The deep population history of northern East Asia from the Late Pleistocene to the Holocene.

Northern East Asia was inhabited by modern humans as early as 40 thousand years ago (ka), as demonstrated by the Tianyuan individual. Using genome-wide data obtained from 25 individuals dated to 33.6-3.4 ka from the Amur region, we show that Tianyuan-related ancestry was widespread in northern East Asia before the Last Glacial Maximum (LGM). At the close of the LGM stadial, the earliest northern East Asian appeared in the Amur region, and this population is basal to ancient northern East Asians. Human populations in the Amur region have maintained genetic continuity from 14 ka, and these early inhabitants represent the closest East Asian source known for Ancient Paleo-Siberians. We also observed that EDAR V370A was likely to have been elevated to high frequency after the LGM, suggesting the possible timing for its selection. This study provides a deep look into the population dynamics of northern East Asia.

Multiple Deeply Divergent Denisovan Ancestries in Papuans.

Genome sequences are known for two archaic hominins-Neanderthals and Denisovans-which interbred with anatomically modern humans as they dispersed out of Africa. We identified high-confidence archaic haplotypes in 161 new genomes spanning 14 island groups in Island Southeast Asia and New Guinea and found large stretches of DNA that are inconsistent with a single introgressing Denisovan origin. Instead, modern Papuans carry hundreds of gene variants from two deeply divergent Denisovan lineages that separated over 350 thousand years ago. Spatial and temporal structure among these lineages suggest that introgression from one of these Denisovan groups predominantly took place east of the Wallace line and continued until near the end of the Pleistocene. A third Denisovan lineage occurs in modern East Asians. This regional mosaic suggests considerable complexity in archaic contact, with modern humans interbreeding with multiple Denisovan groups that were geographically isolated from each other over deep evolutionary time.

An Ancient Harappan Genome Lacks Ancestry from Steppe Pastoralists or Iranian Farmers.

We report an ancient genome from the Indus Valley Civilization (IVC). The individual we sequenced fits as a mixture of people related to ancient Iranians (the largest component) and Southeast Asian hunter-gatherers, a unique profile that matches ancient DNA from 11 genetic outliers from sites in Iran and Turkmenistan in cultural communication with the IVC. These individuals had little if any Steppe pastoralist-derived ancestry, showing that it was not ubiquitous in northwest South Asia during the IVC as it is today. The Iranian-related ancestry in the IVC derives from a lineage leading to early Iranian farmers, herders, and hunter-gatherers before their ancestors separated, contradicting the hypothesis that the shared ancestry between early Iranians and South Asians reflects a large-scale spread of western Iranian farmers east. Instead, sampled ancient genomes from the Iranian plateau and IVC descend from different groups of hunter-gatherers who began farming without being connected by substantial movement of people.

Profiling genetically driven alternative splicing across the Indonesian archipelago.

One of the regulatory mechanisms influencing the functional capacity of genes is alternative splicing (AS). Previous studies exploring the splicing landscape of human tissues have shown that AS has contributed to human biology, especially in disease progression and the immune response. Nonetheless, this phenomenon remains poorly characterized across human populations, and it is unclear how genetic and environmental variation contribute to AS. Here, we examine a set of 115 Indonesian samples from three traditional island populations spanning the genetic ancestry cline that characterizes Island Southeast Asia. We conduct a global AS analysis between islands to ascertain the degree of functionally significant AS events and their consequences. Using an event-based statistical model, we detected over 1,500 significant differential AS events across all comparisons. Additionally, we identify over 6,000 genetic variants associated with changes in splicing (splicing quantitative trait loci [sQTLs]), some of which are driven by Papuan-like genetic ancestry, and only show partial overlap with other publicly available sQTL datasets derived from other populations. Computational predictions of RNA binding activity reveal that a fraction of these sQTLs directly modulate the binding propensity of proteins involved in the splicing regulation of immune genes. Overall, these results contribute toward elucidating the role of genetic variation in shaping gene regulation in one of the most diverse regions in the world.

Phylogenetic evidence clarifies the history of the extrusion of Indochina.

The southeastward extrusion of Indochina along the Ailao Shan-Red River shear zone (ARSZ) is one of two of the most prominent consequences of the India-Asia collision. This plate-scale extrusion has greatly changed Southeast Asian topography and drainage patterns and effected regional climate and biotic evolution. However, little is known about how Indochina was extruded toward the southeast over time. Here, we sampled 42 plant and animal clades (together encompassing 1,721 species) that are distributed across the ARSZ and are not expected to disperse across long distances. We first assess the possible role of climate on driving the phylogenetic separations observed across the ARSZ. We then investigate the temporal dynamics of the extrusion of Indochina through a multitaxon analysis. We show that the lineage divergences across the ARSZ were most likely associated with the Indochinese extrusion rather than climatic events. The lineage divergences began at ~53 Ma and increased sharply ~35 Ma, with two peaks at ~19 Ma and ~7 Ma, and one valley at ~13 Ma. Our results suggest a two-phase model for the extrusion of Indochina, and in each phase, the extrusion was subject to periods of acceleration and decrease, in agreement with the changes of the India-Asia convergence rate and angle from the early Eocene to the late Miocene. This study highlights that a multitaxon analysis can illuminate the timing of subtle historical events that may be difficult for geological data to pinpoint and can be used to explore other tectonic events.

Hydroclimatic changes on multiple timescales since 7800 y BP in the winter precipitation-dominated Central Asia.

Central Asia (CA) is one of the world's most significant arid regions, which is markedly impacted by global warming. A better understanding of the dynamical processes governing its Holocene climate variability is critical for a better understanding of possible future impacts of climate change in the region. To date, most of the existing CA paleoclimate records are from the summer precipitation-dominated eastern CA (ECA), with few records from the winter precipitation-dominated western CA (WCA). Here, we present a precisely dated (~6‰) and highly resolved (<4-y) record of hydroclimatic variations from the WCA covering the period between 7,774 and 656 y BP. Utilizing multiple proxies (δ18O, δ13C, and Sr/Ca) derived from a stalagmite from the Fergana Valley, Kyrgyzstan, we reveal a long-term drying trend in WCA, which is in contrast with the wetting trend in ECA. We propose that different responses of winter and summer westerly jets to seasonal solar insolation over the past 8,000 y may have resulted in an antiphased precipitation relationship between the WCA and ECA. Our data contain dominant quasiperiodicities of 1,400, 50 to 70, and 20 to 30 y, indicating close connections between the WCA climate and the North Atlantic. We further identified a series of droughts and pluvials on centennial-to-decadal timescales, which may have influenced regional societies and trans-Eurasian culture exchanges during historical and prehistorical times.

Earliest Prepared core technology in Eurasia from Nihewan (China): Implications for early human abilities and dispersals in East Asia.

Organized flaking techniques to obtain predetermined stone tools have been traced back to the early Acheulean (also known as mode 2) in Africa and are seen as indicative of the emergence of advanced technical abilities and in-depth planning skills among early humans. Here, we report one of the earliest known examples of prepared core technology in the archaeological record, at the Cenjiawan (CJW) site in the Nihewan basin of China, dated 1.1 Mya. The operational schemes reconstructed from the CJW refit sets, together with shaping patterns observed in the retouched tools, suggest that Nihewan basin toolmakers had the technical abilities of mode 2 hominins, and developed different survival strategies to adapt to local raw materials and environments. This finding predates the previously earliest known prepared core technology from Eurasia by 0.3 My, and the earliest known mode 2 sites in East Asia by a similar amount of time, thus suggesting that hominins with advanced technologies may have migrated into high latitude East Asia as early as 1.1 Mya.

The genetic admixture and assimilation of Ahom: a historic migrant from Thailand to India.

The Northeastern region of India is considered a gateway for modern humans' dispersal throughout Asia. This region is a mixture of various ethnic and indigenous populations amalgamating multiple ancestries. One reason for such amalgamation is that, South Asia experienced multiple historic migrations from various parts of the world. A few examples explored genetically are Jews, Parsis and Siddis. Ahom is a dynasty that historically migrated to India during the 12th century. However, this putative migration has not been studied genetically at high resolution. Therefore, to validate this historical evidence, we genotyped autosomal data of the Modern Ahom population residing in seven sister states of India. Principal Component and Admixture analyses haave suggested a substantial admixture of the Ahom population with the local Tibeto-Burman populations. Moreover, the haplotype-based analysis has linked these Ahom individuals mainly with the Kusunda (a language isolated from Nepal) and Khasi (an Austroasiatic population of Meghalaya). Such unexpected presence of widespread population affinities suggests that Ahom mixed and assimilated a wide variety of Trans-Himalayan populations inhabiting this region after the migration. In summary, we observed a significant deviation of Ahom from their ancestral homeland (Thailand) and extensive admixture and assimilation with the local South Asian populations.

Boundary exchange completes the marine Pb cycle jigsaw.

Material fluxes at the land-ocean interface impact seawater composition and global cycling of elements. However, most attention has been focused on the fluvial dissolved fluxes. For elements like lead (Pb), whose fluvial particulate flux into the ocean is two orders of magnitude higher than the dissolved counterpart, the role of particulates in elemental cycling is potentially important but currently less appreciated. Using both chemical analyses on samples collected from around equatorial Southeast Asia and model simulations, we show that particulate-dissolved exchange is an important mechanism controlling the concentration and isotopic composition of dissolved Pb in the ocean. Our model indicates that Pb contributed from particulate-dissolved exchange at ocean boundaries is larger than, or at least comparable to, other major Pb sources to the seawater before the Anthropocene, when the anthropogenic Pb was absent. Our work highlights the importance of boundary exchange in understanding marine element cycling and weathering-climate feedback.

Strengthening the argument for a large Greater India.

The Sangdanlin section in southern Tibet represents a geologic Rosetta stone to constrain the initiation of the India-Asia collision from its sedimentary and paleomagnetic records. However, geoscientists have arrived at fundamentally divergent interpretations surrounding the age of the strata and its paleomagnetic record. Here, we report paleontologic, petrographic, and paleomagnetic data from the Sangdanlin section that recognize the sequence as a thrust complex containing interlaced Barremian-Albian (Early Cretaceous) and Paleocene strata, each separated by thrust faults. Recognizing two complexly interwoven formations of distinctly different ages contradicts a continuous stratigraphic superposition. Assigning an Early Cretaceous, instead of Paleocene, age to the units collected for paleomagnetic data revises paleogeographic models thereby supporting a large (2,000 to 3,000 km) extent of Greater India, with collision initiating at 55 ± 5 Ma in the western Himalayas. A contiguous plate in the Neotethys Ocean precludes that Asia's southern margin was built through a succession of accreted terrains.

A Rare Noncoding Enhancer Variant in SCN5A Contributes to the High Prevalence of Brugada Syndrome in Thailand.

BACKGROUND: Brugada syndrome (BrS) is a cardiac arrhythmia disorder that causes sudden death in young adults. Rare genetic variants in the SCN5A gene encoding the Nav1.5 sodium channel and common noncoding variants at this locus are robustly associated with the condition. BrS is particularly prevalent in Southeast Asia but the underlying ancestry-specific factors remain largely unknown. METHODS: Genome sequencing of BrS probands and population-matched controls from Thailand was performed to identify rare noncoding variants at the SCN5A-SCN10A locus that were enriched in patients with BrS. A likely causal variant was prioritized by computational methods and introduced into human induced pluripotent stem cell (hiPSC) lines using CRISPR-Cas9. The effect of the variant on SCN5A expression and Nav1.5 sodium channel current was then assessed in hiPSC-derived cardiomyocytes (hiPSC-CMs). RESULTS: A rare noncoding variant in an SCN5A intronic enhancer region was highly enriched in patients with BrS (detected in 3.9% of cases with a case-control odds ratio of 45.2). The variant affects a nucleotide conserved across all mammalian species and predicted to disrupt a Mef2 transcription factor binding site. Heterozygous introduction of the enhancer variant in hiPSC-CMs caused significantly reduced SCN5A expression from the variant-containing allele and a 30% reduction in Nav1.5-mediated sodium current density compared with isogenic controls, confirming its pathogenicity. Patients with the variant had severe phenotypes, with 89% experiencing cardiac arrest. CONCLUSIONS: This is the first example of a functionally validated rare noncoding variant at the SCN5A locus and highlights how genome sequencing in understudied populations can identify novel disease mechanisms. The variant partly explains the increased prevalence of BrS in this region and enables the identification of at-risk variant carriers to reduce the burden of sudden cardiac death in Thailand.

Implementation of First-Trimester Screening and Prevention of Preeclampsia: A Stepped Wedge Cluster-Randomized Trial in Asia.

BACKGROUND: This trial aimed to assess the efficacy, acceptability, and safety of a first-trimester screen-and-prevent strategy for preterm preeclampsia in Asia. METHODS: Between August 1, 2019, and February 28, 2022, this multicenter stepped wedge cluster randomized trial included maternity/diagnostic units from 10 regions in Asia. The trial started with a period where all recruiting centers provided routine antenatal care without study-related intervention. At regular 6-week intervals, one cluster was randomized to transit from nonintervention phase to intervention phase. In the intervention phase, women underwent first-trimester screening for preterm preeclampsia using a Bayes theorem-based triple-test. High-risk women, with adjusted risk for preterm preeclampsia ≥1 in 100, received low-dose aspirin from <16 weeks until 36 weeks. RESULTS: Overall, 88.04% (42 897 of 48 725) of women agreed to undergo first-trimester screening for preterm preeclampsia. Among those identified as high-risk in the intervention phase, 82.39% (2919 of 3543) received aspirin prophylaxis. There was no significant difference in the incidence of preterm preeclampsia between the intervention and non-intervention phases (adjusted odds ratio [aOR], 1.59 [95% CI, 0.91-2.77]). However, among high-risk women in the intervention phase, aspirin prophylaxis was significantly associated with a 41% reduction in the incidence of preterm preeclampsia (aOR, 0.59 [95% CI, 0.37-0.92]). In addition, it correlated with 54%, 55%, and 64% reduction in the incidence of preeclampsia with delivery at <34 weeks (aOR, 0.46 [95% CI, 0.23-0.93]), spontaneous preterm birth <34 weeks (aOR, 0.45 [95% CI, 0.22-0.92]), and perinatal death (aOR, 0.34 [95% CI, 0.12-0.91]), respectively. There was no significant between-group difference in the incidence of aspirin-related severe adverse events. CONCLUSIONS: The implementation of the screen-and-prevent strategy for preterm preeclampsia is not associated with a significant reduction in the incidence of preterm preeclampsia. However, low-dose aspirin effectively reduces the incidence of preterm preeclampsia by 41% among high-risk women. The screen-and-prevent strategy for preterm preeclampsia is highly accepted by a diverse group of women from various ethnic backgrounds beyond the original population where the strategy was developed. These findings underpin the importance of the widespread implementation of the screen-and-prevent strategy for preterm preeclampsia on a global scale. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03941886.

Ancient Mitogenomes Reveal the Maternal Genetic History of East Asian Dogs.

Recent studies have suggested that dogs were domesticated during the Last Glacial Maximum (LGM) in Siberia, which contrasts with previous proposed domestication centers (e.g. Europe, the Middle East, and East Asia). Ancient DNA provides a powerful resource for the study of mammalian evolution and has been widely used to understand the genetic history of domestic animals. To understand the maternal genetic history of East Asian dogs, we have made a complete mitogenome dataset of 120 East Asian canids from 38 archaeological sites, including 102 newly sequenced from 12.9 to 1 ka BP (1,000 years before present). The majority (112/119, 94.12%) belonged to haplogroup A, and half of these (55/112, 49.11%) belonged to sub-haplogroup A1b. Most existing mitochondrial haplogroups were present in ancient East Asian dogs. However, mitochondrial lineages in ancient northern dogs (northeastern Eurasia and northern East Asia) were deeper and older than those in southern East Asian dogs. Results suggests that East Asian dogs originated from northeastern Eurasian populations after the LGM, dispersing in two possible directions after domestication. Western Eurasian (Europe and the Middle East) dog maternal ancestries genetically influenced East Asian dogs from approximately 4 ka BP, dramatically increasing after 3 ka BP, and afterwards largely replaced most primary maternal lineages in northern East Asia. Additionally, at least three major mitogenome sub-haplogroups of haplogroup A (A1a, A1b, and A3) reveal at least two major dispersal waves onto the Qinghai-Tibet Plateau in ancient times, indicating eastern (A1b and A3) and western (A1a) Eurasian origins.

Frequency of pharmacogenomic variants affecting safety and efficacy of immunomodulators and biologics in a South Asian population from Sri Lanka.

BACKGROUND: Immunomodulators are important for management of autoimmune diseases and hematological malignancies. Significant inter-individual variation in drug response/reactions exists due to genetic polymorphisms. We describe frequency of identified genetic polymorphisms among Sri Lankans. METHODS: Sri Lankan data were obtained from an anonymized database of 670 participants. Data on variants and global distribution of Minor Allele frequency (MAF) of other populations (South Asian, Ashkenazi-Jewish, East-Asian, European-Finnish, European-non-Finnish, Latino-American, African/African-American) were obtained from pharmGKB online database. RESULTS: SLC19A1 (rs1051266) variant had a MAF (95% CI) of 63.3% (60.7-65.9). Other common variants included FCGR3A (rs396991), MTHFR (rs1801133), ITPA (rs1127354), CYP2C9*3 (rs1057910) and NUD15*3 (rs116855232), with MAFs of 35.3% (32.7-37.9), 12.2% (10.4-13.9), 10.9% (9.2-12.6), 9.8% (8.2-11.4), 8.3% (6.8-9.8) respectively. Less commonly present variants included CYP2C9*2 (rs1799853) (2.5%[1.7-3.4]), TPMT*3C (rs1142345) (1.9%[1.1-2.6]), TPMT*3B (rs1800460) (0.2%[0-0.5]), CYP3A5*6 (rs10264272) (0.2%[0-0.4]) and CYP3A4*18 (rs28371759) (0.1%[0-0.2]). The SLC19A1 (rs1051266), NUD15*3 (rs116855232), CYP2C9*3 (rs1057910), FCGR3A (rs396991), and ITPA (rs1127354) showed significantly higher frequencies in Sri Lankans compared to many other populations, exceptions include FCGR3A in Ashkenazi-Jewish and ITPA in East-Asians. Conversely, MTHFR (rs1801133), TPMT*3B (rs1800460), and CYP2C9*2 (rs1799853) were significantly less prevalent among Sri Lankans than in  many other populations. Sri Lankans exhibited lower prevalence of TPMT*3C (rs1142345) compared to European-non-Finnish, Latino-Americans, and African/African-Americans; CYP3A4*18 (rs28371759) compared to East-Asians; and CYP3A5*6 (rs10264272) compared to African/African-Americans and Latino-Americans. CONCLUSION: Sri Lankans exhibit higher frequencies in variants reducing methotrexate efficacy (SLC19A1), increasing azathioprine myelotoxicity (NUDT15), and lower frequencies in variants linked to increased azathioprine toxicity (TPMT*3B, TPMT*3C), reduced tacrolimus efficacy (CYP3A4*18), and methotrexate toxicity risk (MTHFR). Beneficial variants enhancing rituximab efficacy (FCGR3A) are more prevalent, while those reducing tacrolimus dosage (CYP3A5*6) are less common. This highlights need for targeted medication strategies to improve treatment outcomes.

11th Asia Oceania Human Proteome Organization Congress Report.

As the first in-person Asia Oceania Human Proteomics Organization (AOHUPO) congress since 2018, the 11th AOHUPO congress was an opportune time for the research community to reconnect and to renew friendships after the long period of restricted travel due to the global pandemic. Moreover, this congress was a great opportunity for the many AO regional proteomics and mass spectrometry scientists to meet in Singapore to exchange ideas and to present their latest findings. Cohosted by the Singapore Society for Mass Spectrometry and the Malaysian Proteomics Society and held in conjunction with the seventh Asia Oceania Agricultural Proteomics Organization Congress and Singapore Society for Mass Spectrometry 2023, the meeting featured both human and agricultural proteomics. Over five hundred scientists from the AO region converged on the MAX Atria @ Singapore EXPO, Changi, Singapore from May 8 to 10 for the main congress. The diverse program was made up of 64 invited speakers and panellists for seven plenary lectures, 27 concurrent symposia, precongress and postcongress workshops, and 174 poster presentations. The AOHUPO society were able to celebrate not only their 20th anniversary but also the outstanding academic research from biological and agricultural proteomics and related 'omics fields being conducted across the Asia-Oceania region.

Rats and the city: Implications of urbanization on zoonotic disease risk in Southeast Asia.

Urbanization is rapidly transforming much of Southeast Asia, altering the structure and function of the landscape, as well as the frequency and intensity of the interactions between people, animals, and the environment. In this study, we explored the impact of urbanization on zoonotic disease risk by simultaneously characterizing changes in the ecology of animal reservoirs (rodents), ectoparasite vectors (ticks), and pathogens across a gradient of urbanization in Kuching, a city in Malaysian Borneo. We sampled 863 rodents across rural, developing, and urban locations and found that rodent species diversity decreased with increasing urbanization-from 10 species in the rural location to 4 in the rural location. Notably, two species appeared to thrive in urban areas, as follows: the invasive urban exploiter Rattus rattus (n = 375) and the native urban adapter Sundamys muelleri (n = 331). R. rattus was strongly associated with built infrastructure across the gradient and carried a high diversity of pathogens, including multihost zoonoses capable of environmental transmission (e.g., Leptospira spp.). In contrast, S. muelleri was restricted to green patches where it was found at high densities and was strongly associated with the presence of ticks, including the medically important genera Amblyomma, Haemaphysalis, and Ixodes. Our analyses reveal that zoonotic disease risk is elevated and heterogeneously distributed in urban environments and highlight the potential for targeted risk reduction through pest management and public health messaging.

Low dinosaur biodiversity in central China 2 million years prior to the end-Cretaceous mass extinction.

Whether or not nonavian dinosaur biodiversity declined prior to the end-Cretaceous mass extinction remains controversial as the result of sampling biases in the fossil record, differences in the analytical approaches used, and the rarity of high-precision geochronological dating of dinosaur fossils. Using magnetostratigraphy, cyclostratigraphy, and biostratigraphy, we establish a high-resolution geochronological framework for the fossil-rich Late Cretaceous sedimentary sequence in the Shanyang Basin of central China. We have found only three dinosaurian eggshell taxa (Macroolithus yaotunensis, Elongatoolithus elongatus, and Stromatoolithus pinglingensis) representing two clades (Oviraptoridae and Hadrosauridae) in sediments deposited between ∼68.2 and ∼66.4 million y ago, indicating sustained low dinosaur biodiversity, and that assessment is consistent with the known skeletal remains in the Shanyang and surrounding basins of central China. Along with the dinosaur eggshell records from eastern and southern China, we find a decline in dinosaur biodiversity from the Campanian to the Maastrichtian. Our results support a long-term decline in global dinosaur biodiversity prior to 66 million y ago, which likely set the stage for the end-Cretaceous nonavian dinosaur mass extinction.

Increased variability of the western Pacific subtropical high under greenhouse warming.

SignificanceThe western Pacific subtropical high (WPSH) channels moisture from the tropics that underpins the East Asian summer climate. Interannual variability of the WPSH dominates climate extremes in the densely populated countries of East Asia. In 2020, an anomalously strong WPSH led to catastrophic floods with hundreds of deaths, 28,000 homes destroyed, and tens of billions in economic damage in China alone. How the frequency of such strong WPSH events will change is of great societal concern. Our finding of an increase in future WPSH variability, translating into an increased frequency of climate extreme as seen in the 2020 episode, highlights the increased risks for the billions of people in the densely populated East Asia with profound socioeconomic consequences.

Discovering disease-causing pathogens in resource-scarce Southeast Asia using a global metagenomic pathogen monitoring system.

SignificanceMetagenomic pathogen sequencing offers an unbiased approach to characterizing febrile illness. In resource-scarce settings with high biodiversity, it is critical to identify disease-causing pathogens in order to understand burden and to prioritize efforts for control. Here, metagenomic next-generation sequencing (mNGS) characterization of the pathogen landscape in Cambodia revealed diverse vector-borne and zoonotic pathogens irrespective of age and gender as risk factors. Identification of key pathogens led to changes in national program surveillance. This study is a "real world" example of the use of mNGS surveillance of febrile individuals, executed in-country, to identify outbreaks of vector-borne, zoonotic, and other emerging pathogens in a resource-scarce setting.

Uncovering the true burden of hereditary angioedema due to C1-inhibitor deficiency: A focus on the Asia-Pacific region.

Hereditary angioedema (HAE) due to C1-inhibitor deficiency or dysfunction is a rare genetic disorder that causes recurrent episodes of swelling in various parts of the body. Treatment goals of HAE aim to "normalize" life for all patients; however, lack of diagnostic facilities and limited access to effective treatment options in developing nations cause delays in diagnosis and place a significant burden on patients. In this review, we aim to highlight the burden of disease caused by C1-inhibitor HAE across the Asia-Pacific region, considering its epidemiology, morbidity and mortality, and socioeconomic and psychological impact. We also review the availability of guideline-recommended diagnostic facilities and treatments, and how patients are currently managed. Data were collected from published literature and HAE experts in the region, who provided information regarding diagnosis and management in their countries. Current practice was reviewed against international guidelines, as well as local guidelines/consensus used in Australia, Japan, and China. Suggestions are provided for improving the time to diagnosis in the region, increasing access to guideline-recommended treatments, and providing support to reduce the burden on patients and caregivers. There is an urgent need to improve HAE services and provide access to life-saving treatment in developing countries, and efforts should be made to increase awareness of guideline recommendations in high-income economies that do not currently provide long-term prophylactic treatments.