Eva Maria Cutiongco-De la Paz

Introduction: The diagnostic utility of HbA1c for identifying prediabetes remains uncertain, particularly across diverse racial and ethnic populations. We evaluated concordance between HbA1c, fasting plasma glucose (FPG), and oral glucose tolerance testing (OGTT) in a Filipino-American cohort. Research Design and Methods: We analyzed cross-sectional data from 149 Filipino-American adults without known diabetes in the San Francisco Bay Area. Prediabetes prevalence was assessed using American Diabetes Association criteria for HbA1c, FPG, and OGTT. Agreement between diagnostic methods was evaluated, and metabolic characteristics were compared across glycemic categories. Results: Prediabetes prevalence differed substantially by diagnostic method: 35% by HbA1c, 8.1% by FPG, and 8.7% by OGTT. Overall agreement between tests was low. Among individuals classified as prediabetic by HbA1c, the majority did not meet criteria by FPG or OGTT. However, higher HbA1c levels were associated with increased body mass index, waist-hip ratio, blood pressure, triglycerides, fasting insulin, and HOMA-IR. Conclusions: In this Filipino-American cohort, HbA1c identifies a substantially larger group of individuals with prediabetes compared to glucose-based tests, with limited concordance between methods. Individuals classified as prediabetic by HbA1c exhibit features consistent with insulin resistance. These findings highlight potential differences in metabolic phenotypes captured by alternative diagnostic criteria and underscore the need for longitudinal studies to determine their relative prognostic value. 1) What is already known on this topic: HbA1c, FPG, and OGTT are all used to diagnose prediabetes, but prior studies show poor agreement between these tests and substantial variation in prevalence estimates across populations. Evidence suggests these differences may be influenced by underlying physiology and race/ethnicity, yet data in Filipino-Americans—especially for prediabetes—have been limited. 2) What this study adds: In Filipino-Americans, HbA1c identifies a much higher prevalence of prediabetes than FPG or OGTT, with low concordance between methods. Individuals classified as prediabetic by HbA1c alone show metabolic features consistent with insulin resistance, suggesting this group represents a meaningful at-risk phenotype. 3) How this study might affect research, practice or policy: These findings suggest that reliance on a single diagnostic test may misclassify risk and that HbA1c may capture additional at-risk individuals in this population. They support the need for longitudinal studies and potential reconsideration of diagnostic thresholds or combined testing approaches tailored to specific populations.

Breast cancer is the most prevalent cancer affecting women, particularly in Asia, with the highest incidence in the Philippines. Despite ongoing efforts, the understanding of breast cancer biology remains inadequate, compounded by the lack of effective screening programs and timely treatments. Addressing these issues, biobanks and other repositories for biological specimens have gained global momentum. The University of the Philippines- Philippine General Hospital (UP-PGH) has established a cancer biobank, demonstrating the viability of a government-supported initiative for cancer research in the Philippines. The study involves a prospective observation of 100 Filipino breast cancer patients at various disease stages, leveraging the expertise of UP-PGH, Philippine Genome Center (PGC), and University of the Philippines Diliman - Institute of Biology (UPD-IB). It integrates the collection, processing, and storage of biospecimens alongside comprehensive patient data. Procedures include RNA extraction, library preparation, and sequencing. Additionally, a subset of patients participates in an in vitro three-dimensional (3D) cell culture experiment for chemotherapy pre-screening. The aggregated data aims to uncover therapeutic strategies that can lead to personalized treatments where standard clinical approaches are inadequate. Key techniques include ultrasound-guided core needle biopsy, meticulous normal breast tissue collection, and precise tumor percentage determination to ensure high-quality RNA extraction, sequencing, and 3D cell culture. The study also addresses challenges encountered in prior biobanking endeavors. Ultimately, this research aims to contribute significantly to breast cancer research, positioning itself as a model for collaborative research, biobank establishment, and the advancement of precision medicine in developing countries, such as the Philippines.

Breast cancer is the most prevalent cancer affecting women, particularly in Asia, with the highest incidence in the Philippines. Despite ongoing efforts, the understanding of breast cancer biology remains inadequate, compounded by the lack of effective screening programs and timely treatments. Addressing these issues, biobanks and other repositories for biological specimens have gained global momentum. The University of the Philippines- Philippine General Hospital (UP-PGH) has established a cancer biobank, demonstrating the viability of a government-supported initiative for cancer research in the Philippines. The study involves a prospective observation of 100 Filipino breast cancer patients at various disease stages, leveraging the expertise of UP-PGH, Philippine Genome Center (PGC), and University of the Philippines Diliman - Institute of Biology (UPD-IB). It integrates the collection, processing, and storage of biospecimens alongside comprehensive patient data. Procedures include RNA extraction, library preparation, and sequencing. Additionally, a subset of patients participates in an in vitro three-dimensional (3D) cell culture experiment for chemotherapy pre-screening. The aggregated data aims to uncover therapeutic strategies that can lead to personalized treatments where standard clinical approaches are inadequate. Key techniques include ultrasound-guided core needle biopsy, meticulous normal breast tissue collection, and precise tumor percentage determination to ensure high-quality RNA extraction, sequencing, and 3D cell culture. The study also addresses challenges encountered in prior biobanking endeavors. Ultimately, this research aims to contribute significantly to breast cancer research, positioning itself as a model for collaborative research, biobank establishment, and the advancement of precision medicine in developing countries, such as the Philippines.

Adipose tissue dysfunction in obesity is a major global public health risk, contributing to insulin resistance and chronic diseases such as diabetes and cardiovascular disorders. Here, we identify a dominant c.37A>G p.(Arg13Gly) variant in the long isoform of CIDEC (CIDEC-L), a key regulator of lipid droplet (LD) size, as the underlying cause of familial obesity. Affected individuals display marked subcutaneous fat accumulation in white adipose tissue (WAT), elevated fat content in brown adipose tissue (BAT) and insulin resistance. Accordingly, patient-derived iPSCs differentiated into white adipocytes exhibit accelerated LD growth, a phenotype mirrored by CIDEC-L ^R13G overexpression. Mechanistically, we find that the p.Arg13Gly variant disrupts the N-terminal structural order of CIDEC-L, shifting its phase separation properties to enable, rather than restrict, lipid exchange through condensation plates between LDs. Notably, knock-in mice with the analogous Cidec-L p.(Arg10Gly) mutation recapitulate the human BAT hypertrophy and exhibit impaired thermogenesis. These findings establish the CIDEC-L ^R13G variant as the first example of a dominantly inherited monogenic obesity driven by a dysfunctional adipocyte LD protein, revealing a critical role for CIDEC-L in restraining fat accumulation and maintaining metabolic health.

Type 2 diabetes mellitus leads to debilitating complications that affect the quality of life of many Filipinos. Genetic variability contributes to 30% to 70% of T2DM risk. Determining genomic variants related to type 2 diabetes mellitus susceptibility can lead to early detection to prevent complications. However, interethnic variability in risk and genetic susceptibility exists. This study aimed to identify variants associated with type 2 diabetes mellitus among Filipinos using a case-control design frequency matched for age and sex. A comparison was made between 66 unrelated Filipino adults with type 2 diabetes mellitus and 121 without. Genotyping was done using a candidate gene approach on genetic variants of type 2 diabetes mellitus and its complications involving allelic association and genotypic association studies with correction for multiple testing. Nine (9) significant variants, mostly involved in glucose and energy metabolism, associated with type 2 diabetes mellitus in Filipinos were found. Notably, a CDKAL1 variant (rs7766070) confers the highest level of risk while rs7119 (HMG20A) and rs708272 (CETP) have high risk allele frequencies in this population at 0.77 and 0.66, respectively, making them potentially good markers for type 2 diabetes mellitus screening. The data generated can be valuable in developing genetic risk prediction models for type 2 diabetes mellitus to diagnose and prevent the condition among Filipinos.

High blood level of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease. Although genetic variants linked to high LDL-C have been studied in other populations, there have been no previous studies among Filipinos. This study aims to determine the association of candidate genetic variants to high LDL-C. We performed an age- and sex-matched case-control study that compared Filipino participants with high LDL-C levels (n=60) with controls (n=60). DNA was extracted from blood samples and genotyped for candidate SNPs using a customized microarray chip. Logistic regression analyses were used to determine the composite association of genetic and clinical variables to the condition. Of the initial eleven SNPs associated with high LDL-C in univariate analyses, only the variant rs9644568 in the intergenic region downstream of the LPL gene remained significantly associated with high LDL-C levels on multiple regression analysis and variable selection after adjustment for hypertension. The G allele was observed as the risk allele in a recessive model. The variant rs9644568-G in the LPL gene was associated with high blood LDL-C levels among Filipinos. In combination with hypertension, this genetic profile may identify individuals who are susceptible to develop high LDL-C in this population.

Introduction. Sulfonylureas (SUs) are commonly used drugs for type 2 diabetes mellitus (T2DM) in the Philippines. This study aimed to associate genetic variants with poor response to gliclazide and glimepiride among Filipinos. Methodology. Two independent, dichotomous longitudinal substudies enrolled 139 and 113 participants in the gliclazide and glimepiride substudies, respectively. DNA from blood samples underwent customized genotyping for candidate genes using microarray. Allelic and genotypic features and clinical associations were determined using exact statistical methods. Results. Three months after sulfonylurea monotherapy, 18 (13%) were found to be poorly responsive to gliclazide, while 7 (6%) had poor response to glimepiride. Seven genetic variants were nominally associated (pAGBL4 and rs2229437 of PRCP) had the highest genotypic association; other variants include rs9806699, rs7119, rs6465084 and rs1234315. For glimepiride response, 2 variants were nominally associated: CLCN6-NPPA-MTHFR gene cluster – rs5063 and rs17367504 – and rs2299267 from the PON2 loci. Conclusion. Genetic variants were found to have a nominal association with sulfonylurea response among Filipinos. These findings can guide for future study directions on pharmacotherapeutic applications for sulfonylurea treatment in this population.

Phosphatase and tensin homolog deleted on chromosome 10, or PTEN, is a well-characterized tumor suppressor with both lipid and protein phosphatase activities. PTEN is often downregulated by epigenetic mechanisms such as hypermethylation, which leads to constitutive activation of the PI3K–Akt pathway. Large datasets from next-generation sequencing, however, revealed that mutations in PTEN may not only hamper protein function but may also affect interactions with downstream effectors, leading to variable oncogenic readouts. Here, two novel PTEN mutations, Q171R and Y65S, identified in Filipino colorectal cancer patients, were phenotypically characterized in NIH3T3 and HCT116 cells, alongside the C124S canonical mutant and wild-type controls. The novel mutants increased cellular proliferation, resistance to apoptosis and migratory capacity. They induced gross morphological changes including cytoplasmic shrinkage, increased cellular protrusions and extensive cytoskeletal reorganization. The mutants also induced a modest increase in Akt phosphorylation. Further mechanistic studies will help determine the differential oncogenic potencies of these mutants, and resolve whether the structural constraints imposed by the mutations may have altered associations with downstream effectors.