Exploring the role of consanguinity in thalassemia prevalence in Pakistan: an in-depth analysis of genetic and cultural factors affecting public health

Abstract

Thalassemia syndromes, inherited disorders marked by reduced hemoglobin production, pose a significant global health challenge, particularly in regions with high rates of consanguineous marriages. α- and β-Thalassemia vary in severity, ranging from asymptomatic carriers to severe anemia requiring lifelong transfusions. Consanguinity, common in areas like Southeast Asia, the Mediterranean, and Africa, significantly contributes to the high prevalence of β-thalassemia in countries such as Pakistan and India, where rates can reach up to 73%. This cultural practice, deeply rooted in family ties and tradition, complicates public health efforts focused on prevention and management. Current treatment strategies rely heavily on supportive care, including regular blood transfusions and iron chelation therapy, with curative options limited by donor availability and economic constraints. Preventive efforts highlight the importance of mandatory premarital and prenatal screening, genetic counseling, and public education to reduce hereditary transmission of thalassemia. Despite progress in genomic medicine, there remain challenges in delivering comprehensive genetic services in affected regions. Addressing the complex relationship between genetic predisposition, cultural customs, and healthcare access is crucial to mitigating the prevalence and impact of thalassemia globally.

HIGHLIGHTS

• Thalassemia prevalence is high in regions with consanguineous marriages.

• Pakistan has a high β-thalassemia burden, with 5–7% population carriers.

• Key treatments include blood transfusions, iron chelation, and hematopoietic stem cell transplantation.

• Consanguinity increases genetic disorder risks, impacting healthcare efforts.

• Cultural norms sustain high consanguinity rates, challenging disease prevention.

Introduction

Advances in medical research have significantly enhanced the understanding of the genetic causes of thalassemia, enabling more individualized screening and counseling. Genetic testing plays a crucial role in early diagnosis by identifying carrier status and specific mutations, which is particularly vital for couples with a 25% risk of having an affected child if they share the same mutation^[1]. Techniques like in vitro fertilization with preimplantation genetic diagnosis help reduce this risk. Prenatal screening, including amniocentesis or chorionic villus sampling, further aids in detecting fetal inheritance of the condition, empowering couples to make informed reproductive decisions^[2]. Thalassemia syndromes are inherited disorders characterized by a decrease or absence in hemoglobin (Hb) chain production due to genetic factors, leading to persistent anemia that can vary in severity^[3]. If one parent has β-thalassemia minor and the other has a β-globin gene defect, such as a sickle cell defect, counseling is essential to address the risk of disease transfer to their children^[4]. Cultural practices like cousin marriages in regions such as Pakistan contribute to the high prevalence of thalassemia, as consanguinity increases the likelihood of inheriting the condition. Research aims to examine the role of consanguinity in the prevalence of thalassemia in Pakistan, identify at-risk families, and provide insights for more effective genetic counseling. This knowledge enables healthcare practitioners to develop targeted genetic screening and counseling strategies, particularly for families related by blood, empowering patients with informed decisions on family planning and long-term health management. Healthcare professionals must understand the genetic patterns of thalassemia to identify high-risk families, provide proper interventions, and manage severe cases through treatments like blood transfusions, iron chelation therapy, or bone marrow transplants^[5]. As a result, genetic advancements have improved patient care, family planning, and overall health outcomes while equipping families with the knowledge to make informed choices about their long-term well-being^[6].

Methodology

A comprehensive and systematic review was conducted using PubMed and Google Scholar to explore the influence of consanguinity on thalassemia prevalence in Pakistan. Keywords such as “Thalassemia,” “Consanguinity,” “Genetic Disorders,” and “Pakistan” were meticulously selected to capture the breadth of available research published between 2000 and 2025.

Studies providing detailed insights into genetic inheritance, epidemiology, and preventive strategies were prioritized. Non-English articles and those lacking specific data on the consanguinity–thalassemia link were excluded. Also the articles that were commentary pieces, were editorials, or lacked empirical data were not added. To ensure the robustness of the analysis, references from included studies were rigorously examined, creating a comprehensive and reliable dataset for this investigation. For this, data were taken from peer-reviewed journal articles, original research, and systematic reviews focusing on the relationship between consanguinity and thalassemia prevalence in Pakistan.

Selected articles were reviewed in-depth to extract key data, including study population, sample size, geographical location, genetic findings, reported prevalence rates, and noted preventive interventions. Emphasis was placed on studies using primary data from Pakistani regions with high rates of consanguinity.

Furthermore, backward citation tracking was employed to identify additional relevant studies cited within the selected literature. The synthesis of data focused on thematic analysis of genetic patterns, cultural factors influencing consanguinity, and public health initiatives addressing thalassemia.

As this study is based on secondary data from published research, no ethical approval was required. However, all sources were evaluated for scientific rigor, ethical compliance in original data collection, and publication in reputable journals.

Thalassemia and its types

Thalassemia is a monogenic autosomal recessive disorder, meaning it manifests only when an individual inherits defective alleles of globin genes from both parents. Carriers are typically asymptomatic but can transmit the disorder to offspring, with a 25% risk of having an affected child if both parents are carriers^[5].

Main types

The main types, α- and β-thalassemia, arise from mutations in globin genes, causing either a shortage or altered production of the α- and β-globin chains of adult Hb, respectively^[7].

α-Thalassemia results from deletions or mutations in the HBA1 and HBA2 genes on chromosome 16, where disease severity depends on the number of gene deletions – ranging from silent carrier states to lethal hydrops fetalis^[8]. In contrast, β-thalassemia is caused by over 200 mutations in the HBB gene on chromosome 11, which reduce or eliminate β-globin chain production through mechanisms such as nucleotide substitutions, frameshifts, and promoter defects^[5,8].

Primary forms

Thalassemia manifests in various forms, each with numerous subtypes. α- and β-Thalassemia encompass two primary forms:

• Thalassemia major: this condition requires inheritance of the gene defect from both parents.

• Thalassemia minor: this occurs when the faulty gene is inherited from one parent, leading individuals to be carriers of the disease. Symptoms are typically absent in most cases^[9]. Figure 1 summarizes the types of thalassemia and the genetic errors involved in each type.

Figure 1.

Types of thalassemia.

These genetic defects disrupt the balance of α- and β-globin chains, causing ineffective red blood cell formation, hemolysis, and chronic anemia. In β-thalassemia, excess α-globin chains damage erythroid precursors, while in α-thalassemia, unstable Hb variants like HbH or Hb Bart’s form due to excess β or γ chains. Additionally, mutations in modifier genes such as KLF1 influence disease severity by increasing fetal Hb, offering a compensatory effect in β-thalassemia. Variations in transcriptional elements, such as the TATA-binding region, further impact gene expression and contribute to phenotypic variability among patients^[5].

Prevalence

This condition is notably common in tropical and subtropical regions worldwide, such as Southeast Asia, the Mediterranean, the Indian subcontinent, and Africa. Estimated prevalence rates range from 12% to 50% for α-thalassemia and from 1% to 20% for β-thalassemia in these areas^[10]. Globally, there are approximately 300 million individuals who carry β-thalassemia, constituting about more than 5% of the world’s population. Additionally, it has been reported that approximately 50 000 infants are born each year with β-thalassemia, including both minor and major forms of the disorder^[11].

Consanguineous marriages

Consanguineous marriage (CM) refers to the union between closely related family members, such as first or second cousins, or individuals who share a common ancestor or closer blood relationship through maternal lineage. These marriages can be categorized into Type 1 (first cousins), Type 2 (second cousins), and Type 3 (more distant or complex familial relationships). It has been widely acknowledged that CMs play a significant role in transmitting congenital defects and autosomal recessive diseases across generations, increasing the risk of adverse outcomes for offspring, including postnatal mortality^[12].

Regional differences

Pakistan and India are countries where CM rates are notably high, with reported incidences reaching 73% in Pakistan and ranging from 5% to 60% in India. There is a significant contrast in the prevalence of CMs between Europe (1%) and regions like West Asia, South India, and North Africa (20–50%)^[13]. The acceptance and prevalence of CMs are shaped by cultural norms, religious beliefs, and economic factors across different societies. There is ongoing discourse regarding how to reconcile these cultural norms with the potential health and socioeconomic impacts of such marriages^[14].

Genetic impact

CMs elevate the likelihood that both parents carry identical recessive genes, which is markedly higher compared to nonconsanguineous unions. Consequently, populations where consanguinity is prevalent experience a higher frequency of autosomal recessive disorders^[15]. The influence of cultural consanguinity is evident in the prevalence of β-thalassemia, with rates as high as 96% among children born from first-cousin, distant blood relative, and intra-caste marriages, compared to just 4% in marriages across different castes^[16].

Burden of thalassemia

The burden of thalassemia on patients arises from both the complications of the disease itself and the challenges associated with its treatment. Direct treatment costs include iron chelation therapy, blood transfusions, doctor visits, medications, laboratory tests, and hospitalization costs^[17]. For many thalassemia cases, accessing suitable HLA-matched donors is often impractical due to obstacles such as limited availability, high costs, and the significant risks of mortality and morbidity associated with hematopoietic stem cell transplantation (HSCT). This places a substantial financial strain on parents who typically shoulder the lifelong expenses of their child’s care. Thalassemia imposes significant psychosocial, physical, and financial hardships on both patients and their families^[18]. Figure 2 depicts some common complications associated with thalassemia that are life-threatening to the individual.

Figure 2.

Overview of systemic complications in thalassemia, including endocrine, hematologic, and organ-specific manifestations (e.g., splenomegaly, hepatomegaly, hypothyroidism, diabetes, infertility, and persistent anemia).

Influence of CMs

Among the contributing factors, the widespread practice of CM stands out as a primary reason for the high prevalence of β-thalassemia in Pakistan. The findings reveal that β-thalassemia rates are notably elevated (76.7%) in marriages between first cousins compared to those between second cousins (23.3%)^[19]. The preference for CMs in society is strongly influenced by various cultural and socio-structural factors. These include the desire to reinforce family bonds, uphold agnatic solidarity, manage dowry-related financial matters, seek familial support during marital challenges, and adhere to cultural norms that limit individual autonomy in choosing a spouse^[20]. Additional factors contributing to CMs include the belief that such unions preserve family cohesion and stability. Couples from these marriages may find it easier to adjust due to shared upbringing and familiarity with the family structure. Moreover, some individuals opt for CMs out of concern about marrying into unfamiliar families, which they fear could bring hidden health or financial complications^[21]. Marriages between closely related individuals are typically driven by cultural norms, traditions, or perceived socioeconomic and psychological advantages^[22].

Religious and cultural norms

In many Islamic regions, religious and cultural norms emphasize that the groom and bride should not be genetically related. Despite this, attitudes in these regions often show high acceptance and even preference for cousin marriages. More than 95% of the population in these countries are Muslims, living within a semi-conservative religious and social framework that generally supports cousin marriages^[23]. Currently, consanguinity is widely practiced and esteemed in many communities, especially among Muslims^[24].

Regional statistics

Within CMs (comprising 66% of the sample), the highest prevalence is observed in the Sindh region at 71%, followed by Baluchistan at 70% and Punjab at 65% in Pakistan (Fig. 3).

Figure 3.

Regional prevalence of thalassemia in Pakistan, highlighting variations among Sindh, Baluchistan, and Punjab provinces.

These rates range from 72% to 78% within socioeconomically disadvantaged groups and are notably high in rural areas at 71%. Nearly half of women aged 15–29 years have married their first cousins. The prevalence of first-cousin marriages among rural women decreased by 2% between 1990 and 2018, while among urban women, it increased by 3.8% during the same period, as graphed in Figure 4.

Figure 4.

Trends in the prevalence of first-cousin marriages among rural and urban women (1990–2018).

The incidence of first-cousin marriages has slightly declined across all provinces: by 5% in Punjab, 4% in Khyber Pakhtunkhwa, and 3% in Baluchistan. However, in Sindh, these marriages have seen an 8% increase over the past three decades, as shown in Figure 5.

Figure 5.

Shifting patterns in the incidence of first-cousin marriages across Pakistani provinces over the last three decades.

In 1990, an increase in women’s educational attainment from middle school to secondary school correlated with an 11% decrease in the incidence of women marrying their cousins^[25].

Thalassemia in Pakistan

Pakistan ranks among the countries with the highest burden of thalassemia globally, with an estimated 100 000 patients dependent on regular transfusions^[26]. In Pakistan, β-thalassemia (β-thal) trait frequency ranges between 5.0% and 7.0%; thus, there are more than 10 million carriers in the country; and every year, around 5000 children are diagnosed to carry β-thal major (β-TM) in Pakistan^[27]. Thalassemia poses a significant health challenge in Pakistan, affecting an estimated 5–6 million children with the disease or its symptoms. Approximately 5000 thalassemia homozygotes are born annually, and 6% of the population carries genes for the disorder due to abnormal Hb production. Certain ethnic groups, such as Punjabis, Sindhis, Gujaratis, Bengalis, and Parsis, have a notably higher prevalence of thalassemia. Among Punjabis who migrated from West Pakistan, the frequency of thalassemia trait is approximately 4.7%, while in Gujaratis, it is around 5%. In certain tribal areas of Baluchistan, the carrier rate can be as high as 19%^[16]. Over 5000 children with β-TM are born annually in Pakistan, where the carrier rate varies between 5% and 7% across different regions, with an average rate of 5%^[27].

Treatment modalities

The management of thalassemia primarily involves supportive care, such as regular blood transfusions and iron chelation therapy, to prevent complications related to iron overload. Iron overload is a significant side effect of frequent transfusions, and chelation therapy is essential to remove excess iron from the body. Blood transfusion therapy should be started in case of severe anemia after confirmation of the diagnosis of thalassemia. However, individuals with Hb > 7 g/dl should also be evaluated for factors like growth retardation, increasing splenomegaly, facial changes as well as the expansion of bone, should be measured^[28].

Despite these treatments, many patients with thalassemia face significant health challenges, and the only potential cure is HSCT^[29]. HSCT involves the transplantation of stem cells from a compatible donor to replace the defective hematopoietic system of the thalassemia patient. However, finding a suitable HLA-matched donor is often difficult, and the procedure is associated with significant risks, including mortality and morbidity^[7]. For patients who cannot undergo HSCT, lifelong transfusions remain the mainstay of treatment, requiring strict adherence to chelation therapy to manage iron overload. The financial burden on families and healthcare systems can be substantial, particularly in resource-limited settings where access to comprehensive care may be limited. Furthermore, the psychosocial impact of thalassemia, including the stigma associated with the disease, can be profound for patients and their families, exacerbating the challenges they face in managing the condition^[30].

Impact of public health strategies on thalassemia prevention

Public health strategies have proven effective in reducing thalassemia incidence through systematic carrier screening, education, and premarital counseling programs^[31]. Countries like Iran, Saudi Arabia, Turkey, and Iraq have shown remarkable success after implementation of premarital screening programs, with at least more than half reduction in cases born with thalassemia.^[32] Moreover, in Cyprus, the cases have decreased by up to 90%, after the implementation of government policies to screen for thalassemia before marriage^[33]. The setup of National Thalassemia Registries in Singapore has also provided valuable demographic information and facilitates disease prevention through public awareness, carrier screening, genetic counseling, and antenatal/pre-implantation testing.^[34] These efforts have led to dramatic declines in new thalassemia births. In Pakistan, such programs are still in nascent stages and face challenges related to awareness, funding, and policy enforcement. Scaling successful models to local contexts could significantly reduce disease burden^[35].

Beyond consanguinity: additional genetic and socioeconomic influences

While consanguinity remains a dominant contributor to thalassemia prevalence in Pakistan, it is not the sole determinant. Other genetic and socio-environmental factors also warrant critical attention. Spontaneous mutations, although less common, can lead to disease in individuals from non-consanguineous backgrounds, particularly in isolated or genetically homogenous populations^[36]. Population migration, genetic drift, and founder effects can also influence prevalence patterns^[37,38]. Furthermore, socioeconomic barriers, including limited access to healthcare, lack of awareness, and cultural stigma, significantly hinder early diagnosis and management^[35].

Conclusion

Thalassemia presents a major public health challenge in countries with high rates of consanguinity, such as Pakistan, as shown in Figure 6.

Figure 6.

Regional variations in consanguineous marriage incidence rates across Pakistan, India, Europe, and North Africa.

The strong cultural preference for CMs significantly contributes to the high prevalence of thalassemia, particularly β-thalassemia, in these regions. While significant progress has been made in the management and treatment of thalassemia, the burden of disease remains high, and prevention efforts must be intensified. Public health strategies should focus on raising awareness about the genetic risks associated with CMs, promoting genetic counseling, and implementing effective screening programs to reduce the incidence of thalassemia. Addressing the complex interplay between cultural practices, genetic predisposition, and healthcare access is essential to mitigate the impact of thalassemia and improve the quality of life for affected individuals and their families.

Ethical approval

This is a review article and does not have any data concerning a patient, so ethical approval is not required.

Consent

This is a review article, not a study of patients, so consent is not required.

Sources of funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

S.O.A. conceived the study, did the literature search, and wrote the manuscript. Y.A. wrote the manuscript and did the interpretation. A.A.R. reviewed and edited the article. A.S. reviewed the article and did the referencing

Conflicts of interest disclosure

The authors declare no conflicts of interest.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Abedin Samadi.

Provenance and peer review

Not applicable.

Data availability statement

No data are available.

Assistance with the study

None.