Mapping and annotating genomic loci to prioritize genes and implicate distinct polygenic adaptations for skin color.

Evidence for adaptation of human skin color to regional ultraviolet radiation suggests shared and distinct genetic variants across populations. However, skin color evolution and genetics in East Asians are understudied. We quantified skin color in 48,433 East Asians using image analysis and identified associated genetic variants and potential causal genes for skin color as well as their polygenic interplay with sun exposure. This genome-wide association study (GWAS) identified 12 known and 11 previously unreported loci and SNP-based heritability was 23-24%. Potential causal genes were determined through the identification of nonsynonymous variants, colocalization with gene expression in skin tissues, and expression levels in melanocytes. Genomic loci associated with pigmentation in East Asians substantially diverged from European populations, and we detected signatures of polygenic adaptation. This large GWAS for objectively quantified skin color in an East Asian population improves understanding of the genetic architecture and polygenic adaptation of skin color and prioritizes potential causal genes.

Image-based investigation of lip aging features in a large number of Korean women.

BACKGROUND: The lips play a significant role in shaping facial aesthetics. Due to the distinct attributes of lips in contrast to other facial skin, a unique approach is imperative for managing lip aging. We analyzed lip characteristics (morphology, wrinkles, and color) to investigate visual changes and distinctive attributes of aging lips. METHODS: By utilizing image data processing methods, including facial landmark detection, pattern recognition, and color quantification, we extracted 11 lip characteristic indices (four morphological indices, four wrinkle indices, and three color indices) from high-resolution images of 1000 Korean women aged 20-69. Correlation tests were conducted to assess the relationship between lip characteristic indices and age, and also between lip morphological and wrinkle indices. RESULTS: Lip height significantly decreased, while lip width and lip ratio (lip width divided by the sum of the upper and lower lip height) significantly increased with aging. Lip wrinkles significantly increased with aging, whereas lip colors (redness and yellowness) decreased. The lip wrinkle indices, which are segmented for the first time in this study, exhibited significant correlations with lip width, and three of them additionally were correlated with lip ratio (p < 0.05). The results imply such morphological changes can be associated with wrinkle formation of human lips. CONCLUSION: The indices suggested in this study can be used for assessing lip aging characteristics, and the study results can contribute to deeper understanding of lip aging.

Skin aging-related microbial types separated by Cutibacterium and α-diversity.

BACKGROUND: Studies on the skin microbiome have been conducted to uncover the relationship between skin microbes and the host. However, most of these studies have primarily focused on analyzing individual microbial compositions, which has resulted in a limited understanding of the overall relationship. METHODS: We analyzed the facial skin characteristics and microbial profiles of 100 healthy Korean female volunteers using the V1-V2 region of the 16S ribosomal RNA gene. RESULTS: The two most prominent features of the facial skin microbiome, the proportion of Cutibacterium and α-diversity, were associated with most of the skin characteristics. Based on clustering results, we proposed four types of facial skin microbiome: type C for Cutibacterium, type B for balanced, type CB for those between types C and B, and type O for others. Type C, which has a high proportion of Cutibacterium, showed high levels of pigmentation, wrinkles, pores, and sagging pores, indicating a tendency for severe skin aging. Type B, which has no dominant species and high microbial diversity, had lower values for pigmentation and wrinkles indicating less severe skin aging. Type CB was an intermediate type between type C and type B in terms of microbial composition and the level of skin aging. Type O dominated by microorganisms other than Cutibacterium, had high levels of sebum and pores but low levels of wrinkles. CONCLUSION: We proposed a criterion for classifying facial skin microbial types, each of which showed distinct facial skin aging features. Our simplified microbial types will contribute to a better understanding of facial skin microbial studies.

Longitudinal study of the interplay between the skin barrier and facial microbiome over 1 year.

Skin is a diverse ecosystem that provides a habitat for microorganisms. The skin condition and the skin microbiome interact each other under diverse environmental conditions. This study was conducted on 10 study participants for a one-year, from September 2020 to August 2021, to investigate the variability of skin microbiome and skin biophysical parameters [TEWL, hydration, and elasticity (R5)] according to season, and to understand the interplay between skin microbiome and skin characteristics. We identified that Cutibacterium, Corynebacterium, Staphyloccocus, unclassified genus within Neisseriaceae, and Streptococcus were major skin microbial taxa at the genus level, and fluctuated with the seasons. Cutibacterium was more abundant in winter, while Corynebacterium, Staphylococcus, and Streptococcus were more abundant in summer. Notably, Cutibacterium and skin barrier parameter, TEWL, exhibited a co-decreasing pattern from winter to summer and showed a significant association between Cutibacterium and TEWL. Furthermore, functional profiling using KEGG provided clues on the impact of Cutibacterium on the host skin barrier. This study enhances our understanding of the skin microbiome and its interplay with skin characteristics and highlights the importance of seasonal dynamics in shaping skin microbial composition.

Genome-scale metabolic modeling and in silico analysis of opportunistic skin pathogen Cutibacterium acnes.

Cutibacterium acnes, one of the most abundant skin microbes found in the sebaceous gland, is known to contribute to the development of acne vulgaris when its strains become imbalanced. The current limitations of acne treatment using antibiotics have caused an urgent need to develop a systematic strategy for selectively targeting C. acnes, which can be achieved by characterizing their cellular behaviors under various skin environments. To this end, we developed a genome-scale metabolic model (GEM) of virulent C. acnes, iCA843, based on the genome information of a relevant strain from ribotype 5 to comprehensively understand the pathogenic traits of C. acnes in the skin environment. We validated the model qualitatively by demonstrating its accuracy prediction of propionate and acetate production patterns, which were consistent with experimental observations. Additionally, we identified unique biosynthetic pathways for short-chain fatty acids in C. acnes compared to other GEMs of acne-inducing skin pathogens. By conducting constraint-based flux analysis under endogenous carbon sources in human skin, we discovered that the Wood-Werkman cycle is highly activated under acnes-associated skin condition for the regeneration of NAD, resulting in enhanced propionate production. Finally, we proposed potential anti-C. acnes targets by using the model-guided systematic framework based on gene essentiality analysis and protein sequence similarity search with abundant skin microbiome taxa.

GWAS Identifies Multiple Genetic Loci for Skin Color in Korean Women.

Human skin color is largely determined by genetic factors. Recent GWASs have reported several genetic variants associated with skin color, mostly in European and African populations. In this study, we performed GWAS in 17,019 Korean women to identify genetic variants associated with facial skin color, quantitatively measured as CIELAB color index. We identified variants in three, one, and six genomic loci associated with facial skin color index L∗, a∗, and b∗ values, respectively, and replicated the associations (combined analysis P-value < 5.0 × 10-8). The significant loci included variants in known genes (OCA2 rs74653330, BNC2 rs16935073, rs72620727 near KITLG, and SLC6A17 rs6689641) and to our knowledge previously unreported genes (SCARB1 rs10846744, SYN2 rs12629034, and LINC00486 rs6543678). This is GWAS to elucidate genetic variants of facial skin color in a Korean female population. Further functional characterizations of the investigated genes are warranted to elucidate their contribution to skin pigmentation-related traits.

Association of APOE genotype with lipid profiles and type 2 diabetes mellitus in a Korean population.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with chronic hyperglycemia and lipid metabolism. A previous genome-wide association study revealed the TOMM40-APOE region as novel locus for T2DM susceptibility. OBJECTIVE: This association study was conducted to determine the genetic effects of APOE single nucleotide polymorphisms (SNPs) on T2DM susceptibility and lipid profiles in a Korean population. METHODS: A total of 6 tagging SNPs, including rs7412 and rs429358, were selected for ε genotype analysis and genotyped in 1436 subjects, consisting of 352 T2DM patients and 1084 unaffected controls. RESULTS: Logistic regression analyses were conducted and there were no significant associations among the APOE 6 tagging SNPs, ε genotypes, and haplotypes with T2DM susceptibility. To investigate the association of the APOE tagging SNPs with the lipid profiles, a regression analysis was conducted. As a result, rs7412 was significantly associated with the total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) levels (Pcorr = 2.30 × 10-5 and 3.39 × 10-13, respectively) in the unaffected controls. The ε2 allele and ε3 allele were significantly associated with the TC (Pcorr = 4.46 × 10-6 and 0.02, respectively) and LDL levels (Pcorr = 3.54 × 10-14 and 0.0006, respectively) in the unaffected controls. Further analysis of only the unaffected controls was conducted. As a result, the APOE alleles ε2 and ε3 showed a significant association with the TC and LDL levels (P < 0.05). CONCLUSION: The results of this study may help in understanding APOE polymorphisms and ε alleles and lipid profiles, which have been highly linked to T2DM, in a Korean population.

Comparative analysis of skin characteristics evaluation by a dermatologist and the Janus-III measurement system.

BACKGROUND: The Janus-III measurement system evaluates the overall skin characteristics such as skin pore, wrinkle, sebum, porphyrin, skin pigmentation, and skin color using high-resolution facial images. The values are measured from five different facial areas, namely, the forehead, nose, corner of/skin below the eyes, and cheeks. Owing to its convenience and diverse measuring characteristics, Janus-III has been widely used in skin research and the cosmetic industry in Korea. In our previous study, we revealed the consistency and reliability of the system with repeatedly measured values. Its measuring performance was investigated statistically, but to make it more reliable for academic skin research, additional verification by a professional dermatologist is needed. MATERIALS AND METHODS: In this study, we conducted comparative analysis of three skin characteristics (pigmented spot, skin color, and eye wrinkle) by a dermatologist and the Janus-III measurement system. We utilized 330 image data that were cropped from the whole facial images of 330 different participants to avoid correlation among the three measuring items. Pearson's correlation coefficient exhibited similar patterns between the system and the dermatologist's findings. RESULTS: The main finding of our study was that the measured value of skin characteristics by the Janus-III system showed clear correlation with the values evaluated by a dermatologist, especially in a pigmented spot. CONCLUSION: Therefore, it would be a plausible idea to consider the Janus-III system for specialized research of skin characteristics even with a small sample size.

GWAS Analysis of 17,019 Korean Women Identifies the Variants Associated with Facial Pigmented Spots.

Variation in skin pigmentation can be affected by both environmental factors and intrinsic factors such as age, gender, and genetic variation. Recent GWASs revealed that genetic variants of genes functionally related to a pigmentation pathway were associated with skin pigmentary traits. However, these GWASs focused on populations with European ancestry, and only a few studies have been performed on Asian populations, limiting our understanding of the genetic basis of skin pigmentary traits in Asians. To evaluate the genetic variants associated with facial pigmented spots, we conducted a GWAS analysis of objectively measured facial pigmented spots in 17,019 Korean women. This large-scale GWAS identified several genomic loci that were significantly associated with facial pigmented spots (five previously reported loci and two previously unreported loci, to our knowledge), which were detected by UV light: BNC2 at 9p22 (rs16935073; P-value = 2.11 × 10-46), PPARGC1B at 5q32 (rs32579; P-value = 9.04 × 10-42), 10q26 (rs11198112; P-value = 9.66 × 10-38), MC1R at 16q24 (rs2228479; P-value = 6.62 × 10-21), lnc01877 at 2q33 (rs12693889; P-value = 1.59 × 10-11), CDKN2B-AS1 at 9p21 (rs643319; P-value = 7.76 × 10-9), and MFSD12 at 19p13 (rs2240751; P-value = 9.70 × 10-9). Further functional characterization of the candidate genes needs to be done to fully evaluate their contribution to facial pigmented spots.

A non-synonymous variant rs12614 of complement factor B associated with risk of chronic hepatitis B in a Korean population.

BACKGROUND: Hepatitis B is known to cause several forms of liver diseases including chronic hepatitis B (CHB), and hepatocellular carcinoma. Previous genome-wide association study of CHB risk has demonstrated that rs12614 of complement factor B (CFB) was significantly associated with CHB risk. In this study, fine-mapping study of previously reported GWAS single nucleotide polymorphism (SNP; CFB rs12614) was performed to validate genetic effect of rs12614 on CHB susceptibility and identify possible additional causal variants around rs12614 in a Korean population. This association study was conducted in order to identify genetic effects of CFB single nucleotide polymorphisms (SNPs) and to identify additional independent CHB susceptible causal markers within a Korean population. METHODS: A total of 10 CFB genetic polymorphisms were selected and genotyped in 1716 study subjects comprised of 955 CHB patients and 761 population controls. RESULTS: A non-synonymous variant, rs12614 (Arg32Trp) in exon2 of CFB, had significant associations with risk of CHB (odds ratio = 0.43, P = 5.91 × 10- 10). Additional linkage disequilibrium and conditional analysis confirmed that rs12614 had independent genetic effect on CHB susceptibility with previously identified CHB markers. The genetic risk scores (GRSs) were calculated and the CHB patients had higher GRSs than the population controls. Moreover, OR was found to increase significantly with cumulative GRS. CONCLUSIONS: rs12614 showed significant genetic effect on CHB risk within the Korean population. As such rs12614 may be used as a possible causal genetic variant for CHB susceptibility.

Association analysis of NOX5 polymorphisms with Hirschsprung disease.

BACKGROUND/PURPOSE: Hirschsprung disease (HSCR) is a developmental disease characterized by the absence of ganglion cells in the intestinal region. NADPH oxidase5 (NOX5) has been identified as one of the possible candidate genes for risk of Hirschsprung disease in our recent genome wide association study (GWAS). In this study, we performed a replication study to analyze the association of NOX5 polymorphisms with HSCR risk and conducted an extended analysis to investigate further associations for sub-groups and haplotypes. METHODS: A total of 23 NOX5 single nucleotide polymorphisms (SNPs) were genotyped in 187 HSCR patients and 283 unaffected controls. Statistical analysis was performed to examine the effects of genotype on risk of HSCR and HSCR subtype. RESULTS: Logistic regression analyses revealed that six SNPs (rs59355559, rs62010828, rs34990910, rs11856030, rs311905, and rs8024894) were associated with risk of HSCR (minimum p = 0.007 at rs62010828). Moreover, three SNPs (rs59355559, rs62010828, and rs8024894) were significantly associated with risk of long-segment HSCR (L-HSCR) subtype and 5 SNPs (rs59355559, rs62010828, rs34990910, rs11856030, and rs8024894) were found to be associated with risk of TCA subtype. CONCLUSION: Our results demonstrate that genetic variants in NOX5 have genetic effects on risk of HSCR, which may serve as useful preliminary information for further study. LEVELS OF EVIDENCE: Level III of prognosis study.

Association analysis of RTEL1 variants with risk of adult gliomas in a Korean population.

Previous studies have identified multiple loci for inherited susceptibility to glioma development, including the regulator of telomere elongation helicase 1 (RTEL1). However, the association between RTEL1 variants and risk of glioma has not been well understood. Therefore, we sought to comprehensively examine the genetic interaction between RTEL1 variants and risk of glioma with respect to defined histological and molecular subtypes. We employed a case-control study involving 250 adult glioma patients with previous molecular alterations and 375 population-based controls within Korean populations. Statistical analyses on the association between RTEL1 single nucleotide polymorphisms (SNPs) and glioma risk were conducted using unconditional logistic regression. Additional conditional and stepwise analyses were performed on significant RTEL1 SNPs. We detected significant associations (Bonferroni P < .05) between six SNPs (rs6089953, rs3848669, rs6010620, rs3787089, rs6062302, and rs115303435) and risk of glioma in the Korean subjects. The two coding variants, rs6062302 (D664D) and rs115303435 (A1059T), were plausibly causal variants and were independent among the significantly associated RTEL1 variants. The glioma subgroup analyses showed that the causal variants (rs6062302 and rs115303435) may be associated with increased risk of glioma regardless of histological grades and molecular alterations. This study provides a deeper understanding of relationships between RTEL1 variants and risk of glioma. Further studies are required to ascertain the impact of those variants on glioma susceptibility.

Genetic association of complement component 2 variants with chronic hepatitis B in a Korean population.

BACKGROUND & AIMS: Numerous single nucleotide polymorphisms associated with an increased risk of liver diseases, chronic hepatitis B and chronic hepatitis B-related hepatocellular carcinoma have been identified. In this study, we scrutinized the genetic effects of C2 variants, which were conflicting in previous results, on the risk of chronic hepatitis B in a Korean population. METHODS: We genotyped 22 common C2 genetic variants of 977 chronic hepatitis B cases including 302 chronic hepatitis B-related hepatocellular carcinoma cases and 785 population controls. Statistical analysis was performed to examine the effects of genotype on the risk of chronic hepatitis B and chronic hepatitis B-related hepatocellular carcinoma. RESULTS: Logistic regression analyses showed that six C2 single nucleotide polymorphisms had significant associations with the risk of chronic hepatitis B and chronic hepatitis B-related hepatocellular carcinoma among the Korean subjects. Stepwise analysis revealed that causal markers (rs9267665 and rs10947223) were identified among the C2 variants (stepwise P = 3.32 × 10-9 and 2.04 × 10-5 respectively). In further conditional analysis with previous chronic hepatitis B-associated loci, these two single nucleotide polymorphisms were independently associated with the risk of chronic hepatitis B. In addition, we investigated the ability of genetic risk scores combining 12 multi-chronic hepatitis B loci to predict the risk of chronic hepatitis B. Individuals with higher genetic risk scores showed increased risk for chronic hepatitis B. CONCLUSIONS: Our results suggested that the C2 gene might be a susceptibility locus for chronic hepatitis B in Korean populations. The cumulative genetic effects may contribute to future etiological explanations for chronic hepatitis B.

Clinical usefulness of intraductal ultrasonography for the management of acute biliary pancreatitis.

BACKGROUND AND AIM: Identifying a bile duct (BD) stone in patients with acute biliary pancreatitis (ABP) is important for the management and prevention of recurrent attack of pancreatitis. However, small BD stones may not be detected on endoscopic retrograde cholangiopancreatography (ERCP). The aim of this study was to prospectively evaluate the usefulness of intraductal ultrasonography (IDUS) in patients suspected to have ABP but with no evidence of choledocholithiasis on ERCP. METHODS: A total 92 patients suspected with ABP without evidence of BD stones on imaging studies including ERCP were enrolled. Wire-guided IDUS was performed during ERCP in all patients. Stones or sludge detected by IDUS were confirmed after endoscopic sphincterotomy (EST) and extraction. If IDUS finding was negative, then we swept the BD with a balloon catheter and/or basket without EST. After endoscopic management, comparison between IDUS and endoscopic finding was carried out to determine the diagnostic accuracy of IDUS. RESULTS: Among the 92 patients, IDUS revealed BD stones in 33 (35.9%). All 33 patients' stones were confirmed by endoscopic visualization after EST and BD exploration. During the mean follow up of 24 months, recurrent pancreatitis did not occur in 90 of 92 patients (97.9%) with ABP after endoscopic treatment according to the IDUS findings. CONCLUSIONS: IDUS improves diagnostic accuracy for the detection of clinically occult BD stones in patients suspicious ABP. IDUS-guided endoscopic management for patients with ABP can avoid unnecessary EST and help prevent recurrent pancreatitis.

Usefulness and safety of endoscopic treatment for nonampullary duodenal adenoma and adenocarcinoma.

BACKGROUND AND AIM: Safety and efficacy data on endoscopic treatment of duodenal neoplasm are limited. We suggest the technical feasibility of endoscopic procedures by evaluating the results of endoscopic treatment for nonampullary duodenal adenoma and adenocarcinoma. METHODS: Forty-five patients who underwent endoscopic treatment for nonampullary duodenal adenoma with or without malignant transformation between September 2003 and March 2012 were included. Endoscopic polypectomy of duodenal polyp (DPP), duodenal endoscopic mucosal resection (DEMR), and duodenal endoscopic submucosal dissection (DESD) were selected as endoscopic treatments for each lesion. RESULTS: Mean lesion size was 9.1 mm, and most lesions were located in the second portion of the duodenum. There were 40 adenomas and five early-stage adenocarcinomas arising from adenomas. Of the 45 duodenal neoplasms, five patients were treated with DPP, 33 with DEMR, and seven patients with a large duodenal lesion underwent DESD. Minimum of 1-year follow-up endoscopies were performed in 42 patients, excepting three patients treated after October 2011. Median follow-up was 24.8 months. Of the 45 patients, en bloc resection was performed in 43 (95.6%). A complete resection was performed in 41 patients (91.1%). No significant bleeding events occurred. Perforations occurred in three patients who underwent DESD. All perforations were noticed during the procedures and completely closed by endoscopic clipping. There was one recurrence at 6 months after DPP. CONCLUSION: Endoscopic treatment is minimally invasive management for duodenal adenomas and superficial adenocarcinomas. It would be helpful for medical doctors in the management of duodenal neoplasms.

[Endoscopic submucosal dissection of a leiomyoma originating from the muscularis propria of upper esophagus].

The technique of endoscopic submucosal dissection is occasionally used for resection of myogenic tumors originating from muscularis mucosa or muscularis propria of stomach and esophagus. However, endoscopic treatments for esophageal myogenic tumors >2 cm have rarely been reported. Herein, we report a case of large leiomyoma originating from muscularis propria in the upper esophagus. A 59-year-old woman presented with dysphagia. Esophagoscopy and endoscopic ultrasonography revealed an esophageal subepithelial tumor which measured 25 × 20 mm in size, originated from muscularis propria, and was located at 20 cm from the central incisors. The tumor was successfully removed by endoscopic submucosal dissection and there were no complications after en bloc resection. Pathologic examination was compatible with leiomyoma.

Specific movement of esophagus during transient lower esophageal sphincter relaxation in gastroesophageal reflux disease.

BACKGROUND/AIMS: Transient lower esophageal sphincter relaxation (TLESR) is the main mechanism of gastroesophageal reflux disease (GERD). The aim of this study was to investigate the characteristics of transient lower esophageal sphincter movement in patients with or without gastroesophageal reflux by high-resolution manometry (HRM). METHODS: From June 2010 to July 2010, we enrolled 9 patients with GERD (GERD group) and 9 subjects without GERD (control group), prospectively. The manometry test was performed in a semi-recumbent position for 120 minutes following ingestion of a standardized, mixed liquid and solid meal. HRM was used to identify the frequency and duration of TLESR, esophageal shortening length from incomplete TLESR, upper esophageal sphincter (UES) response, and the related esophageal motor responses during TLESR. RESULTS: TLESR occurred in 33 in the GERD group and 34 in the control group after 120 minutes following food ingestion. Duration of TLESR and length of esophageal shortening did not differ between 2 groups. UES pressure increase during TLESR was mostly detected in patients with GERD, and UES relaxation was observed frequently in the control group during TLESR. TLESR-related motor responses terminating in TLESR were predominantly observed in the control group. CONCLUSIONS: Increased UES pressure was noted frequently in the GERD group, suggesting a mechanism for preventing harmful reflux, which may be composed mainly of fluid on the larynx or pharynx. However, patients with GERD lacked the related motor responses terminating in TLESR to promote esophageal emptying of refluxate.