Consanguinity, endogamy, and genetic disorders in Tunisia

Consanguinity refers to marriages between individuals who share at least one common ancestor. In clinical genetics, a consanguineous marriage is defined as a union between two individuals who are related as second cousins or closer, with the inbreeding coefficient (F) equal or higher than 0.0156 (Bittles 2001). However, reports on consanguinity rates may sometimes include marriages between third cousins or more distantly related individuals (Hamamy 2011). It is estimated that more than 690 million people in the world are consanguineous (Bittles and Black 2010). Middle East, Northern Africa, and South Asia are regions that have historically and culturally had a high rate of consanguineous unions (Al-Awadi et al. 1985; Al-Gazali et al. 1997; Jaber et al. 1997; Bittles et al. 2002; Bener and Alali 2006). Recent studies have shown that 20 % to 50 % of marriages in Arab countries are between relatives (Tadmouri et al. 2009; Bittles 2011; Hamamy et al. 2011). The rate was 68 % in Egypt (Mokhtar and Abdel-Fattah 2001), 51–58 % in Jordan (Khoury and Massad 1992; Sueyoshi and Ohtsuka 2003; Hamamy et al. 2005), 52 % in Qatar (Bener and Alali 2006; Bener and Hussain 2006), 50 % in the United Arab Emirates (Bener et al. 1996), 54 % in Kuwait (Al-Awadi et al. 1985; Hijazi and Haider 2001), 58 % in Saudi Arabia (El-Hazmi et al. 1995), 40 % to 47 % in Yemen (Jurdi and Saxena 2003; Gunaid et al. 2004), and 50 % in Oman (Rajab et al. 2000). Consanguineous unions are also frequent in many Non-Arab Middle Eastern countries such as Turkey with 21.2 % (Basaran et al. 1988) and Iran with 38.6 % (Saadat et al. 2004). The tendency in these societies of marrying relatives is a deeply rooted cultural trait (Hamamy 2011) related to ethnical, cultural, and socioeconomic factors (Khlat and Khoury 1991). Among Arab societies, it is believed that a consanguineous marriage preserves family structure and provides social, economic, and cultural benefits (Khlat et al. 1986; Bittles 2008). These consanguineous marriages generally involve first or second cousins or relatives within the large family or the same tribe (Al-Khabory and Patton 2008). Theoretically, the offspring of related parents are more often homozygous by descent than those of non-consanguineous parents. In this context, recent studies based on high density SNPs genotype data (Carothers et al. 2006; McQuillan et al. 2008; Kirin et al. 2010; Nothnagel et al. 2010) reported a gradual increase in average genome-wide homozygosity with increasing levels of consanguinity and endogamy, which is defined as marriage within one's own tribe or group as required by custom or law (Lathrop and Pison 1982). Consequently, such consanguineous matings have a relatively higher risk of producing offspring with genetic damage, caused by the expression of rare recessive genes inherited from common ancestors, than that of the general population (Khlat and Khoury 1991; Teebi 1994). A positive correlation between inbreeding and numerous health outcomes has been reported in several studies. Indeed, unions between relatives are generally associated with an increased risk of abortions, stillbirths (Al-Awadi et al. 1986; Hussain 1998, 1999; Hussain et al. 2001), perinatal mortality (Stoltenberg et al. 1999), and congenital malformations (Abdulrazzaq et al. 1997; Chehab et al. 2006; Yunis et al. 2006). Consanguineous marriages are also recognized as being associated with higher risk for autosomal recessive diseases than in the general population (Taillemite et al. 1985; Alwan and Modell 1997; Kumaramanickavel et al. 2002) by favoring the expression of recessive deleterious alleles. Many reports have highlighted a positive association between inbreeding and a number of recessive single gene disorders like achromatopsia (Tchen et al. 1977), Leber's congenital amaurosis, xeroderma pigmentosum (Mokhtar et al. 1998), and metabolic defects like aminoacidopathies and mucopolysaccharidoses (Jaouad et al. 2009). However, some authors believe that a long practice of inbreeding over several generations leads to the elimination of deleterious recessive mutations from the population gene pool (Khoury et al. 1987). On the other hand and to the best of our knowledge, no significant association has been reported in the literature between inbreeding and autosomal dominant disorders (Zlotogora 1997b; Hamamy et al. 2007). For complex diseases, the contribution of inbreeding to these conditions remains contentious and under investigated. Some authors suggest that inbreeding could exert a greater influence on the etiology of multifactorial diseases, when autosomal recessive alleles are causally implicated (Bittles and Black 2010). Indeed, the enhancing of disease susceptibility gene dose resulting from increased homozygosity may affect the risk of developing the disease (Bittles 2001). Other authors explain certain complex impairments by genetic disturbances and epistatic effects due to homozygosity at disease susceptibility loci which alter the capability to adapt to environmental risks (Acevedo-Whitehouse et al. 2003). However, other reports claim that it is unlikely that consanguinity contributes significantly to complex diseases once basic lifestyle factors have been controlled as highlighted by an editorial in Nature Genetics (No authors listed 2006). A limited number of reports have focused on the inbreeding effect on multifactorial disorders (Jaber et al. 1997; Soliman et al. 1999; Bener et al. 2001; Rudan et al. 2003, 2006; Hamamy et al. 2005; Alzolibani 2009; Mansour et al. 2009). These studies have revealed an important role of inbreeding in the etiology of many specific diseases following a multifactorial pattern of inheritance like diabetes mellitus, hypertension, mental disorders, and cancer. The outcome of these studies suggests the implication of deleterious recessive variants in the etiology of such diseases (Campbell et al. 2009; Bittles and Black 2010). In Tunisia, as in many Arab countries, there is a high preference for unions between relatives. Local customs, social and geographic isolation, along with the ethnic heterogeneity of the Tunisian population made up of a mosaic of communities [Amazigh (Berber), Roman, Arab, etc.] have all influenced mate selection and contributed to an increased level of endogamy and consanguinity (Ben Arab et al. 2004). According to the National Office for Family and Population Affairs data, consanguinity remained relatively high during 1991 to 2001 with rates of close and unknown consanguineous unions representing, respectively, 21 % and 19 % of all marriages in the country. A similar level of inbreeding has also been reported by other studies (Chalbi and Zakaria 1998; Ben Mrad and Chalbi 2006). While consanguineous matings continue to be commonly practiced in several areas of Tunisia, their health impact remains underestimated because of the limited number of epidemiological studies. A better understanding of the impact of inbreeding on the occurrence of some specific diseases may raise public awareness of the potential negative effects of intra-family marriages. One possible method to study these possible inbreeding effects is to compare the level of inbreeding among parents of individuals affected with different disorders and a healthy control sample. The purpose of this current study is to assess the rate of consanguineous unions in the Tunisian general population, to evaluate the risk associated to inbreeding on a large class of Mendelian monogenic conditions after stratifying the disorders according to their pattern of inheritance, and to investigate if consanguineous unions contribute significantly to common complex diseases such as diabetes and cancer, which are major public health problems.