Genome-wide scan revealed that polymorphisms in the PNPLA3, SAMM50, and PARVB genes are associated with development and progression of nonalcoholic fatty liver disease in Japan.

We examined the genetic background of nonalcoholic fatty liver disease (NAFLD) in the Japanese population, by performing a genome-wide association study (GWAS). For GWAS, 392 Japanese NAFLD subjects and 934 control individuals were analyzed. For replication studies, 172 NAFLD and 1,012 control subjects were monitored. After quality control, 261,540 single-nucleotide polymorphisms (SNPs) in autosomal chromosomes were analyzed using a trend test. Association analysis was also performed using multiple logistic regression analysis using genotypes, age, gender and body mass index (BMI) as independent variables. Multiple linear regression analyses were performed to evaluate allelic effect of significant SNPs on biochemical traits and histological parameters adjusted by age, gender, and BMI. Rs738409 in the PNPLA3 gene was most strongly associated with NAFLD after adjustment (P = 6.8 × 10(-14), OR = 2.05). Rs2896019, and rs381062 in the PNPLA3 gene, rs738491, rs3761472, and rs2143571 in the SAMM50 gene, rs6006473, rs5764455, and rs6006611 in the PARVB gene had also significant P values (<2.0 × 10(-10)) and high odds ratios (1.84-2.02). These SNPs were found to be in the same linkage disequilibrium block and were associated with decreased serum triglycerides and increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in NAFLD patients. These SNPs were associated with steatosis grade and NAFLD activity score (NAS). Rs738409, rs2896019, rs738491, rs6006473, rs5764455, and rs6006611 were associated with fibrosis. Polymorphisms in the SAMM50 and PARVB genes in addition to those in the PNPLA3 gene were observed to be associated with the development and progression of NAFLD.

NUDT3 rs206936 is associated with body mass index in obese Japanese women.

The predominant risk factor of metabolic syndrome is intra-abdominal fat accumulation, which is determined by waist circumference, waist-hip ratio measurements and visceral fat area (VFA); the latter can be accurately measured by performing computed tomography (CT). In addition to environmental factors, genetic factors play an important role in obesity and fat distribution. New genetic loci associated with body mass index (BMI) and adiposity have been identified by genome-wide association studies (GWASs). This study utilized CT to investigate whether single nucleotide polymorphisms (SNPs) that confer susceptibility to higher BMI are associated with VFA, subcutaneous fat area (SFA), and the ratio of VFA to SFA (V/S ratio). We measured the VFA and SFA of 1424 obese Japanese subjects (BMI ≥ 25 kg/m(2), 635 men and 789 women) who were genotyped for 13 single nucleotide polymorphisms (SNPs) reported by recent GWASs, namely, TNNI3K rs1514175, PTBP2 rs1555543, ADCY3 rs713586, IRS1 rs2943650, POC5 rs2112347, NUDT3 rs206936, LINGO2 rs10968576, STK33 rs4929949, MTIF3 rs4771122, SPRY2 rs534870, MAP2K5 rs2241423, QPCTL rs2287019, and ZC3H4 rs3810291. The G-allele of NUDT3 rs206936 was significantly associated with increased BMI (P = 5.3 × 10(-5)) and SFA (P = 0.00039) in the obese Japanese women. After adjustment with BMI, the association between rs206936 and SFA was not observed. This significant association was not observed in the men. The other SNPs analyzed were not significantly associated with BMI, VFA, SFA, or V/S ratio. Our results suggest that NUDT3 rs206936 is associated with BMI in Japanese women.

Association between type 2 diabetes genetic susceptibility loci and visceral and subcutaneous fat area as determined by computed tomography.

Visceral fat accumulation has an important role in the development of several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that contribute to the development of type 2 diabetes have been identified by genome-wide association studies. To examine the association of type 2 diabetes susceptibility loci and visceral fat accumulation, we genotyped 1279 Japanese subjects (556 men and 723 women), who underwent computed tomography for measurements of visceral fat area (VFA) and subcutaneous fat area (SFA) for the following single-nucleotide polymorphisms (SNPs): NOTCH2 rs10923931, THADA rs7578597, PPARG rs1801282, ADAMTS9 rs4607103, IGF2BP2 rs1470579, VEGFA rs9472138, JAZF1 rs864745, CDKN2A/CDKN2B rs564398 and rs10811661, HHEX rs1111875 and rs5015480, TCF7L2 rs7901695, KCNQ1 rs2237892, KCNJ11 rs5215 and rs5219, EXT2 rs1113132, rs11037909, and rs3740878, MTNR1B rs10830963, DCD rs1153188, TSPAN8/LGR5 rs7961581, and FTO rs8050136 and rs9939609. None of the above SNPs were significantly associated with VFA. The FTO rs8050136 and rs9939609 risk alleles exhibited significant associations with body mass index (BMI; P=0.00088 and P=0.0010, respectively) and SFA (P=0.00013 and P=0.00017, respectively). No other SNPs were significantly associated with BMI or SFA. Our results suggest that two SNPs in the FTO gene are associated with subcutaneous fat accumulation. The contributions of other SNPs are inconclusive because of a limitation of the sample power.

Genetic variations in the CYP17A1 and NT5C2 genes are associated with a reduction in visceral and subcutaneous fat areas in Japanese women.

Visceral fat accumulation has an important role in increasing the morbidity and mortality rates, by increasing the risk of developing several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that are associated with increased systolic and diastolic blood pressures have been identified by genome-wide association studies in Caucasian populations. This study investigates whether single nucleotide polymorphisms (SNPs) that confer susceptibility to high blood pressure are also associated with visceral fat obesity. We genotyped 1279 Japanese subjects (556 men and 723 women) who underwent computed tomography for measuring the visceral fat area (VFA) and subcutaneous fat area (SFA) at the following SNPs: FGF5 rs16998073, CACNB2 rs11014166, C10orf107 rs1530440, CYP17A1 rs1004467, NT5C2 rs11191548, PLEKHA7 rs381815, ATP2B1 rs2681472 and rs2681492, ARID3B rs6495112, CSK rs1378942, PLCD3 rs12946454, and ZNF652 rs16948048. In an additive model, risk alleles of the CYP17A1 rs1004467 and NT5C2 rs11191548 were found to be significantly associated with reduced SFA (P=0.00011 and 0.0016, respectively). When the analysis was performed separately in men and women, significant associations of rs1004467 (additive model) and rs11191548 (recessive model) with reduced VFA (P=0.0018 and 0.0022, respectively) and SFA (P=0.00039 and 0.00059, respectively) were observed in women, but not in men. Our results suggest that polymorphisms in the CYP17A1 and NT5C2 genes influence a reduction in both visceral and subcutaneous fat mass in Japanese women.

Replication study of 15 recently published Loci for body fat distribution in the Japanese population.

AIM: Visceral fat accumulation plays an integral role in morbidity and mortality rates by increasing the risk of developing metabolic disorders such as type 2 diabetes, dyslipidemia, and hypertension. New genetic loci associated with fat distribution, measured by waist-hip ratios and computed tomography (CT), have recently been identified by genome-wide association studies in European-descent populations. This study used CT to investigate whether single nucleotide polymorphisms (SNPs) that confer susceptibility to fat distribution are associated with visceral fat area (VFA) and subcutaneous fat area (SFA) in the Japanese population. METHODS: We measured the VFAs and SFAs of 1424 obese Japanese subjects (BMI≥25 kg/m(2), 635 men and 789 women) that were genotyped at 15 SNPs, namely, TBX15 rs984222, DNM3 rs1011731, LYPLAL1 rs4846567, GRB14 rs10195252, NISCH rs6784615, ADAMTS9 rs6795735, CPEB4 rs6861681, LY86 rs1294421, VEGFA rs6905288, RSPO3 rs9491696, NFE2L3 rs1055144, ITPR2 rs718314, HOXC13 rs1443512, ZNRF3 rs4823006 and THNSL2 rs1659258. RESULTS: The G-allele of LYPLAL1 rs4846567 was borderline associated with an increased ratio of VFA to SFA (V/S ratio; p= 0.0020). LYPLAL1 rs4846567 had a stronger effect on the V/S ratio in women (p= 0.0078) than in men (p= 0.12); however, neither result was significant after Bonferroni correction for multiple comparisons. NISCH rs6784615 was nominally associated with increased VFA (p=0.040) and V/S ratio (p= 0.020). The other SNPs analyzed were not significantly associated with body mass index (BMI), VFA, or SFA. CONCLUSION: Our results suggest that LYPLAL1 rs4846567 and NISCH rs6784615 may influence fat distribution in the Japanese population.