Deletion of CDKAL1 affects high-fat diet-induced fat accumulation and glucose-stimulated insulin secretion in mice, indicating relevance to diabetes.

Background/objective: The CDKAL1 gene is among the best-replicated susceptibility loci for type 2 diabetes, originally identified by genome-wide association studies in humans. To clarify a physiological importance of CDKAL1, we examined effects of a global Cdkal1-null mutation in mice and also evaluated the influence of a CDKAL1 risk allele on body mass index (BMI) in Japanese subjects.

Methods: In Cdkal1-deficient (Cdkal1⁻/⁻) mice, we performed oral glucose tolerance test, insulin tolerance test, and perfusion experiments with and without high-fat feeding.

Genome-wide association study of coronary artery disease in the Japanese.

A new understanding of the genetic basis of coronary artery disease (CAD) has recently emerged from genome-wide association (GWA) studies of common single-nucleotide polymorphisms (SNPs), thus far performed mostly in European-descent populations. To identify novel susceptibility gene variants for CAD and confirm those previously identified mostly in populations of European descent, a multistage GWA study was performed in the Japanese. In the discovery phase, we first genotyped 806 cases and 1337 controls with 451 382 SNP markers and subsequently assessed 34 selected SNPs with direct genotyping (541 additional cases) and in silico comparison (964 healthy controls).

Detection of common single nucleotide polymorphisms synthesizing quantitative trait association of rarer causal variants.

Genome-wide association (GWA) studies have identified hundreds of common (minor allele frequency ≥5%) single nucleotide polymorphisms (SNPs) associated with phenotype traits or diseases, yet causal variants accounting for the association signals have rarely been determined. A question then raised is whether a GWA signal represents an "indirect association" as a proxy of a strongly correlated causal variant with similar frequency, or a "synthetic association" of one or more rarer causal variants in linkage disequilibrium (D' ≈ 1, but r(2) not large); answering the question generally requires extensive resequencing and association analysis. Instead, we propose to test statistically whether a quantitative trait (QT) association of an SNP represents a synthetic association or not by inspecting the QT distribution at each genotype, not requiring the causal variant(s) to be known.

Confirmation of ALDH2 as a Major locus of drinking behavior and of its variants regulating multiple metabolic phenotypes in a Japanese population.

Background: Normative alcohol use (or drinking behavior) influences the risk of cardiovascular disease in a multi-faceted manner. To identify susceptibility gene variants for drinking behavior, a 2-staged genome-wide association study was performed in a Japanese population.

Methods And Results: In the stage-1 scan, 733 cases and 729 controls were genotyped with 456,827 SNP markers.

Blood pressure and hypertension are associated with 7 loci in the Japanese population.

Background: Two consortium-based genome-wide association studies have recently identified robust and significant associations of common variants with systolic and diastolic blood pressures in populations of European descent, warranting further investigation in populations of non-European descent.

Methods And Results: We examined the associations at 27 loci reported by the genome-wide association studies on Europeans in a screening panel of Japanese subjects (n=1526) and chose 11 loci showing association signals (1-tailed test in the screening, P<0.3) for an extensive replication study with a follow-up panel of 3 Japanese general-population cohorts (n < or =24 300).

Gene-environmental interaction regarding alcohol-metabolizing enzymes in the Japanese general population.

Epidemiological studies have shown that excessive alcohol consumption is a potent risk factor to develop hypertension. In addition, some polymorphisms of the alcohol metabolism genes have been reported to exert significant impacts on the risk of alcoholism. We investigate the relevance of genetic susceptibility to drinking behavior and its influence on the sensitivity to pressor effects of alcohol in the Japanese general population.