Altruism as an Explanation for Human Consanguinity.

BACKGROUND: Human inbreeding is a sociobiological puzzle. Despite widespread knowledge of its potential for genetic disorders, human consanguinity remains surprisingly common. The current reasons explaining its continued persistence in today's modern world have major shortcomings. SUMMARY: We propose that the Neolithic Agrarian revolution modified the structure of populations. It increased competition for the limited resources in which a larger group had better chances of survival. As a result, small, drifting, socially open bands of hunter-gatherers were transformed into bigger, less mobile, and more powerful kinship groups (tribes). In this transformation, a central role was played by human trust - an aspect of human altruism which is a universal sociobiological principle of behavior. Altruism (and trust) is an essential premise of social contracts such as economic cooperation, marriage arrangement, and creation of alliances between people. In kinship groups, human trust is limited to kin, so tribes remain small, economically poor, and consanguineous due to lack of nonkin mates. The expanding of trust from kin to that of nonbiological relatives increases the size of human groups, fosters economic wealth, and decreases the rate of consanguinity. Key Messages: The lack of nonkin altruism leads to: (a) poverty (due to poor economic cooperation with nonkin), (b) maintaining small group size, and (c) inbreeding.

Consensus Statement by an Expert Panel on the Diagnosis and Management of Iron Deficiency Anemia in the Gulf Cooperation Council Countries.

BACKGROUND: Iron deficiency (ID) and ID anemia (IDA) are common in the member states of the Gulf Cooperation Council (GCC). The unique genetic and lifestyle factors of the patient population in the region have necessitated the development of recommendations to help educate health-care professionals on appropriate diagnosis and management of ID/IDA. METHODS: A panel of regional experts, including gastroenterologists and hematologists with expertise in the treatment of IDA, was convened to develop regional practice recommendations for ID/IDA. After reviewing the regional and international literature, the expert panel developed consensus recommendations for screening, diagnosis, and treatment of patients with IDA in the GCC region. RESULTS: The recommendations proposed were customized to the patient population keeping in view the increasingly recognized burden of coeliac disease, high fertility and obesity rates, high prevalence of alpha- and beta-thalassemia traits, and poor tolerance and low treatment compliance with oral iron therapy. CONCLUSIONS: This consensus statement proposes recommendations for screening, diagnosis, and treatment of IDA in the GCC region.

Breast cancer protection by genomic imprinting in close kin families.

Human inbreeding generally reduces breast cancer risk (BCR). When the parents are biologically related, their infants have a lower birth weight due to smaller body organs. The undersized breasts, because of fewer mammary stem cells, have a lower likelihood of malignant conversion. Fetal growth is regulated by genomically imprinted genes which are in conflict; they promote growth when derived from the father and suppress growth when derived from the mother. The kinship theory explicates that the intensity of conflict between these genes affects growth and therefore the size of the newborn. In descendants of closely related parents, this gene clash is less resulting in a smaller infant. In this review, we elucidate the different mechanisms by which human inbreeding affects BCR, and why this risk is dissimilar in different inbred populations.

Prevalence of neutropenia in children by nationality.

BACKGROUND: A high prevalence of neutropenia has been reported in several ethnic groups amongst whom many healthy individuals with low neutrophil counts undergo unnecessary investigations. This study aims to ascertain the prevalence of neutropenia (NP) in a large cohort of children from North African, Middle Eastern, and Asian countries residing in the United Arab Emirates. METHODS: Neutrophil counts of 26,542 children (one day to six years of age) from 86 countries were analyzed. The subjects were enrolled in the Well-Child-Care program of Ambulatory Health Services of Emirate of Abu Dhabi, United Arab Emirates. NP was defined as a neutrophil count <1.5 × 10(9)/L and severe NP <0.5 × 10(9)/L. RESULTS: The neutrophil counts reached a nadir in the fourth week of life and changed slightly from the age of six-months to six-years. The frequency of NP was (from West-to-East): North African Arabs 15.4 %, Green Crescent Arabs 9.8 %, Peninsular Arabs 10.9 %, Iranians 3.1 %, Afghanis 2.5 %, Pakistanis 5.6 %, Indians 10.2 %, and Filipinos 7.3 %. The frequency of severe NP in North African Arabs (Sudanese) was 2.8 %, Green Crescent and Peninsular Arabs ≤1 %, Indians 1.5 %, and Filipinos 1.8 %. In 12,703 Emirati children, the frequency of NP was 10.6 % similar to their adult counterparts. CONCLUSION: The prevalence of childhood NP varied considerably by geoethnicity. Measures to prevent the inappropriate investigations of healthy children with benign neutropenia are proposed.

KIN AND NON-KIN MARRIAGES AND FAMILY STRUCTURE IN A RICH TRIBAL SOCIETY.

Human consanguinity is often attributed to poverty, lack of education and social insecurity. Nevertheless, kin unions continue to be arranged in socioeconomically transformed societies. This study examined the structure of families and marriages in the rich tribal society of the United Arab Emirates, which has had a high gross domestic product for the last two generations and currently has one of the highest in the world. The respondents were 217 national medical students whose families are proportionally distributed to the population of the country emirates. The rate of parental consanguinity (defined as a union of any two cousins) was 36%. The social status and mean size of consanguineous and non-consanguineous families were not significantly different. In non-consanguineous families, polygamy was more common and the number of half-siblings per family was higher. The extended families were on average 7% larger among non-consanguineous families. In contrast, for the extended families of the participants' grandparents, non-consanguineous families were smaller than their consanguineous counterparts. Participants from consanguineous families indicated that marriage of either a son or daughter was more difficult to arrange than did participants from non-consanguineous families. Though consanguineous parents had their offspring marry consanguineously more often than non-consanguineous parents, the numbers of married offspring in the two groups of families were not different. Consanguineous parents have more difficulty than non-consanguineous parents in finding spouses for themselves and for their offspring, and they arranged kin marriages for their children more often.

Red cell parameters in infant and children from the Arabian Peninsula.

α+-Thalassemia trait and iron deficiency anemia are frequent causes of microcytosis and a common diagnostic challenge in Arabian children. In this study, their prevalences and effects on the red cell parameters were evaluated in 28,457 children aged one day to 6 years. α+-Thalassemia trait was considered to be present when mean cell volume (MCV) was <94 fL at birth and iron deficiency anemia when red cell distribution width (RDW) was >14.5%. The prevalence of α+-thalassemia trait was 15.7% (502/3,191), which was similar to previously reported values for adults (9-14%). Iron deficiency anemia peaked at 7 months (53%) and then declined at a rate of 8% per year. The nadirs of red blood cell count (RBC) and hemoglobin concentration (Hb) occurred at two months of age (physiological anemia). Subsequently, Hb increased at a rate similar to that of MCV, demonstrating the two processes are coupled. The third percentile MCV in children older than 3 months was ≤64 fL, which was significantly lower than that in European children. The third percentile Hb, on the other hand, was similar to that in European children. Thus, α+-thalassemia trait and iron deficiency anemia are exceptionally frequent in Arabian children and their red cell indices are considerably different from European-based norms. Careful interpretation of red cell parameters is required for the evaluation of microcytic anemia in Arabian children.

Half of the Emirati population has abnormal red cell parameters: challenges for standards and screening guidelines.

In populations with high prevalences of iron deficiency and thalassemia trait, many apparently healthy individuals have abnormal erythroid parameters, which may cause diagnostic problems in clinical practice. We studied the prevalence and causes of red cell parameter values outside their reference ranges in 394 healthy individuals of Bedouin Arab origin, who had complete blood counts (CBCs), hemoglobin (Hb) analyses and serum ferritin tests done. Their mean age ± standard deviation (SD) was 24.8 ± 4.9 years and 51.8% were females. Overall, 53.0% (209/394) had low Hb, MCV or MCH or high RDW. Anemia was present in 27.0% (55/204) of the women and 3.0% (6/190) of the men. Overall prevalence of MCV < 80.0 fL was 45.0% (176/394) and MCH < 27.0 pg was 48.0% (190/394); RDW > 14.0% was found in 21.0% (43/204) of women and 7.0% (14/190) of men. Of the women, 16.0% had iron deficiency anemia (33/204) and 65.0% had ferritin values of < 30.0 µg/L (133/204). The estimated prevalence of α-thalassemia (α-thal) trait in men was 32.0% (60/190) and that of ß-thalassemia (ß-thal) trait in both sexes was 3.0% (12/394). In conclusion, half of the healthy Emirati population have abnormal CBC values. For clinical purposes, they require reference standards for red cells that are derived from their own population. Screening of women for iron deficiency is justified due to a high prevalence of iron deficiency.

Hemoglobin A2 Lowered by Iron Deficiency and α -Thalassemia: Should Screening Recommendation for ß -Thalassemia Change?

Screening for ß -thalassemia trait (BTT) relies on measuring hemoglobin (Hb) A2. Since multiple factors can affect HbA2 levels, the screening can become unreliable. In 1356 healthy Arabs enrolled into a federally funded premarital BTT screening program, the effects of iron deficiency (ID), α (+)-thalassemia trait, gender, smoking, and tribalism on HbA2 were studied. The complete blood count and hemoglobin fractions were determined on the entire cohort; serum ferritin (<15 µ g/L) in 391 subjects was used to determine ID. BTT was present in 29 (2.1%) subjects (HbA2 > 3.5%). Among 77(20.3%) subjects with ID, the mean HbA2 (2.30 ± 0.23%) was 0.2% lower than in subjects without iron deficiency (2.50 ± 0.24%, P < 0.0001). In 65 (38%)/172 subjects with phenotypic α (+)-thalassemia trait, the mean HbA2 (2.43 ± 0.24%) was 0.13% lower than in subjects without α (+)-thalassemia trait, P < 0.0001. The mean HbA2 did not differ between males and females, smokers and nonsmokers, and between the tribes. Thus, 35 (2.6%) subjects with HbA2 between 3.2 and 3.5% were at a risk of false negative diagnosis of BTT. Since iron deficiency and α (+)-thalassemia are both common and both lower HbA2, modifications in screening recommendations for BTT are proposed.

ß-Thalassemia in Abu Dhabi: consanguinity and tribal stratification are major factors explaining the high prevalence of the disease.

Tribalism and consanguineous marriages are common in parts of the world with a high prevalence of the ß-thalassemia (ß-thal) mutations, and increase the risks of homozygosity for this and other recessive disorders. We explored the frequency of ß-thal genes and ß-thal carriers in 5672 subjects screened before marriage, of whom 2262 were couples. The mean coefficient of inbreeding (F) in the population was estimated from self-reported relationships to prospective spouses in 383 subjects. Overall frequency of ß-thal mutations and ß-thal carriers in the population were 1.16 and 2.3%, respectively. Among the 14 largest tribes, ß-thal carrier frequencies varied from 0 to 13.6%. The estimated F in the population was 0.022. The expected number of couples needed to be screened to detect one couple who were both ß-thal carriers in the non inbreeding (F = 0) and inbreeding (F = 0.022) population was 1858 and 646, respectively. However, among 2262 couples, 10 were both ß-thal carriers, i.e., 1 in 226 couples, significantly (p = 0.02) more than expected by taking only inbreeding into account. Although ß-thal mutations are relatively rare, the burden of ß-thal disease is increased eight-fold by tribalism and consanguinity.

Erythrocyte reference values in Emirati people with and without α+ thalassemia.

BACKGROUND: Interpreting the erythroid lineage in populations with high frequency of α+ thalassemia allele is challenging due to the high prevalence of α+ thalassemia homozygotes. For such populations, separate reference values for normal and α+ thalassemia homozygotes are needed. METHODS: We studied the erythroid lineage in 1,079 citizens of United Arab Emirates (UAE). Subjects with abnormal hemoglobin (39), iron deficiency (136) or erroneous entries (8) were excluded. MCV distribution in the remaining individuals (896) was visibly bimodal. Statistical mixture analysis with Normix program was used to separate subpopulations with normal and small red cells. Hardy-Weinberg equation was used to estimate genotype frequencies. RESULTS: MCV of 78.0 fl separated phenotype-derived normal homozygotes (715) from phenotype-derived α+ thalassemia homozygotes (181). The erythrocyte indices were significantly different between the two groups (p < 0.0001). The overall prevalence of phenotype-derived α+ thalassemia homozygotes (-α/-α) was 0.20 and markedly varied among tribes, 0 to 0.31 (Mean = 0.15). The frequency of phenotype-derived α+ thalassemia allele was 0.44; when accounting for tribal population structure and inbreeding, the calculated frequency was 0.34. These values were very similar to those found in the same population by genotyping and other phenotyping methods. The erythrocyte reference values for phenotype-derived normal homozygotes in Emiratis closely overlapped with those for Caucasians and normal homozygotes defined by genotyping. The reference values for phenotype-derived α+ thalassemia homozygotes in Emiratis also closely overlapped with those for α+ thalassemia homozygotes defined by genotyping. CONCLUSION: In populations with frequent α+ thalassemia mutations, two sets of erythrocyte reference values could be determined without genotyping.

Acute Thrombocytopenia, Leucopenia, and Multiorgan Dysfunction: The First Case of SFTS Bunyavirus outside China?

We report a 57-year-old man with acute thrombocytopenia, leucopenia, and multiorgan dysfunction. Patient was from North Korea and was temporarily working in Dubai, United Arab Emirates, when he fell ill in March 2009. At the same time and unknown to us, many patients with similar clinical manifestations were admitted to hospitals in China. The Chinese cases-identified between March and July 2009-were recently reported to have been infected with a tick-born strain of bunyavirus, a new disease. The virus infection was documented in patients from central China and the region that shares the border with North Korea. The clinical manifestations, the time of disease onset, and geographical link of the patient with the region in which the disease is endemic suggest that the patient had SFTS bunyavirus infection.

Choice of kin in consanguineous marriages: effects of altruism and ecological factors.

BACKGROUND: Despite being associated with multiple genetic problems, consanguineous marriages continue to remain extremely prevalent worldwide. Studying the variation of kin preferences in diverse inbred societies may provide some answers to this paradox. AIM: To find the reasons for specific kin choice in different geographical areas of the world. METHOD: We used a set of sociobiological rules (kin altruism, sexuality and inbreeding avoidance) and ecological constraints (e.g. tribal warfare, food availability) that influence human behaviour. The cumulative help that the extended family can provide to a nuclear family was calculated using the coefficient of relatedness between kin in different types of consanguineous families. RESULTS: The maximum potential support for kin markedly varied between different types of consanguineous marriages. Overall, members of consanguineous families received up to two-and-half times more support than members of non-consanguineous families. In various inbred cultures, preference for a specific type of kin was determined by prevailing ecological limitations and sociobiological factors interacting in a complex manner. CONCLUSION: In different inbred populations, the ideal kin for a consanguineous marriage is the one who can provide the most altruistic support; however, this choice is influenced by biological rules of behaviour and ecological constraints.

Prevalence, phenotype and inheritance of benign neutropenia in Arabs.

BACKGROUND: Benign neutropenia, i.e., neutropenia not associated with an increased risk of infection, may result in serious medical consequences when a 'standard' definition of neutropenia (absolute neutrophil count (ANC) < 1.5 x 10(9)cells/L) is universally applied to all races. The aims of this study were to determine the prevalence of benign neutropenia among healthy Arabs and evaluate its mode of inheritance. METHODS: ANCs were studied prospectively amongst a healthy indigenous population (n = 1032) from the United Arab Emirates undergoing a nation-wide sickle-cell and thalassemia screening program. The mean neutrophil count and the prevalence of benign neutropenia were compared by age, sex and amongst various tribes. RESULTS: The mean neutrophil count (x 10(9)cells/L) was 3.3 (range 0.95-7.6). Benign neutropenia was present in 110 (10.7%) subjects of whom 24 (2.3%) individuals had moderate neutropenia (ANC 0.5 - 1.0 x 10(9) cells/L). In the 22 tribe-family groups, the prevalence of benign neutropenia varied between 0% and 38%. Benign neutropenia showed no difference in the frequency amongst the sexes (p = 0.23) and it was independent of age (Spearman's rho = 0.05, p = 0.13). The age-related mean neutrophil count was the lowest in Arabs when compared with other ethnic groups (Blacks, Europeans and Mexicans). The inheritance of benign neutropenia was consistent with an autosomal dominant pattern; however, the diversity of observed phenotypes suggested the presence of more than one genetic variant for this trait. CONCLUSION: Arabs have a high prevalence of benign neutropenia that may be inherited as an autosomal dominant trait.

Validation of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires for Arabic-speaking Populations.

Information about quality of life in patients with cancer in Arab populations in 21 countries is inadequate. The objective of this study was to assess the psychometric properties of the Arabic version of the European Organization for Research and Treatment of Cancer (EORTC) general quality of life questionnaire (QLQ-C30) and of the breast cancer-specific questionnaire (QLQ-BR23) in Arab breast cancer patients. The questionnaires were administered to 87 breast cancer patients 3 months after surgery. The mean age of patients was 48.6 years (SD: 9.9), 76% were married, all had staged disease (I, 9%; II, 46%; III, 44%; IV, 1%). The percentage of patients who underwent mastectomy and lumpectomy were 49% and 51%, respectively. Questionnaire reliability was assessed using Cronbach's alpha coefficient, in which the values were all >0.7, with the exception of cognitive function and pain in the QLQ-C30 (Cronbach's alpha 0.67 and 0.51, respectively) and breast symptoms in the QLQ-BR23 (Cronbach's alpha 0.50). The questionnaires' validity was confirmed using "known group comparisons," which showed that the QLQ-C30 discriminated between mastectomy and lumpectomy patients on the emotional and cognitive function scales (P < 0.001) and QLQ-BR23 discriminated as well on the function scales and for systemic side effects (P < 0.001). For the most part, QLQ-C30 and QLQ-BR23 distinguished clearly between subgroups of patients differing in their Hospital Anxiety and Depression Scale. In summary, the Arabic versions of the EORTC QLQ-C30 and QLQ-BR23 are reliable and valid tools for assessment of quality of life in Arab patients with cancer.

Consanguineous marriages and endemic malaria: can inbreeding increase population fitness?

BACKGROUND: The practice of consanguineous marriages is widespread in countries with endemic malaria. In these regions, consanguinity increases the prevalence of alpha+-thalassemia, which is protective against malaria. However, it also causes an excessive mortality amongst the offspring due to an increase in homozygosis of recessive lethal alleles. The aim of this study was to explore the overall effects of inbreeding on the fitness of a population infested with malaria. METHODS: In a stochastic computer model of population growth, the sizes of inbred and outbred populations were compared. The model has been previously validated producing results for inbred populations that have agreed with analytical predictions. Survival likelihoods for different alpha+-thalassemia genotypes were obtained from the odds of severe forms of disease from a field study. Survivals were further estimated for different values of mortality from malaria. RESULTS: Inbreeding increases the frequency of alpha+-thalassemia allele and the loss of life due to homozygosis of recessive lethal alleles; both are proportional to the coefficient of inbreeding and the frequency of alleles in population. Inbreeding-mediated decrease in mortality from malaria (produced via enhanced alpha+-thalassemia frequency) mitigates inbreeding-related increases in fatality (produced via increased homozygosity of recessive lethals). When the death rate due to malaria is high, the net effect of inbreeding is a reduction in the overall mortality of the population. CONCLUSION: Consanguineous marriages may increase the overall fitness of populations with endemic malaria.

Consanguinity affects selection of alpha-thalassemia genotypes and the size of populations under selection pressure from malaria.

BACKGROUND: In populations with alpha(+)-thalassemia gene deletion, the practice of consanguineous marriages is common. AIM: The study explored the impact of consanguinity (inbreeding) on the selection of alpha(+)-thalassemia genotypes in a computer model. METHOD: In a population under selection pressure from malaria, a single protective mutation (-alpha/alphaalpha genotype) was introduced among normal genotypes (alphaalpha/alphaalpha), and mating allowed to proceed. Heterozygote (-alpha/alphaalpha) and homozygote (-alpha/-alpha) children were 1.5 and 2.5 times more likely to survive malaria than those with normal genotypes. Using different coefficients of inbreeding (F, range 0-0.12), we examined the effect of population size, and the mean number of generations required for the homozygote frequency to reach 0.5. RESULTS: On average, consanguineous populations were larger than randomly mating populations and the size was directly proportional to F. In more inbred populations,-alpha/-alpha homozygotes reached a frequency of 0.5 faster than in less inbred populations. As the frequency of the alpha(+)-thalassemia allele in a population increases, however, the positive effect of inbreeding on the population growth decreases. CONCLUSION: Under selection pressure from malaria, consanguinity may increase the speed of selection of-alpha/-alpha homozygotes and provide an advantage regarding population growth over non-consanguineous populations.

Genetic benefits of consanguinity through selection of genotypes protective against malaria.

Consanguineous marriages are usually socially driven and can be genetically harmful. The detrimental effects of inbreeding are the consequence of homozygosity of harmful genes. On the other hand, beneficial effects of inbreeding, theoretically, could be expected in those who are homozygous for protective recessive and codominant genes. Here, we argue that the most common monogenetic conditions in humans, namely, alpha-thalassemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, hemoglobin C, and Duffy antigen negative red blood cells, which have evolved under pressure from malaria, had their survival and selection enhanced by consanguineous marriages in malaria-infested regions of the world. This hypothesis is supported by several observations. First, the presence of two mutations in homozygotes involving the listed conditions (except G6PD deficiency) imparts better protection against malaria than the presence of one or no mutation (heterozygous or normal genotypes, respectively); consanguinity increases the number of homozygotes, especially at low allele frequency. For G6PD deficiency, inbreeding could increase the allele frequency of the G6PD-deficient allele. Second, there is overlap between, on the one hand, the geographic distributions of malaria, thalassemias, and other red blood cell conditions that protect against malaria and, on the other hand, consanguineous marriages. Third, the distribution of different intensities of malaria infestation is matched with the frequency of human inbreeding. These observations, taken together, offer strong support to the hypothesis that the culture of consanguineous marriages and the genetics of protection against malaria have co-evolved by fostering survival against malaria through better retention of protective genes in the extended family.