Among a predictive set of 80 SNPs, six loci were identified that had a significant degree of functional connectivity (GRAIL P < 0.05), including three clusters of β-defensin genes, two chemokine genes (CCL18 and CXCL12), and TNFRSF13B. Conclusion This study identifies genome-wide significant associations and replicates results of previous GWAS. Multimarker modeling implicated for the first time common variation in genes involved in anti-microbial immunity in airway mucosa influences lung function.

Background and Objectives:Type 2 diabetes and lifestyle factors have been associated with dementia risk, but the impact of a healthy lifestyle on diabetes-related dementia remains largely unknown. We aimed to investigate whether the increased risk of dementia among individuals with diabetes can be offset by a broad combination of healthy lifestyle factors.Methods:This prospective study utilized data from the UK Biobank cohort. An overall lifestyle score ranging from 0 to 7 was created, with 1 point for each of the seven healthy lifestyle factors: no current smoking, moderate alcohol consumption, regular physical activity, healthy diet, adequate sleep duration, less sedentary behavior, and frequent social contact. Incident dementia was ascertained using linkage with electronic health records. Cox proportional hazards models were used to examine the associations between diabetes, healthy lifestyle score, and dementia incidence.Results:We included 167 946 participants aged 60 years or older without dementia at baseline (mean age 64.1 [SD 2.8] years, 51.7% female). During a median follow-up of 12.3 years, 4351 developed all-cause dementia. Participants with diabetes, but not those with prediabetes, showed a higher risk of dementia than those with normoglycemia. Compared with diabetes-free participants who had a lifestyle score of 7, the hazard ratios (HRs) for dementia were 4.01 (95% CI 3.06–5.25) and 1.74 (95% CI 1.11–2.72) in those with diabetes who had a lifestyle score of 0-2 and 7, respectively. Among participants with diabetes, the HR for dementia comparing a lifestyle score of 7 versus 0-2 was 0.46 (95% CI 0.28–0.75). This finding corresponded to a reduction in the 10-year absolute risk of dementia from 5.22% (95% CI 3.94%–6.73%) to 1.72% (95% CI 0.92%–2.97%). The inverse association between healthy lifestyle score and dementia risk was independent of glycemic control and diabetes medication.Conclusions:Adherence to a broad range of healthy lifestyle factors was associated with a significantly lower risk of dementia among participants with diabetes. Behavioral lifestyle modification through multifactorial approaches should be a priority for prevention and delayed onset of dementia in patients with diabetes.

Founder or isolated populations have advantages for genetic studies due to decreased genetic and environmental heterogeneity. However, whereas longer range linkage disequilibrium (LD) in these populations is expected to facilitate gene localization, extensive LD may actually limit the ability for gene discovery. The North American Hutterite population is one of the best characterized young founder populations and members of this isolate have been the subjects of our studies of complex traits, including fertility, asthma and cardiovascular disease, for >20 years. Here, we directly assess the patterns and extent of global LD using single nucleotide polymorphism (SNP) genotypes with minor allele frequencies (MAFs) ≥5% from the Affymetrix GeneChip® Mapping 500K array in 60 relatively unrelated Hutterites and 60 unrelated Europeans (HapMap CEU). Although LD among some marker pairs extends further in the Hutterites than in Europeans, the pattern of LD and minor allele frequencies are surprisingly similar. These results indicate that 1) identifying disease genes should be no more difficult in the Hutterites than in outbred European populations, 2) the same common susceptibility alleles for complex diseases should be present in the Hutterites and outbred European populations, and 3) imputation algorithms based on HapMap CEU should be applicable to the Hutterites.

We previously reported that paternally-inherited human leukocyte antigen (HLA) alleles are a template for women's preference for male odors (P = 0.0007). However, it has been suggested that sequence variation in a nearby olfactory receptor (OR) cluster on chromosome 6p influences smell preference. To determine if the HLA-linked OR genes contribute to previously observed HLA-mediated behaviors, we use the odor preference data from our earlier study in combination with a new resequencing study of four functional HLA-linked OR genes in the same subjects. Our results indicate that OR alleles in the genes surveyed are not in linkage disequilibrium (LD) with HLA variation and do not explain the previous findings of HLA-associated odor preference.

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