In Silico identification of a common mobile element insertion in exon 4 of RP1.

Mobile element insertions (MEIs) typically exceed the read lengths of short-read sequencing technologies and are therefore frequently missed. Recently, a founder Alu insertion in exon 4 of RP1 has been detected in Japanese patients with macular dystrophy by PCR and gel electrophoresis. We aimed to develop a grep search program for the detection of the Alu insertion in exon 4 of RP1 using unprocessed short reads. Among 494 unrelated Korean patients with inherited eye diseases, 273 patients with specific retinal phenotypes who were previously genotyped by targeted panel or whole exome sequencing were selected. Five probands had a single heterozygous truncating RP1 variant, and one of their unaffected parents also carry this variant. To find a hidden genetic variant, whole genome sequencing was performed in two patients, and it revealed AluY c.4052_4053ins328/p.(Tyr1352Alafs*9) insertion in RP1 exon 4. This AluY insertion was additionally identified in other 3 families, which was confirmed by PCR and gel electrophoresis. We developed simplified grep search program to detect this AluY insertion in RP1 exon 4. The simple grep search revealed a median variant allele frequency of 0.282 (interquartile range, 0.232-0.383), with no false-positive results using 120 control samples. The MEI in RP1 exon 4 was a common founder mutation in Korean, occurring in 1.8% of our cohort. The RP1-Alu grep program efficiently detected the AluY insertion, without the preprocessing of raw data or complex installation processes.

The Korean undiagnosed diseases program: lessons from a one-year pilot project.

BACKGROUND: The Korean Undiagnosed Diseases Program (KUDP) was launched in January 2017 as a one-year pilot project to address the increasing global interest in patients with undiagnosed rare diseases. The purpose of this paper is to summarize the project results and emphasize the unmet research needs among patients with undiagnosed rare diseases in Korea. RESULTS: Patient enrollment, assessment, and diagnostic processes were determined by the KUDP clinical expert consortium. Patients followed a diagnostic workflow after being categorized into one of four groups: I) insufficient clinical information or lack of standard diagnostic processes; II) undiagnosed due to low disease awareness; III) clinically diagnosed but unconfirmed genetically due to genetic heterogeneities; or IV) unknown disease due to complex, atypical clinical presentations. After excluding two patients from group I, 97 patients were enrolled, including 10 in group II, 67 in group III, and 20 in group IV. Most of them (92 of 97, 94.8%) were pediatric patients (< 18 years old) and 59 (60.8%) were male. The primary symptoms for 80 patients (82.5%) were neurologic. During the one-year pilot study, 72 patients completed a diagnostic assessment including clinical and molecular genetic analyses; some patients also underwent pathological or biochemical analysis. Twenty-eight of these patients (28/72, 38.9%) achieved molecular genetic diagnosis. Thirteen patients were diagnosed based on traditional tests, including biochemical assay, single or targeted genetic analysis, and chromosomal microarray. We performed whole exome sequencing on 52 patients, among whom 15 (28.8%, 15/52) reached a final diagnosis. One new disorder was identified via international collaboration. CONCLUSIONS: Using an efficient clinical diagnostic workflow, this KUDP pilot study resulted in a fair diagnostic success rate, improving the potential for additional diagnoses and new scientific discovery of complex and rare diseases. KUDP also satisfied unmet needs for rare diseases with multisystem involvement, highlighting the value of emerging genomic technologies for further research into rare and still-undiagnosed conditions.

Genome-wide methylation analysis identifies ELOVL5 as an epigenetic biomarker for the risk of type 2 diabetes mellitus.

Genome-wide DNA methylation has been implicated in complex human diseases. Here, we identified epigenetic biomarkers for type 2 diabetes (T2D) underlying obesogenic environments. In a blood-based DNA methylation analysis of 11 monozygotic twins (MZTW) discordant for T2D, we discovered genetically independent candidate methylation sites. In a follow-up replication study (17 MZTW pairs) for external validation, we replicated the T2D-association at a novel CpG signal in the ELOVL fatty acid elongase 5 (ELOVL5) gene specific to T2D-discordant MZTW. For concordant DNA methylation signatures in tissues, we further confirmed that a CpG site (cg18681426) was associated with adipogenic differentiation between human preadipocytes and adipocytes isolated from the same biopsy sample. In addition, the ELOVL5 gene was significantly differentially expressed in adipose tissues from unrelated T2D patients and in human pancreatic islets. Our results demonstrate that blood-derived DNA methylation is associated with T2D risk as a proxy for cumulative epigenetic status in human adipose and pancreatic tissues. Moreover, ELOVL5 expression was increased in cellular and mouse models of induced obesity-related diabetes. These findings may provide new insights into epigenetic architecture by uncovering methylation-based biomarkers.

Obesity-related CpG Methylation (cg07814318) of Kruppel-like Factor-13 (KLF13) Gene with Childhood Obesity and its cis-Methylation Quantitative Loci.

The cg07814318 hypermethylation of Kruppel-like factor 13 (KLF13) gene has been reported for its relevancy with Body Mass Index (BMI) from European origin. We explored the cg07814318 methylation and its cis-meQTL (cis-methylation quantitative loci) of KLF13 from a childhood obesity cohort. The cg07814318 methylation in blood was significantly associated with obesity and correlated with several obesity-related physical and biochemical traits. We examined the same loci from purified three human cell types (n = 47), i.e., pre-adipocytes, adipocytes and islets. The cg07814318 methylation pattern in pre-adipocytes and islets were significant higher in cells from subjects with a higher BMI compared with control subjects. By exome sequencing of KLF13 gene in blood with the same cohort, we found nine SNPs (single nucleotide polymorphisms) within its gene body, and two SNPs (rs11537749 and rs12595641) were as cis-meQTL of cg07814318. There was the 2.01% methylation change of cg07814318 between homozygous dominant and recessive genotypes, especially, in rs12595641. The sequencing variations within KLF13 genes could drive dynamic modifications of obesity-related CpG methylation. Differential DNA methylation patterns in the KLF13 gene determined from separate blood samples showed that this criterion could be used as a surrogate for representing overall epigenetic changes in cells related to obesity.

Activating transcription factor 3 is a target molecule linking hepatic steatosis to impaired glucose homeostasis.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) contributes to impaired glucose tolerance, leading to type 2 diabetes (T2D); however, the precise mechanisms and target molecules that are involved remain unclear. Activating transcription factor 3 (ATF3) is associated with ß-cell dysfunction that is induced by severe stress signals in T2D. We aimed to explore the exact functional role of ATF3 as a mechanistic link between hepatic steatosis and T2D development. METHODS: Zucker diabetic fatty (ZDF) rats were utilized for animal experiments. An in vivo-jetPEI siRNA delivery system against ATF3 was used for loss-of-function experiments. We analyzed the baseline cross-sectional data derived from the biopsy-proven NAFLD registry (n=322). Human sera and liver tissues were obtained from 43 patients with biopsy-proven NAFLD and from seven healthy participants. RESULTS: ATF3 was highly expressed in the livers of ZDF rats and in human participants with NAFLD and/or T2D. Insulin resistance and hepatic steatosis were associated with increased ATF3 expression and decreased fatty acid oxidation via mitochondrial dysfunction and were attenuated by in vivo ATF3 silencing. Knockdown of ATF3 also ameliorated glucose intolerance, impaired insulin action, and inflammatory responses in ZDF rats. In patients with NAFLD and/or T2D, a significant positive correlation was observed between hepatic ATF3 expression and surrogate markers of T2D, mitochondrial dysfunction, and macrophage infiltration. CONCLUSIONS: Increased hepatic ATF3 expression is closely associated with hepatic steatosis and incident T2D; therefore, ATF3 may serve as a potential therapeutic target for NAFLD and hepatic steatosis-induced T2D. LAY SUMMARY: Hepatic activating transcription factor 3 (ATF3) may play an important role in oxidative stress-mediated hepatic steatosis and the development of type 2 diabetes (T2D) in a Zucker diabetic fatty (ZDF) rat model and in human patients with non-alcoholic fatty liver disease (NAFLD). Therefore, ATF3 may be a useful biomarker for predicting the progression of NAFLD and the development of T2D. Furthermore, given the significant association between hepatic ATF3 expression and both hepatic steatosis and impaired glucose homeostasis, in vivo ATF3 silencing may be a potential central strategy for preventing and managing NAFLD and T2D.

Exome-based genome-wide association study and risk assessment using genetic risk score to prostate cancer in the Korean population.

PURPOSE: To investigate exome-wide genetic variants associated with prostate cancer (PCa) in Koreans and evaluate the discriminative ability by the genetic risk score (GRS). PATIENTS AND METHODS: We prospectively recruited 1,001 PCa cases from a tertiary hospital and conducted a case-control study including 2,641 healthy men (Stage I). Participants were analyzed using HumanExome BeadChip. For the external validation, additionally enrolled 514 PCa cases and 548 controls (independent cohort) were analyzed for the identified single nucleotide polymorphisms (SNPs) of Stage I (Stage II). The GRS was calculated as a non-weighted sum of the risk allele counts and investigated for accuracy of prediction of PCa. RESULTS: the mean age was 66.3 years, and the median level of prostate specific antigen (PSA) was 9.19 ng/ml in PCa cases. In Stage I, 4 loci containing 5 variants (rs1512268 on 8p21.2; rs1016343 and rs7837688 on 8q24.21; rs7501939 on 17q12, and rs2735839 on 19q13.33) were confirmed to reach exome-wide significance (p<8.3x10-7). In Stage II, the mean GRS was 4.23 ± 1.44 for the controls and 4.78 ± 1.43 for the cases. As a reference to GRS 4, GRS 6, 7 and 8 showed a statistically significant risk of PCa (OR=1.85, 2.11 and 3.34, respectively). CONCLUSIONS: The five variants were validated to associate with PCa in firstly performed exome-wide study in Koreans. The addition of individualized calculated GRS effectively enhanced the accuracy of prediction. These results need to be validated in future studies.

An integrative study identifies KCNC2 as a novel predisposing factor for childhood obesity and the risk of diabetes in the Korean population.

Obesity is a major risk factor for type 2 diabetes. To unravel the genetic determinants of obesity-associated diabetes, we performed a genome-wide study using the 1,000 Genomes-based imputation in a Korean childhood cohort (KoCAS-1, n = 484) and carried out de novo replication in an independent population (KoCAS-2, n = 1,548). A novel variant (rs10879834) with multiple diverse associations for obesity-related traits was also found to be replicated in an adult cohort (KARE, n = 8,842). Functional annotations using integrative epigenetic analyses identified biological significance and regulatory effects with an inverse methylation-expression correlation (cg27154343 in the 5'-UTR of the KCNC2 gene), tissue-specific enhancer mark (H3K4me1), and pathway enrichment (insulin signaling). Further functional studies in cellular and mouse models demonstrated that KCNC2 is associated with anti-obesogenic effects in the regulation of obesity-induced insulin resistance. KCNC2 shRNA transfection induced endoplasmic reticulum (ER) stress and hepatic gluconeogenesis. Overproduction of KCNC2 decreased ER stress, and treatment with metformin enhanced KCNC2 expression. Taken together, these data suggest that reduction of KCNC2 is associated with modified hepatic gluconeogenesis and increased ER stress on obesity-mediated diabetic risk. An integrative multi-omics analysis might reveal new functional and clinical implications related to the control of energy and metabolic homeostasis in humans.

Genome-wide association study in East Asians suggests UHMK1 as a novel bone mineral density susceptibility gene.

To identify genetic variants that influence bone mineral density (BMD) in East Asians, we performed a quantitative trait analysis of lumbar spine, total hip and femoral neck BMD in a Korean population-based cohort (N=2729) and follow-up replication analysis in a Chinese Han population and two Caucasian populations (N=1547, 2250 and 987, respectively). From the meta-analysis of the stage 1 discovery analysis and stage 2 replication analysis, we identified four BMD loci that reached near-genome-wide significance level (P<5×10(-7)). One locus on 1q23 (UHMK1, rs16863247, P=4.1×10(-7) for femoral neck BMD and P=3.2×10(-6) for total hip BMD) was a novel BMD signal. Interestingly, rs16863247 was very rare in Caucasians (minor allele frequency<0.01), indicating that this association could be specific to East Asians. In gender specific analysis, rs1160574 on 1q32 (KCNH1) was associated with femoral neck BMD (P=2.1×10(-7)) in female subjects. rs9371538 in the known BMD region on 6q25 ESR1 was associated with lumbar spine BMD (P=5.6×10(-9)). rs7776725 in the known BMD region on 7q31 WTN16 was associated with total hip BMD (P=8.6×10(-9)). In osteoblasts, endogenous UHMK1 expression was increased during differentiation and UHMK1 knockdown decreased its differentiation, while UHMK1 overexpression increased its differentiation. In osteoclasts, endogenous UHMK1 expression was decreased during differentiation and UHMK1 knockdown increased its differentiation, while UHMK1 overexpression decreased its differentiation. In conclusion, our genome-wide association study identified the UHMK1 gene as a novel BMD locus specific to East Asians. Functional studies suggest a role of UHMK1 on regulation of osteoblasts and osteoclasts.

Genome-wide association studies in East Asians identify new loci for waist-hip ratio and waist circumference.

Sixty genetic loci associated with abdominal obesity, measured by waist circumference (WC) and waist-hip ratio (WHR), have been previously identified, primarily from studies conducted in European-ancestry populations. We conducted a meta-analysis of associations of abdominal obesity with approximately 2.5 million single nucleotide polymorphisms (SNPs) among 53,052 (for WC) and 48,312 (for WHR) individuals of Asian descent, and replicated 33 selected SNPs among 3,762 to 17,110 additional individuals. We identified four novel loci near the EFEMP1, ADAMTSL3 , CNPY2, and GNAS genes that were associated with WC after adjustment for body mass index (BMI); two loci near the NID2 and HLA-DRB5 genes associated with WHR after adjustment for BMI, and three loci near the CEP120, TSC22D2, and SLC22A2 genes associated with WC without adjustment for BMI. Functional enrichment analyses revealed enrichment of corticotropin-releasing hormone signaling, GNRH signaling, and/or CDK5 signaling pathways for those newly-identified loci. Our study provides additional insight on genetic contribution to abdominal obesity.

Identification of a Copy Number Variation on Chromosome 20q13.12 Associated with Osteoporotic Fractures in the Korean Population.

Osteoporotic fractures (OFs) are critical hard outcomes of osteoporosis and are characterized by decreased bone strength induced by low bone density and microarchitectural deterioration in bone tissue. Most OFs cause acute pain, hospitalization, immobilization, and slow recovery in patients and are associated with increased mortality. A variety of genetic studies have suggested associations of genetic variants with the risk of OF. Genome-wide association studies have reported various single-nucleotide polymorphisms and copy number variations (CNVs) in European and Asian populations. To identify CNV regions associated with OF risk, we conducted a genome-wide CNV study in a Korean population. We performed logistic regression analyses in 1,537 Korean subjects (299 OF cases and 1,238 healthy controls) and identified a total of 8 CNV regions significantly associated with OF (p < 0.05). Then, one CNV region located on chromosome 20q13.12 was selected for experimental validation. The selected CNV region was experimentally validated by quantitative polymerase chain reaction. The CNV region of chromosome 20q13.12 is positioned upstream of a family of long non-coding RNAs, LINC01260. Our findings could provide new information on the genetic factors associated with the risk of OF.

Gene and dietary calcium interaction effects on brachial-ankle pulse wave velocity.

BACKGROUND & AIM: Understanding the lifestyle and genetic factors that affect pulse wave velocity (PWV) may provide clues to preventing atherosclerotic cardiovascular events. The aim of this study is to investigate genome-wide genetic and dietary calcium (Ca) intake interaction effects on brachial-ankle pulse wave velocity (baPWV). METHODS: The baPWV was measured, and Ca intake was quantified by administering a food frequency questionnaire (FFQ) to 3198 participants, which included men and women (≥40 years) from the Korean Multi-Rural communities Cohort study (MRCohort). The interaction effects of dietary Ca intake and 19 single-nucleotide polymorphisms (SNPs) on baPWV were assessed using the general linear models. RESULTS: Dietary Ca intake was not significantly associated with baPWV or any type of SNP among the subjects herein. In men, however, the adducin1 (ADD1) rs4961_C SNP had a significant dietary Ca intake-dependent effect on mean baPWV (pinteraction = 0.002). In women, the interaction of zinc finger proteins 618 (ZNF618) rs10817542_A with dietary Ca intake played a significant and key role in mean baPWV (pinteraction = 0.001). In the results of ADD1 rs4961_C in men and ZNF618 rs10817542_A in women, the minor allele-lowest Ca intake tertile (T1) group had significantly higher mean baPWV value than other subgroups of Ca intake tertile-genotype cross-classification whereas genotype was not a significant effector on mean baPWV values among highest Ca intake subgroups (T3). CONCLUSIONS: The baPWV, a phenotype of arterial stiffness, can be modulated in subjects through regulation of dietary Ca intake, particularly in subjects with more vulnerable genotypes.

Meta analysis identifies a novel susceptibility locus associated with heel bone strength in the Korean population.

INTRODUCTION: Calcaneal quantitative ultrasound has been recognized as a non-invasive method for evaluation of bone strength and prediction of osteoporotic fracture. METHODS: To extend a thorough genetic catalog for osteoporotic bone properties, we performed a genome-wide association study (rural cohort I, n=1895) of speed of sound (SOS) using the 1000 genome-based imputation in the discovery stage and then carried out in silico lookups (rural cohort II and III, n=2,967) and de novo genotyping (rural cohort IV, n=4,296) in the replication stage. RESULTS: In the combined meta-analysis (n=9,158), we identified a novel variant associated with SOS (rs2445771 in the GLDN gene, P=2.27×10(-9)) reaching genome-wide significance in the Korean population. We further demonstrated that allele-specific regulatory modifications found to be associated with functional enrichments by ENCODE annotations. CONCLUSION: Our findings could provide additional insights into understanding of genetic and epigenetic regulations on bone metabolism.

Habitual dietary intake of ß-carotene, vitamin C, folate, or vitamin E may interact with single nucleotide polymorphisms on brachial-ankle pulse wave velocity in healthy adults.

PURPOSE: The interaction between genetics and diet may explain the present disagreement in the protective role of vitamin intake on cardiovascular disease. We cross-sectionally assessed the interaction of habitual dietary intake of ß-carotene, vitamin C, folate, and vitamin E with single nucleotide polymorphisms (SNPs) on brachial-ankle pulse wave velocity (baPWV), a measure of arterial stiffness. METHODS: Dietary intakes of ß-carotene, vitamin C, folate, and vitamin E were quantified by a food frequency questionnaire in 3198 healthy men and women (≥ 40 years) from the Korea Multi-Rural communities Cohort study. baPWV was measured, and 19 SNPs were genotyped. The associations and interactions between dietary vitamin intake, SNP genotype, and baPWV were assessed using general linear models. RESULTS: In both men and women, dietary intake of ß-carotene, vitamin C, folate, or vitamin E and baPWV were not directly associated. Vitamin C, folate, and vitamin E intake had an interaction with rs4961 (ADD1) genotype on baPWV in men. rs4961 also interacted with folate intake on baPWV in women. In women, rs10817542 (ZNF618) and rs719856 (CD2AP) had an interaction with ß-carotene and folate intake and rs5443 (GNB3) had an interaction with vitamin E intake on baPWV. In general, minor allele homozygotes with low vitamin intake had higher baPWV than other subgroups. Results were similar when supplement users were excluded. CONCLUSIONS: Higher intake of dietary vitamin C, folate, and vitamin E may be related to high baPWV in healthy Korean men who are minor allele homozygotes of rs4961. In healthy Korean women, dietary folate, ß-carotene, and vitamin E intake may affect baPWV differently according to rs4961, rs10817542, rs719856, or rs5443 genotype. Greater dietary intake of these nutrients may protect those that are genetically vulnerable to stiffening of the arteries.

Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci.

Human height is associated with risk of multiple diseases and is profoundly determined by an individual's genetic makeup and shows a high degree of ethnic heterogeneity. Large-scale genome-wide association (GWA) analyses of adult height in Europeans have identified nearly 180 genetic loci. A recent study showed high replicability of results from Europeans-based GWA studies in Asians; however, population-specific loci may exist due to distinct linkage disequilibrium patterns. We carried out a GWA meta-analysis in 93 926 individuals from East Asia. We identified 98 loci, including 17 novel and 81 previously reported loci, associated with height at P < 5 × 10(-8), together explaining 8.89% of phenotypic variance. Among the newly identified variants, 10 are commonly distributed (minor allele frequency, MAF > 5%) in Europeans, with comparable frequencies with in Asians, and 7 single-nucleotide polymorphisms are with low frequency (MAF < 5%) in Europeans. In addition, our data suggest that novel biological pathway such as the protein tyrosine phosphatase family is involved in regulation of height. The findings from this study considerably expand our knowledge of the genetic architecture of human height in Asians.

Genome-wide association meta-analysis identifies novel variants associated with fasting plasma glucose in East Asians.

Fasting plasma glucose (FPG) has been recognized as an important indicator for the overall glycemic state preceding the onset of metabolic diseases. So far, most indentified genome-wide association loci for FPG were derived from populations with European ancestry, with a few exceptions. To extend a thorough catalog for FPG loci, we conducted meta-analyses of 13 genome-wide association studies in up to 24,740 nondiabetic subjects with East Asian ancestry. Follow-up replication analyses in up to an additional 21,345 participants identified three new FPG loci reaching genome-wide significance in or near PDK1-RAPGEF4, KANK1, and IGF1R. Our results could provide additional insight into the genetic variation implicated in fasting glucose regulation.

Genome-wide association study identifies two novel Loci with sex-specific effects for type 2 diabetes mellitus and glycemic traits in a korean population.

BACKGROUND: Until recently, genome-wide association study (GWAS)-based findings have provided a substantial genetic contribution to type 2 diabetes mellitus (T2DM) or related glycemic traits. However, identification of allelic heterogeneity and population-specific genetic variants under consideration of potential confounding factors will be very valuable for clinical applicability. To identify novel susceptibility loci for T2DM and glycemic traits, we performed a two-stage genetic association study in a Korean population. METHODS: We performed a logistic analysis for T2DM, and the first discovery GWAS was analyzed for 1,042 cases and 2,943 controls recruited from a population-based cohort (KARE, n=8,842). The second stage, de novo replication analysis, was performed in 1,216 cases and 1,352 controls selected from an independent population-based cohort (Health 2, n=8,500). A multiple linear regression analysis for glycemic traits was further performed in a total of 14,232 nondiabetic individuals consisting of 7,696 GWAS and 6,536 replication study participants. A meta-analysis was performed on the combined results using effect size and standard errors estimated for stage 1 and 2, respectively. RESULTS: A combined meta-analysis for T2DM identified two new (rs11065756 and rs2074356) loci reaching genome-wide significance in CCDC63 and C12orf51 on the 12q24 region. In addition, these variants were significantly associated with fasting plasma glucose and homeostasis model assessment of ß-cell function. Interestingly, two independent single nucleotide polymorphisms were associated with sex-specific stratification in this study. CONCLUSION: Our study showed a strong association between T2DM and glycemic traits. We further observed that two novel loci with multiple diverse effects were highly specific to males. Taken together, these findings may provide additional insights into the clinical assessment or subclassification of disease risk in a Korean population.

Intake levels of dietary polyunsaturated fatty acids modify the association between the genetic variation in PCSK5 and HDL cholesterol.

BACKGROUND: A low serum level of high-density lipoprotein cholesterol (HDL-C) is a risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 5 (PCSK5) modulates HDL-C metabolism through the inactivation of endothelial lipase activity. METHODS: Therefore, we analysed the effects of PCSK5 on HDL-C and investigated the association between genetic variation in PCSK5 and dietary polyunsaturated fatty acids (PUFAs) intakes in Korean adults and children. This population-based study which was conducted in South Korea included 4205 adults (43% male) aged 40-69 years and 1548 children (48.6% boys) aged 8-13 years. Dietary intake was assessed using a semiquantitative food frequency questionnaire in adults and modified 3-day food records in children. RESULTS: After adjustments for age and body mass index, we identified a significant association between SNP rs1029035 of the PCSK5 gene and HDL-C concentrations specifically for men in both populations (adults, p=0.004; children, p=0.003; meta, p=7×10(-4)). Additionally, the interaction between the PCSK5 rs1029035 genotype and dietary polyunsaturated fatty acids intake influenced serum HDL-C concentrations in men (adults, p=0.001; children, p=0.008). The deleterious effect of the C allele on serum HDL-C was present only when dietary PUFA intake was less than the dichotomised median level (adults, p=0.011; children, p=0.001). Serum HDL-C concentrations were decreased in men with the C allele genotype and low consumption of dietary PUFA including n-3 and n-6. CONCLUSION: According to these results, men carrying of the C allele were associated with low HDL-C concentrations and might exert beneficial effects on HDL-C concentrations following consumption of a high-PUFA diet.